I know this is my first post, so as an introduction: I am an undergraduate pre-med neuroscience major with a minor in psychology and a long time visitor of bluelight/psychonaut. I am currently in preparation of my undergraduate research/field-experience credits next semester regarding the biochemical and neurological aspects of Chemical Dependance, Learned Helplessness and Tolerance as a Conditioned Response. I am currently attempting to string together and link current findings, literary reviews and hypotheses relevant to the mechanisms surrounding these topics. I invite anyone on these boards to discuss their opinion on the direction of further research in this realm, especially those who have proven themselves to be particularly well versed in neurobiology. I am a research assistant to a group of ten graduate students supervised by two professors holding PhD in Neuroscience and an M.D. (psychiatrist) and adjuncts holding degrees in Neuroscience. We have set out to (1) survey drug users who will offer an objective-as-possible view on sensitization based on personal experience, (2) expand upon recent research that has been done regarding the presence of vesicular glutamine transporters in monoamine, ach- and GABA containing neurons and how this relates to glutamates role in sensitization with a focus on the role of calcium channel blockers and (3) recruit subjects who are diagnosed with A.D.D/A.D.H.D, would describe themselves as risk-takers or having addictive personalities and who take psychostimulants every day to participate in an 8-week study. Whether we will be able to incorporate NMDA antagonists, most likely dextrorphan, into this study remains up to the IRB (which anyone who has conducted research knows is a bitch).
This is a compilation of relevant information to one of the most interesting topics within neuropharmacology, in my opinion. The possibilities concerning what may be interpreted from this information are infinite and the discoveries that have yet to be made in the prevention of tolerance, dependance and undesired drug-seeking impulses (a bit paradoxical). As a community of individuals highly informed and experienced in the realm of neuropharmacology I believe that a conversation regarding these relatively contemporary (the most dated study listed here is from 1989) revelations within the realm of one of the most daunting aspects of psychoactive experimentation would be stimulating and productive to say the least. I have also included a very basic definitions and concepts section so that those who are less educated on the topic of neuroscience who have experienced the effects taken into consideration by these scientific experiments may express their opinions more elegantly (opinions that are valued as a precursor to the plausibility of surveying upon these topics). In this compilation I have paraphrased and quoted many studies without giving fair APA citation, but have still provided the names of the research. So in the spirit of integrity, although certain aspects of this have been written by me, I take no credit for any of this information.
Feel free to share your opinions, speculations on connections between studies, ideas for further research, experiences and corrections (remember I'm simply a research assistant trying to grasp the topics at hand as fully as possible).
Definitions and Concepts
Definitions and Concepts: Synaptic Plasticity
Synaptic Plasticity is the ability of the synapse between two neurons to change in strength in response to transmission over synaptic pathways. This change in strength can be achieved via quantitative changes in neurotransmitters and efficacy of those neurotransmitters upon the receptors they bind to.
The molecular mechanisms of synaptic plasticity can be lent to the NMDA (N-methyl-d-aspartate) and AMPA (alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate) receptors. Opening the NMDA channel depolarizes the post-synaptic cell, leading to an increase in Ca2+ concentration proportional to the strength of the depolarization. Strong depolarization has been linked to long-term enhancement in signal transmission between the two neurons (Long-term potentiation or LTP). This is thought to be a major mechanism of memory and learning. This is concurrent with the Hebbian theory that an increase in synaptic efficacy arises from the presynaptic cell’s repeated and persistent stimulation of the postsynaptic cell, summarized as “cells that fire together, wire together”. As well as inducing LTP, strong depolarization leads to activation of protein kinases that serve to phosphorylate post-synaptic excitatory receptors, improving cation conduction and signaling recruitment of additional receptors into the post-synaptic membrane. The density of the receptors on the post-synaptic membrane affects the neuron’s excitability and response to stimuli. NMDA receptors are added to the membrane via exocytosis and endocytosis, while AMPA receptors are delivered to the synapse by vesicular membrane fusion with the post-synaptic membrane via protein kinase, which (as stated before) is activated by the influx of Ca2+ ions.
Consistent weaker depolarization, however, results in lower post-synaptic calcium concentration. This has been linked to long-term depression, induced by activated protein phosphatases that dephosphorylate cation channels and reverse the activity of protein kinase activation.
Definitions and Concepts: Activity-Dependent Plasticity
The brain undergoes changes based on activity, allowing the functions performed by individuals on a daily basis to change gene expression by specializing in specific activities, based on relative use. For example, a left-handed person can become ambidextrous by repeated use of his right-hand, making both hands equally able. Systematic alterations to behavior cause changes to neuronal activity, which ultimately results in a theoretical “rewiring” of the brain.
Definitions and Concepts: Neurogenesis
Neurogenesis refers to the process by which neurons are generated via the neural stem and progenitor cells. While this process is most active during pre-natal development, recent advances in the study of mammals has revealed the continuation of neuronal generation, deemed “Adult Neurogenesis”. Mainly, this continuation carries on in the hippocampus and subventricular (SVC) zone.
Inhibition of neurogenesis can lead to an increase in the hypothalamic-pituitary-adrenal (HPA) axis stress response. It has been suggested that there is a link between decreased hippocampal neurogenesis and depression, related to the demonstration that the beneficial activity of anti-depressants is reversed when neurogenesis is prevented in mice. Others have suggested that neurogenesis promotes neuroplasticity. Neurodegenerative disorders characteristically inhibit neurogenesis and typically, as in the case of Parkinson’s disease and its effect on dopaminergic neurons in the nigrostriatal, will slowly deplete neuronal population. Sleep deprivation prevents neurogenesis and it has been proposed that this is related to a rise in glucocorticoids such as cortisol. Certain sources of questionable reliability have associated this rise in cortisol, a “stress hormone”, to be associated with being deprived of neural processes that affect various monoamines, neuropeptides and hormones during the various phases of the sleep cycle. Certain examples include N,N-DMT during REM sleep and the release of endogenous opiates during NREM.
Definitions and Concepts: Glutamate
Glutamate is the brain's principal excitatory neurotransmitter for which there are three receptors — the ion channels NMDA, AMPA and kainate — and also another receptor family which is coupled to G-proteins and the second (metabotropic) messenger system. Glutamatergic neurons from the prefrontal cortex and amygdala project onto the mesolimbic reward pathway, from which reciprocal dopaminergic projections arise. There is evidence that the glutamatergic projection from the prefrontal cortex to the nucleus accumbens plays a role in the reinstatement of stimulant-seeking behaviour.
Definitions and Concepts: GABAA and NMDA Structure, Function and Trafficking
GABAA receptors are the major inhibitory neurotransmitter receptors. They are chloride ion channels activated by the binding of the neurotransmitter,
GABA. NMDA receptors are a subclass of the excitatory L-glutamate family of neurotransmitter receptors. They are unique in that they require the simultaneous binding of two neurotransmitters, the co-agonists L-glutamate and glycine, together with the alleviation of a voltage-dependent blockade by magnesium ions that is achieved by the activation of adjacent non-NMDA glutamate receptors in synaptic spines, for channel activation. Both GABAA receptors and NMDA receptors are not only pivotal for normal brain function but they are also important drug targets. NMDA receptors have potential as a therapeutic target post-ischaemia and in neuropathic pain; NMDA receptor channels are highly permeable to calcium ions; thus over-activation leads to excitotoxic neuronal cell death, which may be treated by NMDA receptor antagonists.
