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The Neuropharmacology of Hallucinogens V2

BilZ0r

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I just finished this tonight. This is the first draught. I've sent it off to erowid, so let the editing begin

The Neuropharmacology of Hallucinogens

Introduction

What Are Hallucinogens?
In common usage, the word "hallucinogen" has become a catch all for various pharmacologically-differing substances (e.g., cannabinoids, NMDA receptor antagonists such as ketamine, 3,4-methylenedioxymethamphetamine and lysergic acid diethylamide (LSD)). Indeed, such divergent usage can even be found in scientific texts. Without a specific definition, however, a word is essentially meaningless. In this article, the use of the term "hallucinogen" will be in reference to two groups: chemicals that are chemically and pharmacologically similar to mescaline (the phenethylamine hallucinogens (Shulgin & Shulgin, 1991)), and the chemicals that are chemically and pharmacologically similar to psilocin and LSD (the indole or tryptamine hallucinogens (Shulgin & Shulgin, 1997)). These two groups of chemicals, which at their extremes, seem to share no chemical similarities (Fig. 1A cf. Fig. 1F), have shared pharmacological targets and produce similar behavioural effects (discussed later). Hence, it is sensible to group them together.

What is in a name?
Hallucinogens produce effects in the mind so intense, that they have led people to suggest other names for this group such as entheogen (Ruck et al., 1979) and psychotomimetic (Hoffer, 1967). Entheogen is derived from the Greek, enthos, which means “god within” and is in reference to the spiritual and deep effect hallucinogens can have on the mind, while psychotomimetic means “psychosis mimicking”, and refers to the way that hallcinogenic intoxication is similar to schizophrenia and other mental illnesses. These two descriptions illustrate why the study of hallucinogens is important. An understanding how hallucinogens affect thought could not only help explain not only how mental illness affects the mind, but also the nature of consciousness itself.
 
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How do hallucinogens work?

The history of mechanistic hallucinogen research
Once serotonin’s (5-HT) presence was demonstrated in the brain in 1953 (Twarog & Page, 1953) it was not long until the chemical similarity between LSD and 5-HT was noted and in the same year, Gaddum (1953) demonstrated that LSD antagonized the action of 5-HT in peripheral tissues. Soon afterwards two groups independently proposed the hypothesis that the hallucinogenic action of LSD was due to its ability to block central 5-HT receptors (Gaddum & Hameed, 1954; Woolley & Shaw, 1954). This idea held sway, even after it was shown that the brominated LSD analogue BOL, which was a potent 5-HT antagonist, was devoid of hallucinogenic action (Cerketti & Rothlin, 1955; Woolley & Shaw, 1954), that BOL could block the hallucinogenic effects of LSD and that several other LSD analogues, which were weaker 5-HT antagonists, were more potent in regards to their hallucinogenic action (Gogerty & Dille, 1957; Votava et al., 1958). Anden et al., (1968) was the first to suggest that the primary action of hallucinogens was as a 5-HT receptor agonist, and with the body of evidence already mentioned this idea was rapidly accepted by most. Recent evidence from cortical brain slices has shown that hallucinogens are 5-HT receptor partial agonists (Marek & Aghajanian, 1996), although there is still some debate as to whether all hallucinogens are partial agonists (Villalobos et al., 2004).

