N&PD Moderators: Skorpio | thegreenhand
Note that they said that DA release in D3R rich area correlates with amphetamine induced euphoria. Correlation does not necessarily imply causation. The general consensus among neuroscientists is that dopamine does not directly cause pleasure, although it may do so indirectly. Dopamine mainly acts as motivational signal and novelty signal. There are multiple pleasure centres in the brain called "hedonic hot spots" that cause pleasure through mu-opioid receptors, cannabinoid and benzodiazepine receptors. See this paper: http://nro.sagepub.com/content/12/6/500.abstractDopamine does cause euphoria.
Fig 1.
Note that they said that DA release in D3R rich area correlates with amphetamine induced euphoria. Correlation does not necessarily imply causation.
^Its association
Correlation is a number that exists in any statistical comparison
Ho Chi Min said:^Its association
Correlation is a number that exists in any statistical comparison
Actually you're wrong.
In proper statistical terms "association" delineates a reasonable connection between two variables (whether negative or positive, broken down into low, medium, or high), while "correlation" is a number which exists in any statistical comparison.
Firstly my thanks for clarifying the definition or correlation. I always thought it referred to that weird stuff that grew on sea floor and now it has been confirmed! While i could spend hours discussing the fascinating world of marine fauna we should probably get back on topic.
Its well established mu causes euphoria.OK I'm lost.. so what causes the euphoria from stimulants?
High dose amisulpiride or prochloperazine dont alter amphetamine euphoria at all.In general, claims that any of the monoamines 'cause X' without qualification are extreme oversimplications. In the case of dopamine, it has tons of different functions in various different regions and with various different receptors. If it was merely a matter of stimulating dopamine receptors in order to feel good, dopamine agonists would be some of the most abusable drugs in existence, and yet they aren't even slightly fun. Dopamine regulates movement, for example, in a way entirely separate from its effects on mood. There is good reason to believe that the D3 receptor might largely inhibit euphoria. Even with the same receptors, in different parts of the brain the functional result of agonism could be nearly opposite (and I'm not simply referring to autoreceptors vs. post-synaptic receptors). Certainly when dopamine levels get high enough for long enough in a sensitized brain, they directly cause psychosis which is generally not experienced euphorically. Even when the increased dopamine transmission is mediating the positive effects of a drug, in some parts of the brain the subjective feeling is more desire that satiety. So, it is complicated.
All of that said, neuroleptic dopamine antagonists do cause a 'low' of sorts. Not the same kind of low that occurs when you are coming down from a stimulant (indeed, despite your subjective experience, your brain is still flooded with dopamine during that time, but the experience is rather blunted by tachyphylaxis mechanisms). But it is certainly the case that if you take a high dose of a neuroleptic and then subsequently attempt to take a stimulant, it is not going to work very well. Some neuroleptics of course, particularly at low doses (I'm thinking especially of amisulpride here), will block dopamine receptors but preferentially block presynaptic auto-receptors. Others, particularly those in the the atypical class, aren't really occupying a very high percentage of d2 receptors (and tend to dissociate rapidly), while more potently blocking 5ht receptors, some of which (e.g., 5ht-6) are known to magnify the subjective response to dopamine in the nuccleus accumbens when blocked.
Anyway, I could go on, but really my basic point is just that it is a great deal more complicated than "DA = euphoria" or "5ht = happy" and the like... That kind of logic conceals at least as much as it reveals...
Can you cite a source that the mu opiate receptor is responsible for amphetamines euphoria?