GABAA (γ -aminobutyric acid type A) receptors and NMDA (N-methyl-d-aspartate) receptors are both examples of ligand-gated, heteromeric neurotransmitter receptors whose cell-surface expression is dynamic and tightly regulated. NMDA receptors are localized at excitatory synapses. These synapses are highly structured but dynamic, with the interplay between NMDA receptors and NMDA receptor associated scaffolding proteins regulating the expression of functional cell-surface synaptic and extrasynaptic receptors. Based on current information, inhibitory synapses seem to be less ordered, and a GABAA receptor equivalent of PSD-95 (postsynaptic density-95), the scaffolding molecule pivotal to the organization of
NMDA receptor complexes at synapses, is yet to be validated.
NMDA Channels:
(1) are blocked by Mg2+ in a voltage-dependent way;
(2) are permeable to Ca2+ as well as to Na+ and K+
(3) may adopt multiple conductance states; some of the minor states (small conductances) resemble the major conductance states opened by non-NMDA agonists
(4) posess a trypsin sensitive component necessary for ion channel activation
• NMDA Antagonism
o Example: Memantine
• Non-competitive NMDA receptor antagonist
• Licensed for use in treatment of Alzheimer’s
o Blocks influx of calcium ions
• NMDA Agonism
o Activation requires:
• Binding of glutamate or aspartate
• Binding of the co-agonist glycine or serine
• Glycine potentiates the response to NMDA
• Membrane depolarization by opening the ion channel and expelling the Mg2+ ion blocking the outside.
o Continued exposure to NMDA agonists produces short term and long term decreases in the sensitivity of the NMDA system
o Example NMDA Agonists:
• D-Cycloserine
• Cis-2,3,Piperidinedicarboxylic acid
• L-aspartate
• D-serine
• L-alanine
• GABAA
o The fast response of neurons to GABA that is blocked by agents such as bicuculline is due to direct activation of an anion channel concerned chiefly with passing Cl- ions across the cell membrane.
o This anion channel is called the GABAA receptor
• GABAA Antagonism
o Example: Bicuculline
• Competitive Antagonist
• Blocks Cl- transmission as well as Ca2+-activated ion channels.
• Mimics epilepsy.
o Example: Picrotoxin
• Non-Competitive Antagonist/Channel Blocker
• Blocks Cl- transmission.
• Produces stimulant/convulsant effects, used to counter barbituate overdose.
• GABAA Potentiation
o Benzodiazepines
• Benzodiazepines ) enhance the action of the GABAA receptor by binding to benzodiazepine receptor sites located at the γ subunit, resulting in allosteric activation.
• This produces a calming effect, as GABA is already an inhibitory neurotransmitter.
Definitions and Concepts: Behavioral Sensitization
The term 'behavioural sensitization' refers to the progressively augmented behavioural response that is produced by many drugs of abuse upon their repeated administration. It is not to be confused with tolerance, although behavioral sensitization to drugs that induce tolerance steadily (such as opiates) may have a correlational relationship with tolerance.
Studies and Literary Reviews
Plasticity (Opioids): Involvement of cAMP-Dependent Protein Kinase in μ-Opioid Modulation of NMDA-Mediated Synaptic Currents
There have been reported dual effects of μ-opioids on NMDA-receptor-mediated synaptic events in the hippocampal dentate gyrus: an indirect facilitating effect via suppression of GABAergic interneurons (disinhibition) and a direct inhibitory effect in the presence of γ-aminobutyric acid-A (GABAA) antagonists. The cellular mechanism underlying the inhibitory effect of μ-opioids remains to be determined. In the present study we examine the role of adenosine 3′,5′-cyclic monophosphate (cAMP)-dependent protein kinase (PKA) in μ-opioid-induced inhibition of NMDA currents. This inhibitory effect could be completely reversed by the opioid antagonists naloxone or prevented by a selective μ-antagonist cyprodime, but was not affected by removal of Mg2+ from the external perfusion medium. These findings strongly suggest that NMDA receptor function is subject to the modulation by PKA, and that μ-opioids can inhibit NMDA currents through suppression of the cAMP cascade in the postsynaptic neuron. Combined with our previous findings, the present results also indicate that μ-opioids can modulate NMDA-receptor-mediated synaptic activity in a complex manner.
Plasticity: “Calcium ion activation mediated by GABAAR and NMDA Receptors”
The NMDA subtype of glutamate receptors plays an important role in adult and developmental neuronal plasticity via increases in intracellular Ca2+. Since the voltage-dependent Mg2+ block of NMDA channels operates not only in adult but also in neonatal neurons, their activation during synaptic activity requires external sources of depolarization. In adult neurons, this is largely provided by glutamate acting on AMPA receptors that mediate most of the excitatory drive throughout the mammalian central nervous system. In contrast, GABA, the primary inhibitory transmitter, acting via ionotropic GABAA receptors (GABAA R), increases a chloride conductance that usually hyperpolarizes adult neurons, thus preventing the activation of NMDA R. Thus, the induction of NMDA R–dependent forms of long-term potentiation or depression are facilitated by GABAA-R antagonists. An opposite situation may prevail at early stages of development when the activation of GABAA receptors provides depolarization instead of hyperpolarization. In several types of neonatal neurons, activation of GABAA R triggers action potentials and activates voltage-dependent Ca2+ channels, producing rises of Ca2+. If GABA is the principal fast-acting excitatory transmitter during early postnatal life in the hippocampus as suggested from earlier studies from this laboratory, it may, in contrast to adult neurons, act in synergy with NMDA R, providing the depolarization required to release their voltage-dependent Mg2+ block. If so, GABAA R would play in neonatal neurons the role conferred to AMPA R in more mature neurons and neurons generated during adult neurogenesis may share in the same GABA-NMDA synergy.
Plasticity: Activity-dependent tuning of inhibitory neurotransmission based on GABAAR diffusion dynamics
Excitatory synaptic activity changes the diffusion of GABAA receptors in the hippocampus. Calcium-dependent mechanisms are most likely very important in the induction of Long Term Potentiation. Activities that result in the influx of calcium ions may be used to enhance synaptic plasticity and the diffusion of GABAergic neurotransmitters, transport proteins and neuropeptides.
Plasticity (Learning): “Synaptic stability and plasticity in a floating world”
Synaptic plasticity is an important determinant of learning and memory, the synapse is ever-changing with all constituents turning over around equilibrium. At steady state, in/out synapse flux of receptor is equal to zero, imbalances decrease or increase receptor number at the synapse. Synaptic plasticity at inhibitory and excitatory synapses is calcium-dependant, and a rise in intracellular calcium at excitatory synapses decreases AMPAR (non-NMDA type receptor for glutamate that mediates fast synaptic transmission) diffusion and increases dwell time. AMPAR receptors are both glutamate receptors and cation channels. In general, signals that potentiate excitatory synapses depress inhibitory synapses and vice versa. In response to activity, spines (sites where most excitatory synpases are found) can regulate the diffusion of calcium. Activity dependant neuronal disinhibition and other modifications to neuronal activity involving glutamatergic receptors are also calcium-dependent, as well as being dependent upon the phophatase calcineurin. At mixed synapses in the spinal cord (possessing a mixed glycine-GABA phenotype), increasing neuronal activity decreases diffusion rate and increases synaptic accumlication of Gly-Rs but not GABAA. The regulation of GlyR synaptic content is assumed to modify the affinity between receptors and scaffolds, and is dependent on calcium influx.