It was discovered early in research, that hallucinogens of various types reduced serotonin turnover in the brain, and this was mirrored by the fact that systemically applied hallucinogens inhibited cells in the dorsal raphe nucleus (Aghajanian et al., 1970; Aghajanian et al., 1968). Further, it was shown that indole hallucinogens, microiontophoretically applied to the dorsal raphe, inhibited the firing of cells there (Aghajanian et al., 1972; Aghajanian & Hailgler, 1975; de Montigny & Aghajanian, 1977). Indeed, the ability for these chemicals to inhibit raphe cell firing seemed a likely hypothesis for their mechanism of action, as these cells are the source of cortical serotonin and hence inhibiting them could cause changes throughout the brain that seem fitting of an hallucinogen. There were problems with this theory though; systemically applied phenethylamine hallucinogens had a mixed effect of raphe neurons, inhibiting about half, having no effect on some and even exciting others (Aghajanian et al., 1972; Aghajanian & Hailgler, 1975). Phenethylamine hallucinogens had no effect on raphe neurons when applied direct (Aghajanian et al., 1972; Aghajanian & Hailgler, 1975). Furthermore, the effects LSD induces on the raphe were not proportional to the behavioural effects, the effects of the raphe outlasted the behavioural effects and tolerance to LSD-induced behavioural effects was not proportional to the tolerance induced in the raphe (Trulson et al., 1981). Finally it was shown that the effect indole hallucinogens have on the raphe was mediated by 5-HT1A autoreceptors (Trulson et al., 1981), and that non-hallucinogenic compounds can have the same effect (Rogawski & Aghajanian, 1979). Although this makes the idea that hallucinogens mediate their action via inhibiting raphe cell firing extremely unlikely, it is not impossible that lowered 5-HT release in part mediates hallucinogen action, as systemically applied phenethylamine inhibit some raphe neurons (Aghajanian et al., 1972), and decrease 5-HT turnover (Anden et al., 1974).

The first evidence that the hallucinogens acted by the 5-HT2 receptor was the paper by Glennon et al., (1983). This paper, using a drug discrimination task, showed that in rats trained to discriminate the phenethylamine hallucinogen DOM from saline, the DOM stimulus generalized to both indole and other phenethylamine hallucinogens, but not other 5-HT receptor agonists. It was also shown that this stimulus generalization was blocked by the 5-HT2 receptor antagonist, ketanserin. Glennon et al., (1984a) then reported that the affinity of various hallucinogens for 5-HT2 subtypes but not for other receptors, was tightly correlated with the drugs ED50 in human usage and rat drug discrimination experiments (Fig 2). This correlation has been shown several times (Glennon et al., 1986; Glennon et al., 1984b; Sanders-Bush et al., 1988), and along with a large number of agonist/antagonist experiments (reviewed by Nichols, 2004) it is generally agreed that 5-HT2 receptor subtypes are the primary site of action of hallucinogens. As the number of 5-HT receptor subtypes proliferated, the question became which subtype mediated the hallucinogenic action of hallucinogens. LSD binds potently to the 5-HT1A/1B/1D/1E/1F (Hoyer, 1988; Lovenberg et al., 1993b), to the 5-HT2A/2B/2C (Porter et al., 1999) and to the 5-HT5A/5B/6/7 receptors (Matthes et al., 1993; Monsma et al., 1993; Ruat et al., 1993) but does not bind the to the 5-HT3/4 receptors (Gerald et al., 1995; Peroutka & Hamik, 1988). Along side that, is the fact that all of the phenethylamine hallucinogens studied only bind to the 5-HT2A/2B/2C receptors (Adham et al., 1993; Erlander et al., 1993; Lovenberg et al., 1993a; Nelson et al., 1999; Pierce & Peroutka, 1989; Titeler et al., 1988; Zgombick et al., 1992) and hence these are the only shared targets between LSD and the phenethylamine hallucinogens. Seeing that the 5-HT2B receptor is only expressed very weakly in the brain (Pompeiano et al., 1994; Schmuck et al., 1994) it seems that the 5-HT2A/2C receptors are the only possible candidates as the site of hallucinogenic action.

It is likely that the 5-HT2A receptor is the primary site of action for hallucinogens for many reasons. Firstly there is a preponderance of 5-HT2A to 5-HT2C receptors in the neocortex (Pompeiano et al., 1994; Wright et al., 1995). When 5-HT2 receptor antagonists are used to block the stimulus cue of DOI and LSD in drug discrimination studies, there is a tighter correlation between the antagonists’ affinity for the 5-HT2A receptor and there ability to block the interoceptive cue than there is for the 5-HT2C receptor (Fiorella et al., 1995). Schreiber et al., (1994) was able to block drug discrimination using reportedly 5-HT2A but not 5-HT2C selective antagonists. The indole hallucinogen N,N-dimethyltryptamine (DMT) does not produce tolerance to its hallucinogenic effects in humans (Strassman, 1996) and inline with this, in cultured fibroblasts expressing 5-HT2A/2C receptors, the 5-HT2A receptor does not show desensitization to DMT, but the 5-HT2C receptor does (Smith et al., 1998). Finally, in human trials, the indole hallucinogen psilocybin produced “altered states of consciousness” which were blocked by ketanserin, which has an affinity for the 5-HT2A 10-30 times that of the 5-HT2C receptor (Vollenweider et al., 1998).
 