The purpose of this study was to investigate the role that mu and delta opioid receptor blockade has upon stimulant-induced behavior and neuropeptide gene expression in the striatum. Acute administration of amphetamine (2.5 mg/kg i.p.) caused an increase in behavioral activity and preprodynorphin, substance P, and preproenkephalin mRNA expression. Intrastriatal infusion of the mu opioid antagonist, H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP), or the delta opioid antagonist, H-Tyr-Tic[CH(2)NH]-Phe-Phe-OH (TIPPpsi), significantly decreased amphetamine-induced vertical activity. However, only CTAP reduced amphetamine-induced distance traveled. Quantitative in situ hybridization histochemistry revealed that CTAP blocked amphetamine-induced preprodynorphin and substance P mRNA. However, preproenkephalin mRNA levels in the dorsal striatum were increased to the same extent by CTAP, amphetamine, or a combination of the two drugs. In contrast, TIPPpsi significantly decreased amphetamine-induced mRNA expression of all three neuropeptides. These data indicate that both mu and delta receptor subtypes differentially regulate amphetamine-induced behavior and neuropeptide gene expression in the rat striatum.
Pavlovian cues [conditioned stimulus (CS+)] often trigger intense motivation to pursue and consume related reward [unconditioned stimulus (UCS)]. But cues do not always trigger the same intensity of motivation. Encountering a reward cue can be more tempting on some occasions than on others. What makes the same cue trigger more intense motivation to pursue reward on a particular encounter? The answer may be the level of incentive salience ('wanting') that is dynamically generated by mesocorticolimbic brain systems, influenced especially by dopamine and opioid neurotransmission in the nucleus accumbens (NAc) at that moment. We tested the ability of dopamine stimulation (by amphetamine microinjection) vs. mu opioid stimulation [by d-Ala, nMe-Phe, Glyol-enkephalin (DAMGO) microinjection] of either the core or shell of the NAc to amplify cue-triggered levels of motivation to pursue sucrose reward, measured with a Pavlovian-Instrumental Transfer (PIT) procedure, a relatively pure assay of incentive salience. Cue-triggered 'wanting' in PIT was enhanced by amphetamine or DAMGO microinjections equally, and also equally at nearly all sites throughout the entire core and medial shell (except for a small far-rostral strip of shell). NAc dopamine/opioid stimulations specifically enhanced CS+ ability to trigger phasic peaks of 'wanting' to obtain UCS, without altering baseline efforts when CS+ was absent. We conclude that dopamine/opioid stimulation throughout nearly the entire NAc can causally amplify the reactivity of mesocorticolimbic circuits, and so magnify incentive salience or phasic UCS 'wanting' peaks triggered by a CS+. Mesolimbic amplification of incentive salience may explain why a particular cue encounter can become irresistibly tempting, even when previous encounters were successfully resisted before.
Opioid peptides and receptors are expressed through out the reinforcement network, placing the opioid system in a key position to modulate this circuit. Experimental data have accumulated over nearly 50 years showing that the opioid system is involved with reinforcement processes. Globally, systemic mu and, to a lesser extent, delta agonists produce positive reinforcement, whereas kappa agonists induce aversion, hallucinations, and malaise. Conversely, mu and delta antagonists suppress the positive reinforcing properties of natural rewards and opiate or nonopioid drugs, whereas kappa antagonists facilitate these effects... Many different modalities of chronic cocaine or psychostimulant treatment have been used to investigate the regulation of opioid receptor expression. Generally, literature in the field suggests an increase in mu receptor gene expression in several brain structures. Levels of mu receptor mRNA were increased in the NAc and rostral cingulate cortex after chronic exposure to cocaine or after cocaine CPP... Chronic exposure to amphetamine increased mu receptor gene expression in the rostral CPu and decreased the expression in the shell of the NAc (393). In the FrCx, mRNA levels for mu receptors were increased or not modified depending on the protocol of drug administration, using a cocaine CPP (210) or chronic binge ( 18 ) paradigm, respectively... Several groups investigated the effects of withdrawal from cocaine or amphetamine on mu receptor transcription and observed either an increase or no change in mRNA levels. Mu receptor mRNA levels were increased in the FrCx after cocaine withdrawal ( 18 ) and in the VTA following withdrawal from amphetamine