Plasticity (Learning): Do different kinds of plasticity underlie different kinds of learning?”
This study contrasts activity dependent modulation of presynaptic transmission and NMDA receptor triggered alterations in excitatory amino acid transmission. It proposes that different forms of plasticity might underlie different kinds of learning. To support this idea, freely moving rats are infused with D,L-AP5 (an NMDA-receptor antagonist) causing a dose-dependant impairment of spatial learning known to be sensitive to disruption by hippocampal lesions. The same drug is shown to cause a blockade of hippocampal LTP across a dose range. The conclusions drawn postulate that there are indeed numerous modes of plasticity playing a role in learning, however the researchers emphasize they are not insinuating that the NMDA receptor alterations made in this experiment are characteristic of all the functions it serves, but only focus on it’s mechanisms within hippocampal neurons.
Plasticity: “Homeostatic regulation of synaptic GlyR numbers driven by lateral diffusion.”
Glycinergic transmission is changed in the spinal cord with changes in excitatory transmission. It is an interesting supplement to the above study and reveals that there are distinct mechanisms for plasticity and homeostatic plasticity that are both calcium dependent and focuses on the role of glycine as a co-transmitter during diffusion of calcium ions.
Dependence (Stimulants): Amphetamine induces dendritic growth in VTA dopaminergic neurons
Reinforcing drugs such as amphetamines and opiates induce behavioral sensitization upon repeated administration by inducing dopaminergic neurogenesis in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). This occurs through activation of dopamine receptors in these areas which produces glutamate release and subsequent elevation of local basic fibroblast growth factor (bFGF) concentrations. Dopaminergic neurons of the ventral tegmental area are implicated in the physiology of reward, and long-lasting changes in their function induced by exposure to psychostimulant drugs are related to the pathophysiology of drug abuse. Repeated exposure to amphetamine induces substantial dendritic growth of ventral tegmental area dopaminergic neurons in vivo. Furthermore, we show, by immuno-neutralization of endogenous basic fibroblast growth factor, that the amphetamine-induced increase in astrocytic basic fibroblast growth factor in the ventral tegmental area is essential for these morphological changes. We propose that the amphetamine-induced elaboration of the dendritic arbor of dopaminergic neurons leads to their increased excitability and contributes to compulsive drug-seeking and relapse. Further research could inspect the role of amphetamines upon neurogenesis and the excitability of neurons produced because of this effect.
Dependence (Cocaine): Reinforcing effects of cocaine absent in mutant mice
In mice lacking the mGlu5 subtype of the metabotropic glutamatergic receptor, cocaine still increases dopamine in the nucleus accumbens; but the mice do not self-administer cocaine or show increased locomotor activity
Dependence (Ethanol): Altered NMDA Receptor Antagonist Response in Recovering Ethanol-Dependent Patients
Ethanol is an antagonist of the N-methyl-d-aspartate glutamate receptor. Ethanol dependence upregulates NMDA receptors and contributes to crosstolerance with selective NMDA receptor antagonists in animals. This study evaluated whether recovering ethanol-dependent patients show evidence of a reduced level of response to the effects of the NMDA receptor antagonist, ketamine. In this double-blind study, 34 recently detoxified alcohol-dependent patients and 26 healthy comparison subjects completed 3 test days involving a 40-min infusion of saline, ketamine 0.1 mg/kg, or ketamine 0.5 mg/kg in a randomized order. Recovering ethanol-dependent patients showed reduced perceptual alterations, dysphoric mood, and impairments in executive cognitive functions during ketamine infusion relative to the healthy comparison group. No attenuation of ketamine-induced amnestic effects, euphoria, or activation was observed. The alterations in NMDA receptor function observed in recovering ethanol-dependent patients may have important implications for ethanol tolerance, ethanol dependence, and the treatment of alcoholism.
Dependence (Ethanol): Memantine inhibits ethanol induced NMDA receptor up-regulation
The present study examined the effect of memantine, an uncompetitive NMDA receptor antagonist, on ethanol-induced NMDA receptor up-regulation. Primary glutamatergic rat hippocampal neurons were exposed to ethanol and memantine for 5 days. The ethanol-sensitive NMDA receptor subunits NR1, NR2A and NR2B were quantified by Western immunoblot analysis. Neither ethanol nor memantine alone or in combination were toxic in the concentrations tested. These results may provide a molecular explanation for beneficial effects of memantine on ethanol-induced glutamatergic hyperexcitability reflected in the ethanol withdrawal syndrome and on the development of ethanol dependence.
Dependence (Opoids): MK-801 inhibits morphine tolerance and dependance when co-administered
The NMDA subtype of the glutamate receptor is an important mediator of several forms of neural and behavioral plasticity. The present studies examined whether NMDA receptors might be involved in the development of opiate tolerance and dependence, two examples of behavioral plasticity. The noncompetitive NMDA receptor antagonist MK-801 attenuated the development of tolerance to the analgesic effect of morphine without affecting acute morphine analgesia. In addition, MK-801 attenuated the development of morphine dependence as assessed by naloxone-precipitated withdrawal. These results suggest that NMDA receptors may be important in the development of opiate tolerance and dependence.
Sensitization: “Calcium channel blockers and behavioral sensitization (BS)”
Behavioral sensitization to amphetamine-induced stereotypy was previously shown to consist of two separable phenomena, induction and expression, both of which involve the excitatory amino acids (EAA). In the present experiments, the calcium channel blockers (CCB), nifedipine, diltiazem and verapamil, were shown to block both phenomena; these results are similar to those reported earlier for DNQX, an antagonist of the NMDA receptors for the EAA. The CCB, like DNQX, affect only that percentage of the stereotypic response which results from the sensitization reaction, without affecting the quantitative portion of the response attributable to the acute effect of amphetamine. The results support previous conclusions that the sensitization response consists of two quantitative components, only one of which involves the EAA. The antagonism exhibited by the CCB suggests that behavioral sensitization involves Ca++ and L-type calcium channels.
Sensitization (Stimulants): “Involvement of NMDA receptor stimulation in the VTA and amygdala in BS”
Systemic administration of N-methyl-D-aspartate (NMDA) antagonists prevents the development of behavioral sensitization to amphetamine-like psychostimulants. Pretreatment with the noncompetitive NMDA antagonist, MK-801, resulted in a dose-dependent blockade of behavioral sensitization to cocaine. However, pretreatment with the highest dose of MK-801 (0.25 mg/kg i.p.) alone inhibited the behavioral response to a subsequent cocaine challenge 24 hr later. The induction of behavioral sensitization is known to result, at least partly, from an action by psychostimulants in the ventral tegmental area (VTA). Pretreatment with either NMDA antagonist into the VTA prevented the manifestation of behavioral sensitization. Intracranial pretreatment with MK-801 was also made into the nucleus accumbens and amygdala which have been implicated in psychostimulant-induced sensitization. Whereas MK-801 was without effect in the nucleus accumbens, when microinjected into the ventral amygdala prevented the manifestation of behavioral sensitization to a cocaine challenge. The blockade of sensitization by MK-801 in the VTA was produced with a minimum effective dose of 0.01 nmol, whereas the minimum effective dose in the amygdala was 1.0 nmol. These data demonstrate that stimulation of NMDA receptors in the VTA and amygdala is necessary in the development of behavioral sensitization to and dependance upon cocaine.
Sensitization (Opiates): “MK-801 prevents the development of behavioral sensitization during repeated morphine administration.”