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5-HT2A receptor localization
Given that the 5-HT2A receptor is the site of action for hallucinogens, an attempt to localize the receptor may give insights into how hallucinogens effect consciousness. Early studies attempting to localize the receptor involved in hallucinogen action used halogenated LSD analogues, which presumably had the same non-specific binding pattern as LSD and hence did not report 5-HT2A receptor specifically (Engel et al., 1984; McKenna & Saavedra, 1987; Wong et al., 1987). Most recent studies have used immunocytochemistry to localize 5-HT2A receptors, and generally, their results have been in complete agreement. Jakab and Goldman-Rakic (1998) examined macaque brains and reported dense 5-HT2A receptor immunoreactivity throughout all cortical regions, specifically in the frontal, prefrontal, temporal and occipital cortex. Throughout the cortical sheet there were two intensely stained bands, consisting of layer II and III, and layer V and VI. Most, if not all, pyramidal cells were labeled, especially in the proximal apical dendrites, and many large- and medium-sized interneurons were labeled, while most small-sized interneurons were unlabeled. There were also a small percentage of weakly labeled presynaptic sites, often containing dense core vesicles. Miner et al., (2003) quantified the different locations of 5-HT2A receptors in rat prefrontal cortex using various immunocytometric techniques. Out of 325 identifiable structures, it was reported that 73% of immunoreactive sites were postsynaptic, and the majority of these, extrasynaptic. Twenty-four percent of the labeled profiles were presynaptic, belonged to thin, unmyelinated axons and were often seen to contain dense core vesicles, that is to say, terminals which looked like monoaminergic neurons.

The thalamus is another area where hallucinogens are speculated to work (Lambe & Aghajanian, 2001; Marek et al., 2001) and two studies using in situ hybridization have shows that the reticular and lateral geniculate nuclei as well as the zona incerta of the thalamus all contain 5-HT2A receptor mRNA (Cyr et al., 2000; Pompeiano et al., 1994).
 
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Modern mechanistic hallucinogen research
In cortical slices, the most marked result of 5-HT2A receptor activation is an increase in postsynaptic potentials. In rat piriform cortex pyramidal cells, the phenethylamine hallucinogen DOI and LSD induce inhibitory postsynaptic potentials (IPSPs), by directly exciting GABAergic interneurons (Marek & Aghajanian, 1996). In medial prefrontal cortex (mPFC) pyramidal cells however, 5-HT2A receptor activation, although causing some IPSPSs, mainly causes an increase in the amplitude and especially frequency of spontaneous excitatory postsynaptic potentials/currents (EPSPs/EPSCs), with a small effect on electrically evoked EPSPs, especially in the later phases of the EPSP (Aghajanian & Marek, 1997; Aghajanian & Marek, 1999; Marek & Aghajanian, 1999; Marek & Aghajanian, 1998). The cells that were most excited were layer V pyramidal cells. Areas where applying 5-HT to the cortical slices produced the most robust EPSPs when recording from layer V pyramidal cells closely matches the distribution of 5-HT2A receptor, i.e. layer I and especially layer Va. This in vitro work is mirrored by the fact that DOI induces an increase in extracellular mPFC glutamate in awake behaving animals, as measured by in vivo microdialysis (Scruggs et al., 2003). Also, in two different human trials, psilocybin induced a large increase frontal cortex metabolism with more modest increases in other cortical and subcortical areas (Gouzoulis-Mayfrank et al., 1999; Vollenweider, 2001).

