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Psychedelics

The 5-HT2 receptor family plays a crucial role in regulating the activity of amygdalar microcircuits and projections, modulating both excitatory and inhibitory neurons, in parallel to what is seen in the cerebral cortex. An electron microscopy immunocytochemical study showed localization of 5-HT2A receptors in both the parabrachial and paranigral regions of the VTA, with label identified primarily as dendrites and unmyelinated axons . Dendrites commonly showed 5-HT2A receptor immunoreactivity colocalized with tyrosine hydroxylase. Thus, 5-HT2A receptor activation may directly affect local dendritic release of dopamine as well as release of dopamine in mesocortical and mesolimbic terminal fields.

By contrast, when these investigators used a bath solution with an ionic composition that closely mimicked brain interstitial fluid, spontaneous rhythmic oscillations appeared that could be continuously maintained and were nearly identical to those observed in vivo. Slow oscillation was most robust and occurred first in or near cortical layer V, after a short delay by activity in deeper layers. The activity maximum in layer V was always larger and persisted longer than in any other layers and seemed to be initiated in layer V as an excitatory interaction between pyramidal neurons that propagated through the neocortex. These workers suggest that the basic operation of cortical networks is the generation of self-maintained depolarized states that are tightly regulated through interaction with local GABA/GABAergic neurons and intrinsic membrane conductances. They suggest that the ability of cortical networks to generate persistent and recurring activities even in the absence of ongoing subcortical inputs may be a process that underlies perceptual influences on sensory information processing. A second explanation for the increase in cortical glutamate after hallucinogens was offered by Lambe and Aghajanian , who suggested that 5-HT2A receptor activation on postsynaptic cells might lead to release of a retrograde messenger.

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Although high receptor density was seen in all laminae of the neocortex, the highest binding was observed in the claustrum. Similarly, rat brain autoradiography using the 5-HT2A/2C agonist R-(–)-DOI confirmed the highest binding in the claustrum as well as the frontal cortex . The very high density of 5-HT2A receptors in the claustrum indicated that further inquiry into the structure and function of the claustrum was warranted for this review. The claustrum lies at the confluence of a large number of simple loops with the cortex, so it is natural to ask whether the claustrum might be a previously unrecognized target for psychedelics. Direct microiontophoretic application of the drugs onto LC cell bodies did not have the same effect, indicating some indirect effect of the drugs.

Lee et al. presented evidence that 5-HT2A receptors are upregulated after contusional SCI in rats. They studied the monosynaptic connection between primary muscle afferents and α motoneurons using the Hoffman reflex (H-reflex). The H-reflex is elicited by electrical stimulation of a peripheral nerve that innervates the muscle from which the reflex is recorded. The stimulus generates a short-latency M-wave by direct stimulation of the motor axons innervating the muscle, as well as a long latency H-wave (a measure of the α motoneurons activated by Ia afferents). The authors had previously observed (Lee et al., 2005) increased H-reflex amplitude 4 weeks after contusional SCIs of different severity.

Autoradiography in the rat brain using R-(−)-DOI revealed highest binding in the claustrum and the frontal cortex . Other autoradiographic and in situ hybridization studies have observed high densities of 5-HT2A receptors and transcripts in the cortex (Blue et al., 1988; Mengod et al., 1990; Wright et al., 1995). In addition to direct receptor effects, Cozzi et al. have demonstrated that DMT, DPT, and N,N-diisopropyltryptamine also inhibit the serotonin transporter in human platelets, with KI values of 4 μM, 8.88 μM, 0.59 μM, and 2.3 μM, respectively. They also were inhibitors of rat vesicle monoamine transporter 2 expressed in Sf9 cells, where they were somewhat less potent.

The concentration of the unmetabolized parent 25I-NBOMe in the urine was 7.5 ng/ml, whereas the desmethyl metabolite was 600 ng/ml. This metabolite and the two other minor metabolites were not present in the urine in the absence of prior enzymatic treatment, indicating that they were all glucuronidated. Many Psychedelics are classified under Schedule I of the United Nations Convention on Psychotropic Substances of 1971 as drugs with the greatest potential to cause harm and no acceptable medical uses. In addition, many countries have analogue laws; for example, in the United States, the Federal Analogue Act of 1986 automatically forbids any drugs sharing similar chemical structures or chemical formulas to illicit or prohibited substances if sold for human consumption. Psilocin (4-HO-DMT) is the dephosphorylated active metabolite of the indole alkaloid psilocybin and a substituted tryptamine, which is produced in over 200 species of fungi. Of the Classical psychedelics psilocybin has attracted the greatest academic interest regarding its ability to manifest mystical experiences, although all psychedelics are capable of doing so to variable degrees.

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