Acute administration of morphine (10 mg/kg) to rats elicited an increase in locomotion that became sensitized upon repeated treatment over 14 days. Administration of the noncompetitive N-methyl-D-aspartate receptor (NMDA) antagonist MK-801 (0.1 or 0.25 mg/kg) prior to each morphine injection prevented the development of behavioral sensitization to morphine, an effect that persisted even after a 7-day withdrawal from repeated treatment. Sensitization was also prevented by coadministration of the competitive NMDA receptor antagonist CGS 19755 (10 mg/kg). In contrast, acute pretreatment with MK-801 did not alter the response of sensitized rats to morphine challenge, indicating that MK-801 does not prevent the expression of sensitization. When administered alone, MK-801 produced stereotyped movements at moderate doses (0.25 mg/kg) and horizontal locomotion at higher doses (0.5 mg/kg). Repeated administration of 0.25 mg/kg MK-801 elicited sensitization to its own locomotor stimulatory effects, such that this dose became capable of eliciting horizontal locomotion. Sensitization was not seen during repeated administration of 0.1 mg/kg MK-801 or 10 mg/kg CGS 19755, although both of these pretreatments did produce a sensitized response to subsequent challenge with 0.25 mg/kg MK-801. This effect was enhanced by coadministration of morphine, even though repeated administration of morphine alone failed to sensitize rats to MK-801 challenge. These results suggest a complex interplay between NMDA and opioid receptors, such that NMDA antagonists prevent morphine sensitization while morphine enhances the ability of NMDA antagonists to elicit sensitization to their own locomotor stimulatory effects.
Sensitization (Literary Review): Noncompetitive NMDA Receptor Antagonism and Behavioral Sensitization
This review emphasizes that the conclusions that can be drawn from sensitization experiments about the effects of dizocilpine and related drugs on behavioural plasticity crucially depend on how, when and under what conditions a test for sensitization is conducted.
Sensitization (Stimulants): MK-801 does not prevent acute stimulatory effects of amphetamine or cocaine on locomotor activity or extracellular dopamine levels in rat nucleus accumbens.
Recent work has shown that the development of behavioral sensitization to cocaine, amphetamine, and morphine is prevented by coadministration of N-methyl-D-aspartate (NMDA) antagonists such as MK-801. This suggests that NMDA receptors mediate long-term changes in neuronal responsiveness essential for the development of behavioral sensitization, similar to their role in other forms of neuronal plasticity. However, other studies, suggesting that NMDA receptor antagonists interfere with acute behavioral effects of psychomotor stimulants, call this interpretation into question and suggest that the ability of NMDA antagonists to prevent sensitization may reflect blockade of the acute effects of psychomotor stimulants. To examine this issue, behavioral and microdialysis studies assessed the effect of pretreatment with 0.1 mg/kg MK-801 on the ability of amphetamine and cocaine to stimulate locomotor activity and elevate extracellular dopamine (DA) levels in nucleus accumbens; this dose of MK-801 prevents sensitization when coadministered repeatedly with these stimulants. MK-801 pretreatment enhanced amphetamine-stimulated horizontal locomotion and stereotyped behavior. MK-801 pretreatment produced a modest attenuation of cocaine-stimulated horizontal locomotion, which may have reflected enhancement by MK-801 of certain components of cocaine-stimulated stereotypy. There was no effect of MK-801 pretreatment on the ability of amphetamine or cocaine to elevate extracellular DA levels in nucleus accumbens. These results suggest that the acute effects of cocaine and amphetamine on locomotor activity and extracellular DA levels are not prevented by MK-801, and that MK-801 must act through other mechanisms to prevent the development of behavioral sensitization.
Sensitization (Literary Review): Of alterations in dopaminergic and glutamatergic transmission in the induction and expression of behavioral sensitization.
Rationale and objectives: Repeated exposure to many drugs of abuse results in a progressive and enduring enhancement in the motor stimulant effect elicited by a subsequent drug challenge. This phenomenon, termed behavioral sensitization, is thought to underlie certain aspects of drug addiction. Behavioral sensitization is the consequence of drug-induced neuroadaptive changes in a circuit involving dopaminergic and glutamatergic interconnections between the ventral tegmental area, nucleus accumbens, prefrontal cortex and amygdala.
Methods: The literature was critically reviewed in an effort to discern the relative roles of glutamate and dopamine transmission in the induction and expression of sensitization to amphetamine, cocaine and µ-opioids. In addition, the literature was reviewed to evaluate distinctions between these drugs in the involvement of the relevant brain nuclei listed above.
Results: The common substrates between sensitizing drugs are glutamate transmission, especially at the NMDA receptor, and an action in the ventral tegmental area. In contrast, a role for dopamine is only clearly seen in amphetamine sensitization and critical involvement of nuclei outside the ventral tegmental area is found for cocaine and morphine. While enhanced dopamine transmission is associated with sensitization by all three drugs, a role for glutamate is clearly identified only with cocaine sensitization. Accordingly, glutamatergic cortical and allocortical brain regions such as the prefrontal cortex appear more critical for cocaine sensitization.
Conclusions: The distinctions between drugs in the induction and expression of sensitization indicate that behavioral sensitization can arise from multiple neuroadaptations in multiple brain nuclei. This is not only the result of distinct molecular targets for the drugs, but may also include a differential involvement of learned associations. It is postulated that the relatively more robust pharmacological capacity of amphetamine to release dopamine may induce a form of sensitization that is more dependent on adaptations in mesoaccumbens dopamine transmission compared with cocaine and morphine sensitization.
Sensitization: State-Dependency Hypothesis and the prevention of sensitization by NMDA-Antagonists
According to an alternative "state-dependency" interpretation, NMDA receptor antagonists do not prevent sensitization. Rather, they become a conditioned stimulus for the sensitized response, i.e., it is only elicited in response to combined administration of the NMDA receptor antagonist and the stimulant. This hypothesis is supported by progressive augmentation of the locomotor response to the drug combination during the induction phase, and expression of sensitization when challenged with the combination but not the stimulant alone. To test this hypothesis, rats were treated during a 6-day induction phase with amphetamine (Amph) alone or in combination with the competitive NMDA receptor antagonist CGS 19755 (10 mg/kg) or the non-competitive NMDA receptor antagonist MK-801 (0.05, 0.1 and 0.25 mg/kg).
Miscellaneous: “From glutamate co-release to vesicular synergy: vesicular glutamate transporters”
While originally understood that vesicular glutamate transporters (namely vesicular glutamate transporter 1 (VGLUT1), VGLUT2 and VGLUT3) are sodium ion dependant phosphates that carry glutamate from the cytosol to the synaptic vesicle, recent research and expansion on previous discoveries has implicated the presence of these transport proteins in monoamine, acetylcholine and GABA containing neurons. This gives way to the idea that neurons are not co-localized to independent neuropeptides but rather use multiple non-peptide transmitters. This study emphasizes the intricacy of the chloride anion as a part of synaptic vesicle homeostasis. The impact of Cl- as stimulating glutamate uptake into the vesicle in low concentrations and vice versa has long been understood, however this study raises the question regarding the role of Cl- in regulating glutamate accumulation: do vesicles bear a Cl- channel or transporter? The study proposes the extent of understanding regarding glutamate as being able to judge that it functions as a neurotransmitter and a buffering anion in neurotransmitter terminals. The presence of glutamate being apparently so widespread may lend insight into taking advantage of the role it plays in synaptic transmission and the effects of altering the density and polarization of the receptors it is currently associated with.