The EPSPs induced by 5-HT activating the 5-HT2A receptor in mPFC pyramidal cells are Ca2+ and tetrodotoxin sensitive. The EPSPs and are inhibited by classical presynaptic inhibitors like the group II metabotropic glutamate receptor (mGluR2) agonists (Marek et al., 2000) and ì-opioid receptor agonists (Marek & Aghajanian, 1998). These facts together indicate that the EPSPs are not a product of postsynaptic 5-HT2A receptor activation. On the other hand, the increase in EPSPs does not seem to be due to an increase in afferent neuronal firing, as no cells could be recorded having action potentials when the 5-HT was applied (Aghajanian & Marek, 1997). As mentioned above, if the slice was perfused with a Ca2+ free buffer, then all 5-HT-induced increase in evoked and spontaneous EPSPs were blocked, but if Ca2+ was replaced with Sr2+, the 5-HT induced increase in spontaneous EPSPs returned. Previous experiments had only briefly looked at the effect that 5-HT2A receptor activation has on evoked EPSPs. Here it was noted that the increase in evoked currents caused by 5-HT2A receptor activation induced by DOI were found largely after electrical stimulation (Fig. 3) (Aghajanian & Marek, 1998; Aghajanian & Marek, 1999). Both the spontaneous and evoked EPSPs had all the hallmarks of “asynchronous” transmitter release; a form of release that happens after the action potential has caused classical synchronous or phasic transmitter release, that can be evoked in solutions where Ca2+ is replaced with Sr2+ (Kirischuk & Grantyn, 2003; Rumpel & Behrends, 1999). Thus, it was hypothesized that hallucinogens had their effect by increasing asynchronous transmission via presynaptic 5-HT2A receptors on glutamatergic terminals.

Marek et al., (2001) lesioned the medial thalamus and amygdala of rats in an attempted to define the location and source of the 5-HT2A receptors which were critical for the ability of 5-HT2A receptor agonists to increase spontaneous EPSPs in the layer V of the mPFC. NMDA was infused by cannula to intact animals to lesion the midline and intralaminar nuclei of the thalamus, and using radiofrencies, the basolateral nucleus of the amygdala was lesioned. These nuclei were chosen as the laminar pattern of the projections of these nuclei closely matches the distribution of 5-HT2A receptors in the mPFC (Bacon et al., 1996; Berendse & Groenewegen, 1991). Roughly 18 days after the damage, the animals were sacrificed and cortical slices were taken to insure the accuracy of the lesion, electrophysiological work was done and 5-HT2A, ì-opioid and mGluR2/3 receptors were imaged via autoradiography. It was reported that the thalamic lesions were largely specific to the basolateral, midline and intralaminar nuclei, and where they weren’t, the damage spilled onto thalamic nuclei with no input to layer V. In cortical slices where the midline and intralaminar nuclei were lesioned, there was no change in spontaneous and AMPA induced EPSPs recorded in mPFC pyramidal neurons, but there was 60% decrease in the frequency of 5-HT induced EPSPs. Lesions of the amygdala had no effect on 5-HT induced EPSPs. Lesions to the thalamus lead to a decrease in mGluR2/3 (~20%) and ì-opioid receptor binding (20-50%) throughout the layers of the cortex, but an increase in 5-HT2A receptor binding. These results, although not conclusive, give weight to several ideas. For one, the dramatic decrease in 5-HT2A mediated EPSPs in mPFC pyramidal cells caused by midline and intralaminar lesions indicate that these nuclei, but not the basolateral nucleus of the amygdala, are a major source of the cortical afferents responsible for the EPSPs. It had previously been shown that mGluR2, and ì-opioid receptor activation inhibits 5-HT2A mediated EPSPs, the decrease in their density after thalamic lesioning indicated that some these receptors were located on the thalamocortical neurons. Finally, the fact that thalamic lesions caused a significant decrease in EPSP frequency yet caused in increase in 5-HT2A receptor density, indicates that there is a very limited amount, if any 5-HT2A receptors on midline and intralaminar neurons. Therefore it is very unlikely that 5-HT2A receptors on the presynaptic terminals of thalamocortical neurons are responsible for the increase in EPSPs in mPFC pyramidal cells caused by 5-HT2A receptor agonists.

These results, in synthesis with other research, bring about somewhat of a paradox: a presynaptic action of 5-HT2A receptors, on presynaptic terminals devoid of 5-HT2A receptors. One way to avoid the paradox would be a retrograde messenger. Conceivably 5-HT2A receptor activation on the postsynaptic terminal could lead to the generation of a retrograde messenger, which could activate the presynaptic terminal. This possibility gained more ground after Lambe and Aghajanian (2001) showed the similarity between the EPSPs induced by 5-HT2A receptor activation and antagonists of Kv1.2 and possibly Kv3 containing potassium channels, channels which are blocked by the retrograde messenger arachidonic acid (Poling et al., 1995; Poling et al., 1996). It was reported that there was a correlation between the affinity of various potassium channel antagonists for Kv1.2 containing channels and their ability to induce EPSPs in layer V mPFC pyramidal cells. There were many similarities between the EPSPs induced by the Kv1.2 antagonist á-dendrotoxin (DTX) and 5-HT. The EPSP traces recorded looked similar in both amplitude and frequency, they were induced most strongly in the same layers of the cortex and they were inhibited by ì-opioid agonists and thalamic lesions. Importantly, 5-HT induced EPSPs were only slightly additive with DTX induced EPSPs, and when DTX was added with tetraethylammonium (TEA), a general potassium channel antagonist, 5-HT induced EPSPS were nearly completely occluded (~95%). To exclude the possibility of a ceiling effect, it was shown that nicotine induced EPSPs were completely additive with DTX induced EPSPs. It is believed that the other potassium channel that were blocked by TEA are Kv3.2 containing channels, as it is highly expressed in thalamic neurons (Weiser et al., 1994) and its’ expression is highly decreased by thalamic lesions (Moreno et al., 1995). Interestingly, the Kv1.2 and Kv3.2 are the only two potassium channels which have been shown to be inhibited by arachidonic acid (Poling et al., 1995; Poling et al., 1996). Arachidonic acid can be produced via the action of phospholipase A2 (PLA2), an enzyme that 5-HT2A receptor activation is known to stimulate along with its classical linkage to phospholipase C (PLC) (Kurrasch-Orbaugh et al., 2003). Therefore, it was hypothesized that the EPSPs induced by 5-HT2A receptor agonists are caused by the activation of postsynaptic 5-HT2A receptors, the production of arachidonic acid by PLA2, and its action on presynaptic potassium channels. This raises an interesting problem; although hallucinogens’ behavioral potencies are tightly correlated with their 5-HT2A receptor affinity, there seems to be no correlation between behavioral potencies and their ability to stimulate second messenger production (Nichols, 2004). For example, LSD is approximately 20 times more potent than the hallucinogenic amphetamine DOB in drug discrimination experiments (Glennon et al., 1984a). But in mouse fibroblast cell line NIH3T3, DOB is slightly more potent than LSD at inducing arachidonic acid release, and only around 7 times less potent than LSD at stimulating PLC-mediated inositol phosphate production. The 5-HT2A receptor pathway is not completely defeated though, as it has been shown to be strongly linked to phospholipase D (PLD) in a ADP-ribosylation factor-dependent manner (Mitchell et al., 1998; Robertson et al., 2003). Unfortunately, no studies have looked at the ability of hallucinogens to activate PLD.