Discuss what you think about the validity of these experiments, the efficacy of their methodology, your opinion on what they are proposing and your own experience experimenting with ideas derived from these studies. I have a million ideas and I will soon start posting them but, as usual, I know some of them are completely impossible. I'm glad the last study was incorporated though, it is very recent yet if it is indeed true it shows that even the most highly regarded theories within a field may be refuted and thus improved upon (another example is Adult Neurogenesis). I will post more as I research further, this is simply a fraction of the studies I wish to discuss with others that are not affiliated with my program.
tl;dr read studies on the subject presented here, think about it, tell me what you thought
This is a compilation of relevant information to one of the most interesting topics within neuropharmacology, in my opinion. The possibilities concerning what may be interpreted from this information are infinite and the discoveries that have yet to be made in the prevention of tolerance, dependance and undesired drug-seeking impulses (a bit paradoxical). As a community of individuals highly informed and experienced in the realm of neuropharmacology I believe that a conversation regarding these relatively contemporary (the most dated study listed here is from 1989) revelations within the realm of one of the most daunting aspects of psychoactive experimentation would be stimulating and productive to say the least. I have also included a very basic definitions and concepts section so that those who are less educated on the topic of neuroscience who have experienced the effects taken into consideration by these scientific experiments may express their opinions more elegantly (opinions that are valued as a precursor to the plausibility of surveying upon these topics). In this compilation I have paraphrased and quoted many studies without giving fair APA citation, but have still provided the names of the research. So in the spirit of integrity, although certain aspects of this have been written by me, I take no credit for any of this information.
Feel free to share your opinions, speculations on connections between studies, ideas for further research, experiences and corrections (remember I'm simply a research assistant trying to grasp the topics at hand as fully as possible).
Definitions and Concepts
Definitions and Concepts: Synaptic Plasticity
Synaptic Plasticity is the ability of the synapse between two neurons to change in strength in response to transmission over synaptic pathways. This change in strength can be achieved via quantitative changes in neurotransmitters and efficacy of those neurotransmitters upon the receptors they bind to.
The molecular mechanisms of synaptic plasticity can be lent to the NMDA (N-methyl-d-aspartate) and AMPA (alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate) receptors. Opening the NMDA channel depolarizes the post-synaptic cell, leading to an increase in Ca2+ concentration proportional to the strength of the depolarization. Strong depolarization has been linked to long-term enhancement in signal transmission between the two neurons (Long-term potentiation or LTP). This is thought to be a major mechanism of memory and learning. This is concurrent with the Hebbian theory that an increase in synaptic efficacy arises from the presynaptic cell’s repeated and persistent stimulation of the postsynaptic cell, summarized as “cells that fire together, wire together”. As well as inducing LTP, strong depolarization leads to activation of protein kinases that serve to phosphorylate post-synaptic excitatory receptors, improving cation conduction and signaling recruitment of additional receptors into the post-synaptic membrane. The density of the receptors on the post-synaptic membrane affects the neuron’s excitability and response to stimuli. NMDA receptors are added to the membrane via exocytosis and endocytosis, while AMPA receptors are delivered to the synapse by vesicular membrane fusion with the post-synaptic membrane via protein kinase, which (as stated before) is activated by the influx of Ca2+ ions.
Consistent weaker depolarization, however, results in lower post-synaptic calcium concentration. This has been linked to long-term depression, induced by activated protein phosphatases that dephosphorylate cation channels and reverse the activity of protein kinase activation.
Definitions and Concepts: Activity-Dependent Plasticity
The brain undergoes changes based on activity, allowing the functions performed by individuals on a daily basis to change gene expression by specializing in specific activities, based on relative use. For example, a left-handed person can become ambidextrous by repeated use of his right-hand, making both hands equally able. Systematic alterations to behavior cause changes to neuronal activity, which ultimately results in a theoretical “rewiring” of the brain.
Definitions and Concepts: Neurogenesis
Neurogenesis refers to the process by which neurons are generated via the neural stem and progenitor cells. While this process is most active during pre-natal development, recent advances in the study of mammals has revealed the continuation of neuronal generation, deemed “Adult Neurogenesis”. Mainly, this continuation carries on in the hippocampus and subventricular (SVC) zone.
Inhibition of neurogenesis can lead to an increase in the hypothalamic-pituitary-adrenal (HPA) axis stress response. It has been suggested that there is a link between decreased hippocampal neurogenesis and depression, related to the demonstration that the beneficial activity of anti-depressants is reversed when neurogenesis is prevented in mice. Others have suggested that neurogenesis promotes neuroplasticity. Neurodegenerative disorders characteristically inhibit neurogenesis and typically, as in the case of Parkinson’s disease and its effect on dopaminergic neurons in the nigrostriatal, will slowly deplete neuronal population. Sleep deprivation prevents neurogenesis and it has been proposed that this is related to a rise in glucocorticoids such as cortisol. Certain sources of questionable reliability have associated this rise in cortisol, a “stress hormone”, to be associated with being deprived of neural processes that affect various monoamines, neuropeptides and hormones during the various phases of the sleep cycle. Certain examples include N,N-DMT during REM sleep and the release of endogenous opiates during NREM.
Definitions and Concepts: Glutamate
Glutamate is the brain's principal excitatory neurotransmitter for which there are three receptors — the ion channels NMDA, AMPA and kainate — and also another receptor family which is coupled to G-proteins and the second (metabotropic) messenger system. Glutamatergic neurons from the prefrontal cortex and amygdala project onto the mesolimbic reward pathway, from which reciprocal dopaminergic projections arise. There is evidence that the glutamatergic projection from the prefrontal cortex to the nucleus accumbens plays a role in the reinstatement of stimulant-seeking behaviour.
Definitions and Concepts: GABAA and NMDA Structure, Function and Trafficking
GABAA receptors are the major inhibitory neurotransmitter receptors. They are chloride ion channels activated by the binding of the neurotransmitter,
GABA. NMDA receptors are a subclass of the excitatory L-glutamate family of neurotransmitter receptors. They are unique in that they require the simultaneous binding of two neurotransmitters, the co-agonists L-glutamate and glycine, together with the alleviation of a voltage-dependent blockade by magnesium ions that is achieved by the activation of adjacent non-NMDA glutamate receptors in synaptic spines, for channel activation. Both GABAA receptors and NMDA receptors are not only pivotal for normal brain function but they are also important drug targets. NMDA receptors have potential as a therapeutic target post-ischaemia and in neuropathic pain; NMDA receptor channels are highly permeable to calcium ions; thus over-activation leads to excitotoxic neuronal cell death, which may be treated by NMDA receptor antagonists.
GABAA (γ -aminobutyric acid type A) receptors and NMDA (N-methyl-d-aspartate) receptors are both examples of ligand-gated, heteromeric neurotransmitter receptors whose cell-surface expression is dynamic and tightly regulated. NMDA receptors are localized at excitatory synapses. These synapses are highly structured but dynamic, with the interplay between NMDA receptors and NMDA receptor associated scaffolding proteins regulating the expression of functional cell-surface synaptic and extrasynaptic receptors. Based on current information, inhibitory synapses seem to be less ordered, and a GABAA receptor equivalent of PSD-95 (postsynaptic density-95), the scaffolding molecule pivotal to the organization of
NMDA receptor complexes at synapses, is yet to be validated.