While there is an overarching theme that hallucinogens act by increasing excitatory cortical transmission, two papers challenge this classical stance with evidence that 5-HT2A receptor agonists inhibit N-methyl-D-aspartate (NMDA) receptor mediated currents (Arvanov et al., 1999a; Arvanov et al., 1999b). It was reported that in layer V pyramidal cells in mPFC slices, DOB at low concentrations (0.01-1µM) caused an increase in the currents induced by perfusion with 10µM of NMDA. On the other hand at high concentrations (>1µM) produced a Ca2+/calmodulin kinase II dependent blockade of NMDA-induced currents. The potentiating effect of DOB was Ca2+ sensitive, and presumed to be of presynaptic origin, in line with the above research. The AMPA receptor antagonist CNQX was added, to block the effect of any spontaneously released glutamate, and it was then seen that even low concentrations of DOB would decrease NMDA-induced currents, with an IC50 of 130nM. This was repeated with LSD, and it was shown to have an IC50 of 9nM. The authors stated that the concentration of LSD needed to induce an enhancing effect on NMDA induced currents was >300nM and far above the 10-20nM plasma concentration found in recreational use (Aghajanian & Bing, 1964; Hawks & Chiang, 1986), and hence unphysiological. However, it should be noted that although potentiation of NMDA receptor-mediated currents seems unlikely to be a cause of the hallucinogenic action of 5-HT2A receptor agonists, that does not say they can not act by causing glutamate release as described above. Indeed, if hallucinogens worked solely by inhibiting the NMDA receptor in some fashion, one would expect hallucinogens to generalize to NMDA-receptor antagonists in drug discrimination experiments, but only few do, and to a very small extent (Jones et al., 1998; West et al., 2000). Furthermore, if the NMDA-receptor inhibition theory was the complete explanation of hallucinogen action, it seems surprising that mGluR2/3 agonists, which inhibit 5-HT2A receptor-mediated glutamate release in vitro, also inhibit behavioral aspects of hallucinogens such as head shakes (Klodzinska et al., 2002) and drug-induced stimulus control (Winter et al., 2004). However it seems possible that hallucinogens work by both increasing glutamate release and inhibiting NMDA-receptors. Indeed, if hallucinogens have varying abilities to inhibit NMDA-receptors and induce EPSPs in cortical pyramidal cells, it could explain how different hallucinogens seem to produce the wide ranging subjective effects reported by recreational users (Shulgin & Shulgin, 1991; Shulgin & Shulgin, 1997).
 
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Another possibly important effect of hallucinogens is their ability to alter the firing of the locus coeruleus (LC). Systemic administration of either phenethylamine or indole hallucinogens to anaesthetized animals causes a 5-HT2A receptor dependent decrease in the spontaneous activity of the LC, but an increase in activity evoked by sensory stimulation (Aghajanian, 1980; Rasmussen & Aghajanian, 1986; Rasmussen et al., 1986). This effect was shown to be mediated by 5-HT2A receptors extrinsic to the LC, as hallucinogens microiontophoretically applied to LC cell bodies did not produce this effect. The ability of 5-HT2A receptor agonists to inhibit LC firing was blocked by local administration of GABAA antagonists and the stimulatory action of hallucinogens on LC activity was blocked by NMDA receptor antagonists, but not non-NMDA glutamate receptor antagonists (Chiang & Aston-Jones, 1993). The LC is the major source of the catecholamine neurotransmitter noradrenaline (NA) and has been likened to a “novelty detector” due to its increased activity in response to novel stimuli. The release of NA also seems to gate sensory information to a degree, and to increase the signal to noise ratio, by inhibiting basal neuronal activity but increasing responses to sensory stimulation (reviewed by Sara et al., 1994; Woodward et al., 1991). Interestingly, the laminar distribution of the á1-adrenoreceptor closely matches that of the 5-HT2A receptor (Palacios et al., 1987), and NA induces a á1-adrenoreceptor dependent increase in EPSPs in layer V mPFC cells in a similar fashion to 5-HT (Marek & Aghajanian, 1999). It seems possible then that the increase in sensory evoked LC firing could produce some of cognitive effects induced by hallucinogens, such as ordinary objects appearing fascinating.
 
Putting it all together

Unfortunately, the majority of recent research into hallucinogens has focused on isolated brain regions, specifically using cortical brain slices. This preparation is usually devoid of the spontaneous activity seen in the neocortex of an intact animal. Although one can replicate the slow spontaneous rhythmic activity seen in vivo if the bathing medium closely matches the extracellular ionic composition seen in the brain in situ, one can not replace the cortical and subcortical inputs lost when the section is taken from the brain (Sanchez-Vives & McCormick, 2000). Indeed, these subcortical and especially the thalamic inputs seem especially important when it is hypothesized that thalamic projections are the neurons that supply the increased excitatory input in response to hallucinogens. Furthermore, cortical input from the LC and the raphe nuclei are lost. Yet one can attempt to synthesize the research done and put a larger picture together.

As reviewed above, the mPFC cells that seem to be excited most by application of 5-HT2A receptor agonists are layer V pyramidal cells. In a theory reviewed by Jones (2002), layer V pyramidal cells have been implicated in the binding of separate sensory stimuli into a discrete conscious event. Major sensory stimuli often lead to high frequency, 20-50Hz, oscillatory firing between thalamic relay cells and the area of cortex that they project to. These oscillations are dependent on thalamo-cortico-thalamic circuits, and are believed to code the conscious recognition of the stimuli (Golshani & Jones, 1999; Steriade & Amzica, 1996). This loop is created by thalamic rely “core” cells in specific thalamic nuclei activating layer VI pyramidal cells, and their projections back to the core cells. This loop system would stay in the cortical columns originally activated by the thalamic relay cell, if it did not also activate layer V pyramidal cells. Layer V cells have diverse intracortical projections and importantly, project to many non-specific thalamic nuclei, and hence would “decide” which distant cortical areas could be activated by the original stimulus. This way associated stimuli could be bound to form synchronous activity across the cortex. By activating layer V pyramidal cells’ coritco-cortical and corticalthalamic projections, hallucinogens could cause the spread of high-frequency oscillations to areas that would not normally be activated. In sensory cortexes this could produce effects such as the hallucinations and synesthesia. In the frontal cortex the spreading of high frequency oscillations could result in mood changes and alteration to ego perception.

Other large scale theories of hallucinogen action involve their potential action on the thalamic reticular nucleus (TRN). The TRN is seen to some way works as a filter for transmission of information from the thalamus to the cortex (reviewed by Guillery & Harting, 2003). TRN neurons are nearly exclusively GABAergic, and can switch thalamic relay cells from tonic firing mode to burst firing mode by hyperpolarizing the cell and activating low threshold Ca2+ channels. In tonic mode, relay cells can accurately transmit sensory information because they can firing at rates above 100Hz, but cells in burst fire mode can not fire faster than 15Hz and hence the integrity of information is lost (Kim & McCormick, 1998; McCormick & Feeser, 1990). In a model proposed by Vollenweider and Geyer (2001) activation of 5-HT2A receptors on TRN neurons could activate them in the same way that 5-HT2A receptors activate GABAergic neurons in the cortex, and hence decrease the ability of the TRN to gate information flow effectively.

This author notes that the zona incerta of the thalamus also expressed 5-HT2A receptors (Pompeiano et al., 1994), and projects GABAergic neurons to higher-order thalamic relay cells (Bartho et al., 2002). The zona incerta, unlike most thalamic nuclei receives the its cortical input from almost exclusively layer V pyramidal cells (Bartho et al., 2002; Mitrofanis & Mikuletic, 1999), and hence this seems like another way which hallucinogens could effect cortical function.

Along with any cortico-thalamo-coritcal action of hallucinogens, their action in potentiating LC firing in response to sensory stimuli will also be activating the cortex, possibley in a synergistic fashion to 5-HT2A receptor stimulation. The idea that hallucinogens work at least in part by inhibiting firing of cells in the raphe nuclei was once seen as a major hypothesis, but now seems unlikely, thought it may in some way modulate the subjective effect hallucinogens produce.

Unfortunately, in the end, most of these theories are more speculation, than hypotheses based on empirical observations, as there is only a very limited amount of research on hallucinogens and most of that research is limited to in vitro electrophysiology of cortical cells. Future research needs to look into the effect that hallucinogens have on the thalamus and thalamocortical oscillations. Indeed, when the intracellular cascade responsible for hallucinogen action seems unknown, it is hard to imagine science being able to explain the much more complicated details of hallucinogens’ action on consciousness.
 