NMDA Channels:
(1) are blocked by Mg2+ in a voltage-dependent way;
(2) are permeable to Ca2+ as well as to Na+ and K+
(3) may adopt multiple conductance states; some of the minor states (small conductances) resemble the major conductance states opened by non-NMDA agonists
(4) posess a trypsin sensitive component necessary for ion channel activation
• NMDA Antagonism
o Example: Memantine
• Non-competitive NMDA receptor antagonist
• Licensed for use in treatment of Alzheimer’s
o Blocks influx of calcium ions
• NMDA Agonism
o Activation requires:
• Binding of glutamate or aspartate
• Binding of the co-agonist glycine or serine
• Glycine potentiates the response to NMDA
• Membrane depolarization by opening the ion channel and expelling the Mg2+ ion blocking the outside.
o Continued exposure to NMDA agonists produces short term and long term decreases in the sensitivity of the NMDA system
o Example NMDA Agonists:
• D-Cycloserine
• Cis-2,3,Piperidinedicarboxylic acid
• L-aspartate
• D-serine
• L-alanine
• GABAA
o The fast response of neurons to GABA that is blocked by agents such as bicuculline is due to direct activation of an anion channel concerned chiefly with passing Cl- ions across the cell membrane.
o This anion channel is called the GABAA receptor
• GABAA Antagonism
o Example: Bicuculline
• Competitive Antagonist
• Blocks Cl- transmission as well as Ca2+-activated ion channels.
• Mimics epilepsy.
o Example: Picrotoxin
• Non-Competitive Antagonist/Channel Blocker
• Blocks Cl- transmission.
• Produces stimulant/convulsant effects, used to counter barbituate overdose.
• GABAA Potentiation
o Benzodiazepines
• Benzodiazepines ) enhance the action of the GABAA receptor by binding to benzodiazepine receptor sites located at the γ subunit, resulting in allosteric activation.
• This produces a calming effect, as GABA is already an inhibitory neurotransmitter.
Definitions and Concepts: Behavioral Sensitization
The term 'behavioural sensitization' refers to the progressively augmented behavioural response that is produced by many drugs of abuse upon their repeated administration. It is not to be confused with tolerance, although behavioral sensitization to drugs that induce tolerance steadily (such as opiates) may have a correlational relationship with tolerance.
Studies and Literary Reviews
Plasticity (Opioids): Involvement of cAMP-Dependent Protein Kinase in μ-Opioid Modulation of NMDA-Mediated Synaptic Currents
There have been reported dual effects of μ-opioids on NMDA-receptor-mediated synaptic events in the hippocampal dentate gyrus: an indirect facilitating effect via suppression of GABAergic interneurons (disinhibition) and a direct inhibitory effect in the presence of γ-aminobutyric acid-A (GABAA) antagonists. The cellular mechanism underlying the inhibitory effect of μ-opioids remains to be determined. In the present study we examine the role of adenosine 3′,5′-cyclic monophosphate (cAMP)-dependent protein kinase (PKA) in μ-opioid-induced inhibition of NMDA currents. This inhibitory effect could be completely reversed by the opioid antagonists naloxone or prevented by a selective μ-antagonist cyprodime, but was not affected by removal of Mg2+ from the external perfusion medium. These findings strongly suggest that NMDA receptor function is subject to the modulation by PKA, and that μ-opioids can inhibit NMDA currents through suppression of the cAMP cascade in the postsynaptic neuron. Combined with our previous findings, the present results also indicate that μ-opioids can modulate NMDA-receptor-mediated synaptic activity in a complex manner.
Plasticity: “Calcium ion activation mediated by GABAAR and NMDA Receptors”
The NMDA subtype of glutamate receptors plays an important role in adult and developmental neuronal plasticity via increases in intracellular Ca2+. Since the voltage-dependent Mg2+ block of NMDA channels operates not only in adult but also in neonatal neurons, their activation during synaptic activity requires external sources of depolarization. In adult neurons, this is largely provided by glutamate acting on AMPA receptors that mediate most of the excitatory drive throughout the mammalian central nervous system. In contrast, GABA, the primary inhibitory transmitter, acting via ionotropic GABAA receptors (GABAA R), increases a chloride conductance that usually hyperpolarizes adult neurons, thus preventing the activation of NMDA R. Thus, the induction of NMDA R–dependent forms of long-term potentiation or depression are facilitated by GABAA-R antagonists. An opposite situation may prevail at early stages of development when the activation of GABAA receptors provides depolarization instead of hyperpolarization. In several types of neonatal neurons, activation of GABAA R triggers action potentials and activates voltage-dependent Ca2+ channels, producing rises of Ca2+. If GABA is the principal fast-acting excitatory transmitter during early postnatal life in the hippocampus as suggested from earlier studies from this laboratory, it may, in contrast to adult neurons, act in synergy with NMDA R, providing the depolarization required to release their voltage-dependent Mg2+ block. If so, GABAA R would play in neonatal neurons the role conferred to AMPA R in more mature neurons and neurons generated during adult neurogenesis may share in the same GABA-NMDA synergy.
Plasticity: Activity-dependent tuning of inhibitory neurotransmission based on GABAAR diffusion dynamics
Excitatory synaptic activity changes the diffusion of GABAA receptors in the hippocampus. Calcium-dependent mechanisms are most likely very important in the induction of Long Term Potentiation. Activities that result in the influx of calcium ions may be used to enhance synaptic plasticity and the diffusion of GABAergic neurotransmitters, transport proteins and neuropeptides.
Plasticity (Learning): “Synaptic stability and plasticity in a floating world”
Synaptic plasticity is an important determinant of learning and memory, the synapse is ever-changing with all constituents turning over around equilibrium. At steady state, in/out synapse flux of receptor is equal to zero, imbalances decrease or increase receptor number at the synapse. Synaptic plasticity at inhibitory and excitatory synapses is calcium-dependant, and a rise in intracellular calcium at excitatory synapses decreases AMPAR (non-NMDA type receptor for glutamate that mediates fast synaptic transmission) diffusion and increases dwell time. AMPAR receptors are both glutamate receptors and cation channels. In general, signals that potentiate excitatory synapses depress inhibitory synapses and vice versa. In response to activity, spines (sites where most excitatory synpases are found) can regulate the diffusion of calcium. Activity dependant neuronal disinhibition and other modifications to neuronal activity involving glutamatergic receptors are also calcium-dependent, as well as being dependent upon the phophatase calcineurin. At mixed synapses in the spinal cord (possessing a mixed glycine-GABA phenotype), increasing neuronal activity decreases diffusion rate and increases synaptic accumlication of Gly-Rs but not GABAA. The regulation of GlyR synaptic content is assumed to modify the affinity between receptors and scaffolds, and is dependent on calcium influx.
Plasticity (Learning): Do different kinds of plasticity underlie different kinds of learning?”
This study contrasts activity dependent modulation of presynaptic transmission and NMDA receptor triggered alterations in excitatory amino acid transmission. It proposes that different forms of plasticity might underlie different kinds of learning. To support this idea, freely moving rats are infused with D,L-AP5 (an NMDA-receptor antagonist) causing a dose-dependant impairment of spatial learning known to be sensitive to disruption by hippocampal lesions. The same drug is shown to cause a blockade of hippocampal LTP across a dose range. The conclusions drawn postulate that there are indeed numerous modes of plasticity playing a role in learning, however the researchers emphasize they are not insinuating that the NMDA receptor alterations made in this experiment are characteristic of all the functions it serves, but only focus on it’s mechanisms within hippocampal neurons.