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Yeah, nice work! That list of references is enormous, how much time did this cost you..?
 
Nice to see someone is doing some interesting "research" and writing it up. This is huge work for one and you covered such a huge and unknown topic wideranged.

Keep the spirit!

Big thanks from here also!:D
 
I'd say it took me three months on and off. It's preety much the only piece of serious research and writting I've been during that time. Good, it seems so much shorter once you've finished it. To put that time in perspective, not counting the 10 hours of research, I wrote the original Neuropharmacology of Hallucinogens at erowid in the course of one day.

If anyone wants a printable version, or wants to see the figure legends they should download the *.doc from here.

Anyways, Im off to see my parents, I haven't seen them for a year, I'll see you guys on Monday.
 
Excellent work, man! You fixed pretty much everything that I criticized about your February/March version of the paper. I commend you for doing something that I was too lazy/overworked/strung-out to even make an attempt at (by the way, sorry about not editing your previous version). Mad props!

There are a few minor edits that I suggest (sorry that they are out of order):

Therefore it is very unlikely that 5-HT2A receptors on the presynaptic terminals of corticothalamic neurons are responsible for the increase in EPSPs in mPFC pyramidal cells caused by 5-HT2A receptor agonists.

I think you mean "thalamocortical" instead of "corticothalamic."

On top of those sites, using autoradiography, Marek et al., (2001) found the densest distribution of 5-HT2A receptors in the midline and intralaminar nuclei, a group of nuclei whose cortical projections closely match the laminar distribution of 5-HT2A receptors (Berendse & Groenewegen, 1991).

I think that they found the densest distribution in the cortical efferents of the neurons in the nuclei, rather than in the nucei themselves. Then again, I haven't read that article in about a year.

The 5-HT2A receptor pathway is not completely defeated though, as it has been shown to be strongly linked to phospholipase D (PLD) in a ADP-ribosylation factor-dependent manner (Mitchell et al., 1998; Robertson et al., 2003). Unfortunately, no studies have looked at the ability of hallucinogens to activate PLD.

I would reword the part in bold so that it doesn't imply that the 5-HT2A receptor is an unlikely candidate for mediating the psychoactive effects of hallucinogens. It seems pretty certain that the receptor itself does mediate those effects, but the uncertainty lies in determining which downstream signaling cascade is most important (IMHO its probably some weird combinatiorial shit, but thats pure speculation). Perhaps you should say "However, the 5-HT2A receptor has been shown to be strongly linked…"

Also, in some places, you say mGluR2 instead of mGluR2/3 when referring to physiological experiments using drugs. To my knowledge (again, it's been about a year since I read most of this literature), none of the agonists/antagonists used in these experiments are selective enough to warrant leaving out mGluR3 as a possible mechanistic candidate (unless the receptor is not expressed in the region in question).

I'll look it over again to see if I find other little nitpicky things that should be modified. Again, good job!
 
Thanks for those points 5-HT2. I agree with your point about a combination of 2nd messenger sysmtes. I perhaps wonder if it was the ratio of PLA2/PLC that denoted potency. With a higher ratio meaning more potency. Perhaps PLC activation inhibits EPSPs (increase calcium influx, PKC activation, channel phosphorylation and inhibition), which PLA2 activation potentiates EPSPs... LSD has the highest PLA2/PLC ration....

Your first correction is definatly right, your 2nd one is too (I was looking at that one last night going 'hang on, they didn't do that did they').

Yeah, I've thought about that 3rd one... I'll do something about it, but I don't know quite what.

I've left the mGluR stuff like it was in the original papers... initially I had the whole think mGluR2/3 but some of them use mGluR1/2 ones as well (I think)... but I'll check that one.

P.S. Last time we talked on this subject, you were reading the Ion Channels of Excitable Membranes.... Now I'm reading it...
 
It's posts like this that make me brag about Bluelight and PD to my friends. :) Well done.
 
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