Plasticity: “Homeostatic regulation of synaptic GlyR numbers driven by lateral diffusion.”
Glycinergic transmission is changed in the spinal cord with changes in excitatory transmission. It is an interesting supplement to the above study and reveals that there are distinct mechanisms for plasticity and homeostatic plasticity that are both calcium dependent and focuses on the role of glycine as a co-transmitter during diffusion of calcium ions.
Dependence (Stimulants): Amphetamine induces dendritic growth in VTA dopaminergic neurons
Reinforcing drugs such as amphetamines and opiates induce behavioral sensitization upon repeated administration by inducing dopaminergic neurogenesis in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). This occurs through activation of dopamine receptors in these areas which produces glutamate release and subsequent elevation of local basic fibroblast growth factor (bFGF) concentrations. Dopaminergic neurons of the ventral tegmental area are implicated in the physiology of reward, and long-lasting changes in their function induced by exposure to psychostimulant drugs are related to the pathophysiology of drug abuse. Repeated exposure to amphetamine induces substantial dendritic growth of ventral tegmental area dopaminergic neurons in vivo. Furthermore, we show, by immuno-neutralization of endogenous basic fibroblast growth factor, that the amphetamine-induced increase in astrocytic basic fibroblast growth factor in the ventral tegmental area is essential for these morphological changes. We propose that the amphetamine-induced elaboration of the dendritic arbor of dopaminergic neurons leads to their increased excitability and contributes to compulsive drug-seeking and relapse. Further research could inspect the role of amphetamines upon neurogenesis and the excitability of neurons produced because of this effect.
Dependence (Cocaine): Reinforcing effects of cocaine absent in mutant mice
In mice lacking the mGlu5 subtype of the metabotropic glutamatergic receptor, cocaine still increases dopamine in the nucleus accumbens; but the mice do not self-administer cocaine or show increased locomotor activity
Dependence (Ethanol): Altered NMDA Receptor Antagonist Response in Recovering Ethanol-Dependent Patients
Ethanol is an antagonist of the N-methyl-d-aspartate glutamate receptor. Ethanol dependence upregulates NMDA receptors and contributes to crosstolerance with selective NMDA receptor antagonists in animals. This study evaluated whether recovering ethanol-dependent patients show evidence of a reduced level of response to the effects of the NMDA receptor antagonist, ketamine. In this double-blind study, 34 recently detoxified alcohol-dependent patients and 26 healthy comparison subjects completed 3 test days involving a 40-min infusion of saline, ketamine 0.1 mg/kg, or ketamine 0.5 mg/kg in a randomized order. Recovering ethanol-dependent patients showed reduced perceptual alterations, dysphoric mood, and impairments in executive cognitive functions during ketamine infusion relative to the healthy comparison group. No attenuation of ketamine-induced amnestic effects, euphoria, or activation was observed. The alterations in NMDA receptor function observed in recovering ethanol-dependent patients may have important implications for ethanol tolerance, ethanol dependence, and the treatment of alcoholism.
Dependence (Ethanol): Memantine inhibits ethanol induced NMDA receptor up-regulation
The present study examined the effect of memantine, an uncompetitive NMDA receptor antagonist, on ethanol-induced NMDA receptor up-regulation. Primary glutamatergic rat hippocampal neurons were exposed to ethanol and memantine for 5 days. The ethanol-sensitive NMDA receptor subunits NR1, NR2A and NR2B were quantified by Western immunoblot analysis. Neither ethanol nor memantine alone or in combination were toxic in the concentrations tested. These results may provide a molecular explanation for beneficial effects of memantine on ethanol-induced glutamatergic hyperexcitability reflected in the ethanol withdrawal syndrome and on the development of ethanol dependence.
Dependence (Opoids): MK-801 inhibits morphine tolerance and dependance when co-administered
The NMDA subtype of the glutamate receptor is an important mediator of several forms of neural and behavioral plasticity. The present studies examined whether NMDA receptors might be involved in the development of opiate tolerance and dependence, two examples of behavioral plasticity. The noncompetitive NMDA receptor antagonist MK-801 attenuated the development of tolerance to the analgesic effect of morphine without affecting acute morphine analgesia. In addition, MK-801 attenuated the development of morphine dependence as assessed by naloxone-precipitated withdrawal. These results suggest that NMDA receptors may be important in the development of opiate tolerance and dependence.
Sensitization: “Calcium channel blockers and behavioral sensitization (BS)”
Behavioral sensitization to amphetamine-induced stereotypy was previously shown to consist of two separable phenomena, induction and expression, both of which involve the excitatory amino acids (EAA). In the present experiments, the calcium channel blockers (CCB), nifedipine, diltiazem and verapamil, were shown to block both phenomena; these results are similar to those reported earlier for DNQX, an antagonist of the NMDA receptors for the EAA. The CCB, like DNQX, affect only that percentage of the stereotypic response which results from the sensitization reaction, without affecting the quantitative portion of the response attributable to the acute effect of amphetamine. The results support previous conclusions that the sensitization response consists of two quantitative components, only one of which involves the EAA. The antagonism exhibited by the CCB suggests that behavioral sensitization involves Ca++ and L-type calcium channels.
Sensitization (Stimulants): “Involvement of NMDA receptor stimulation in the VTA and amygdala in BS”
Systemic administration of N-methyl-D-aspartate (NMDA) antagonists prevents the development of behavioral sensitization to amphetamine-like psychostimulants. Pretreatment with the noncompetitive NMDA antagonist, MK-801, resulted in a dose-dependent blockade of behavioral sensitization to cocaine. However, pretreatment with the highest dose of MK-801 (0.25 mg/kg i.p.) alone inhibited the behavioral response to a subsequent cocaine challenge 24 hr later. The induction of behavioral sensitization is known to result, at least partly, from an action by psychostimulants in the ventral tegmental area (VTA). Pretreatment with either NMDA antagonist into the VTA prevented the manifestation of behavioral sensitization. Intracranial pretreatment with MK-801 was also made into the nucleus accumbens and amygdala which have been implicated in psychostimulant-induced sensitization. Whereas MK-801 was without effect in the nucleus accumbens, when microinjected into the ventral amygdala prevented the manifestation of behavioral sensitization to a cocaine challenge. The blockade of sensitization by MK-801 in the VTA was produced with a minimum effective dose of 0.01 nmol, whereas the minimum effective dose in the amygdala was 1.0 nmol. These data demonstrate that stimulation of NMDA receptors in the VTA and amygdala is necessary in the development of behavioral sensitization to and dependance upon cocaine.
Sensitization (Opiates): “MK-801 prevents the development of behavioral sensitization during repeated morphine administration.”
Acute administration of morphine (10 mg/kg) to rats elicited an increase in locomotion that became sensitized upon repeated treatment over 14 days. Administration of the noncompetitive N-methyl-D-aspartate receptor (NMDA) antagonist MK-801 (0.1 or 0.25 mg/kg) prior to each morphine injection prevented the development of behavioral sensitization to morphine, an effect that persisted even after a 7-day withdrawal from repeated treatment. Sensitization was also prevented by coadministration of the competitive NMDA receptor antagonist CGS 19755 (10 mg/kg). In contrast, acute pretreatment with MK-801 did not alter the response of sensitized rats to morphine challenge, indicating that MK-801 does not prevent the expression of sensitization. When administered alone, MK-801 produced stereotyped movements at moderate doses (0.25 mg/kg) and horizontal locomotion at higher doses (0.5 mg/kg). Repeated administration of 0.25 mg/kg MK-801 elicited sensitization to its own locomotor stimulatory effects, such that this dose became capable of eliciting horizontal locomotion. Sensitization was not seen during repeated administration of 0.1 mg/kg MK-801 or 10 mg/kg CGS 19755, although both of these pretreatments did produce a sensitized response to subsequent challenge with 0.25 mg/kg MK-801. This effect was enhanced by coadministration of morphine, even though repeated administration of morphine alone failed to sensitize rats to MK-801 challenge. These results suggest a complex interplay between NMDA and opioid receptors, such that NMDA antagonists prevent morphine sensitization while morphine enhances the ability of NMDA antagonists to elicit sensitization to their own locomotor stimulatory effects.
Sensitization (Literary Review): Noncompetitive NMDA Receptor Antagonism and Behavioral Sensitization
This review emphasizes that the conclusions that can be drawn from sensitization experiments about the effects of dizocilpine and related drugs on behavioural plasticity crucially depend on how, when and under what conditions a test for sensitization is conducted.
Sensitization (Stimulants): MK-801 does not prevent acute stimulatory effects of amphetamine or cocaine on locomotor activity or extracellular dopamine levels in rat nucleus accumbens.
Recent work has shown that the development of behavioral sensitization to cocaine, amphetamine, and morphine is prevented by coadministration of N-methyl-D-aspartate (NMDA) antagonists such as MK-801. This suggests that NMDA receptors mediate long-term changes in neuronal responsiveness essential for the development of behavioral sensitization, similar to their role in other forms of neuronal plasticity. However, other studies, suggesting that NMDA receptor antagonists interfere with acute behavioral effects of psychomotor stimulants, call this interpretation into question and suggest that the ability of NMDA antagonists to prevent sensitization may reflect blockade of the acute effects of psychomotor stimulants. To examine this issue, behavioral and microdialysis studies assessed the effect of pretreatment with 0.1 mg/kg MK-801 on the ability of amphetamine and cocaine to stimulate locomotor activity and elevate extracellular dopamine (DA) levels in nucleus accumbens; this dose of MK-801 prevents sensitization when coadministered repeatedly with these stimulants. MK-801 pretreatment enhanced amphetamine-stimulated horizontal locomotion and stereotyped behavior. MK-801 pretreatment produced a modest attenuation of cocaine-stimulated horizontal locomotion, which may have reflected enhancement by MK-801 of certain components of cocaine-stimulated stereotypy. There was no effect of MK-801 pretreatment on the ability of amphetamine or cocaine to elevate extracellular DA levels in nucleus accumbens. These results suggest that the acute effects of cocaine and amphetamine on locomotor activity and extracellular DA levels are not prevented by MK-801, and that MK-801 must act through other mechanisms to prevent the development of behavioral sensitization.
Sensitization (Literary Review): Of alterations in dopaminergic and glutamatergic transmission in the induction and expression of behavioral sensitization.
Rationale and objectives: Repeated exposure to many drugs of abuse results in a progressive and enduring enhancement in the motor stimulant effect elicited by a subsequent drug challenge. This phenomenon, termed behavioral sensitization, is thought to underlie certain aspects of drug addiction. Behavioral sensitization is the consequence of drug-induced neuroadaptive changes in a circuit involving dopaminergic and glutamatergic interconnections between the ventral tegmental area, nucleus accumbens, prefrontal cortex and amygdala.
Methods: The literature was critically reviewed in an effort to discern the relative roles of glutamate and dopamine transmission in the induction and expression of sensitization to amphetamine, cocaine and µ-opioids. In addition, the literature was reviewed to evaluate distinctions between these drugs in the involvement of the relevant brain nuclei listed above.
Results: The common substrates between sensitizing drugs are glutamate transmission, especially at the NMDA receptor, and an action in the ventral tegmental area. In contrast, a role for dopamine is only clearly seen in amphetamine sensitization and critical involvement of nuclei outside the ventral tegmental area is found for cocaine and morphine. While enhanced dopamine transmission is associated with sensitization by all three drugs, a role for glutamate is clearly identified only with cocaine sensitization. Accordingly, glutamatergic cortical and allocortical brain regions such as the prefrontal cortex appear more critical for cocaine sensitization.
Conclusions: The distinctions between drugs in the induction and expression of sensitization indicate that behavioral sensitization can arise from multiple neuroadaptations in multiple brain nuclei. This is not only the result of distinct molecular targets for the drugs, but may also include a differential involvement of learned associations. It is postulated that the relatively more robust pharmacological capacity of amphetamine to release dopamine may induce a form of sensitization that is more dependent on adaptations in mesoaccumbens dopamine transmission compared with cocaine and morphine sensitization.
Sensitization: State-Dependency Hypothesis and the prevention of sensitization by NMDA-Antagonists
According to an alternative "state-dependency" interpretation, NMDA receptor antagonists do not prevent sensitization. Rather, they become a conditioned stimulus for the sensitized response, i.e., it is only elicited in response to combined administration of the NMDA receptor antagonist and the stimulant. This hypothesis is supported by progressive augmentation of the locomotor response to the drug combination during the induction phase, and expression of sensitization when challenged with the combination but not the stimulant alone. To test this hypothesis, rats were treated during a 6-day induction phase with amphetamine (Amph) alone or in combination with the competitive NMDA receptor antagonist CGS 19755 (10 mg/kg) or the non-competitive NMDA receptor antagonist MK-801 (0.05, 0.1 and 0.25 mg/kg).
Miscellaneous: “From glutamate co-release to vesicular synergy: vesicular glutamate transporters”
While originally understood that vesicular glutamate transporters (namely vesicular glutamate transporter 1 (VGLUT1), VGLUT2 and VGLUT3) are sodium ion dependant phosphates that carry glutamate from the cytosol to the synaptic vesicle, recent research and expansion on previous discoveries has implicated the presence of these transport proteins in monoamine, acetylcholine and GABA containing neurons. This gives way to the idea that neurons are not co-localized to independent neuropeptides but rather use multiple non-peptide transmitters. This study emphasizes the intricacy of the chloride anion as a part of synaptic vesicle homeostasis. The impact of Cl- as stimulating glutamate uptake into the vesicle in low concentrations and vice versa has long been understood, however this study raises the question regarding the role of Cl- in regulating glutamate accumulation: do vesicles bear a Cl- channel or transporter? The study proposes the extent of understanding regarding glutamate as being able to judge that it functions as a neurotransmitter and a buffering anion in neurotransmitter terminals. The presence of glutamate being apparently so widespread may lend insight into taking advantage of the role it plays in synaptic transmission and the effects of altering the density and polarization of the receptors it is currently associated with.
Discuss what you think about the validity of these experiments, the efficacy of their methodology, your opinion on what they are proposing and your own experience experimenting with ideas derived from these studies. I have a million ideas and I will soon start posting them but, as usual, I know some of them are completely impossible. I'm glad the last study was incorporated though, it is very recent yet if it is indeed true it shows that even the most highly regarded theories within a field may be refuted and thus improved upon (another example is Adult Neurogenesis). I will post more as I research further, this is simply a fraction of the studies I wish to discuss with others that are not affiliated with my program.
tl;dr read studies on the subject presented here, think about it, tell me what you thought
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