Please cite this article in press as: Halberstadt AL. Recent advances in the neuropsychopharmacology of serotonergic hallucinogens. Behav Brain Res (2014), http://dx. doi. org/10. 1016/j. bbr. 2014. 07. 016ARTICLE IN PRESSG Model BBR 9035 1-22 12 A. L. Halberstadt / Behavioural Brain Research xxx (2014) xxx-xxx of neurophysiological responses to psilocybin, with PET measuring effects on neuronal ﬁring (reﬂected by changes in metabolic activity and [18F]FDG uptake) and f MRI measuring effects on cortical oscillatory activity. Alternatively, it is possible that the hemodynamic changes induced by psilocybin are unrelated to its hallucinogenic effects. Psilocybin and its O-dephosphorylated metabolite psilocin activate the 5-HT 1Areceptor in vivo [20,166], and 5-HT 1Aagonists are known to alter hemodynamic measures in cingulate cortex and other brain regions [341]. 5. 2. 3. Interactions of the PFC with other structurescortical and subcortical sites Since most of the projections from PFC to cortical and sub-cortical regions originate from pyramidal neurons in deep layers V-VI, hallucinogens could potentially profoundly alter how the PFC regulates activity in downstream regions. Indeed, there is some evi-dence that hallucinogens excite efferent projections from the PFC. For example, DOI activates serotonergic neurons in the dorsal raphe nucleus indirectly by exciting the projection from m PFC [303,342]. Similar ﬁndings have been reported for the projection to the ventral tegmental area [303]. Additionally, a recent study by Mocci et al. [284], Mocci et al. [284] assessed whether 5-HT 2Areceptors modu-late the activity of the projection from m PFC to nucleus accumbens (NAc). Retrodialysis of DOI into the m PFC increased the extracel-lular level of Glu in the NAc by 174%, indicating that DOI activates NAc-projecting m PFC neurons. According to another report, 5-HT 2A receptors excite cortico-cortical projections originating from m PFC [343]. In that study, microiontophretic application of 5-HT excited pyramidal neurons with commissural/callosal projections. Because 5-HT had no effect in the presence of the selective 5-HT 2Aantag-onist MDL 11,939, the most reasonable interpretation is that the excitation is mediated by 5-HT 2Areceptors, but this needs to be conﬁrmed using a selective agonist. The PFC exerts top-down executive control over processing in temporal and parietal cortices [344-347]. As shown by FDG-PET imaging, psilocybin increases absolute cerebral metabolic rates in the parietal and temporal cortices [54,348]. It is conceivable that hallucinogens could enhance the activity of neuronal ensembles in those regions by driving the ﬁring of glutamatergic projections from the PFC. Moreover, 5-HT 2Areceptors are expressed at high to mod-erate densities in temporal and parietal cortical areas [349-353], so the inﬂuence exerted by the PFC would act in concert with any local response induced by hallucinogens. Hallucinogenic drugs produce body image changes, derealization, and depersonalization [354,355], effects that are speciﬁcally linked to altered activity in fronto-parietal cortex and occipital cortex [356]. This is not sur-prising because the posterior parietal cortex is part of the dorsal visual stream and generates multiple egocentric representations of space [357-359]. Likewise, hallucinogens enhance memory recall [360], sometimes producing extremely vivid recollections. Since the medial temporal lobe plays a crucial role in the storage and recall of autobiographical memories [361], it has been proposed that hallucinogen effects on memory recall may be linked to acti-vation of this region. The amygdala, which is involved in generating fear responses and processing the emotional context of sensory input [362], is another subcortical structure potentially affected by changes in the activity of m PFC projections. An f MRI BOLD study in healthy volunteers revealed that psilocybin (0. 16 mg/kg p. o. ) reduces activation of the amygdala by negative and neutral pictures, and the BOLD signal change was inversely correlated with reports of increased positive mood [363]. Likewise, an electrical neuroimag-ing study conducted by the same group found psilocybin impairs processing of facial expression valence in the amygdala and other limbic regions [364]. In healthy subjects, there is an inverse correlation between the density of m PFC 5-HT 2Abinding and theresponsiveness of the amygdala to threatening stimuli [365], sug-gesting processing in the amygdala is regulated by 5-HT 2Areceptors in m PFC. Hence, the ability of psilocybin to reduce emotional pro-cessing in the amygdala could potentially be a consequence of increased inhibitory top-down control from the PFC [364]. The IL subregion of m PFC impairs fear conditioning by inhibit-ing central amygdaloid nucleus output neurons, which project to brainstem and hypothalamic sites responsible for expressing fear responses [366]. Although it was not initially clear how m PFC inhibits the amygdala because the projection is glutamatergic [367,368], the mechanism is now believed to involve excitation of GABAergic neurons in the intercalated nuclei of the amygdala [369-371]. Psilocybin and TCB-2 have been shown to facilitate the extinction of fear conditioning in C57BL/6J mice [372,373], which could be a consequence of activating the projection from IL to the intercalated nuclei. However, it has not been ruled out that psilo-cybin and TCB-2 are acting directly in the amygdala; excitatory and inhibitory neurons in the amygdala express 5-HT 2Areceptors [374,375], and DOI and other 5-HT 2Aagonists act locally to produce direct excitatory and indirect inhibitory effects in the amygdala [376-378]. 5. 2. 4. Interactions of the PFC with other structures: effects on cortico-striato-thalamo-cortical (CSTC) loops It has been theorized that hallucinogen-induced altered states may arise in part through effects on cortico-striato-thalamo-cortical (CSTC) feedback loops [348,356,379]. CSTC loops are parallel, anatomically segregated circuits relaying information between the basal ganglia, thalamus, and cortex [380,381]. In each circuit, projections from multiple cortical regions converge in spe-ciﬁc subregions of the striatum. The striatum, in turn, projects to the pallidum, which sends feedback to the cortex via the thala-mus. In this regime, the thalamus serves as a ﬁlter that restricts or gates the ﬂow of sensory and cognitive information to the cortex. There has been some debate about the exact number of CSTC loops [382,383], but at least ﬁve have been putatively identiﬁed, each serving a different function. The limbic loop, for example, receives input from the temporal lobe, ACA, and medial orbitofrontal cortex, and links the ventral striatum (including NAc, lateral caudate, and ventromedial putamen), ventral pallidum (VP), and mediodorsal thalamus. Vollenweider and Geyer [356] have proposed that psilo-cybin reduces thalamic ﬁltering by activating 5-HT 2Areceptors in the limbic CSTC loop, resulting in excessive stimulation of frontal regions, hyperfrontality, and symptoms such as sensory overload and hallucinations. Although involvement of CSTC loops in the effects of hallucino-gens is admittedly speculative, it does receive some support from the fact that hallucinogens disrupt PPI in humans and in animal models [90,178,179,182,183,384]. Importantly, PPI is regulated by components of the limbic CSTC loop, including m PFC, NAc, and VP [385]. The VP appears to be responsible for the disruption of PPI by hallucinogens [386]. DOI disrupts PPI when infused directly into the VP, but not when infused into the NAc. Likewise, infusion of M100907 into the VP prevents systemically administered DOI from disrupting PPI. It is important to note, however, that the PPI-disruptive effects of DOI are partially blocked when M100907 is infused into the dorsal striatum, so it is not entirely certain that the VP is the only site of action for DOI. 5. 3. Visual cortex Hallucinogens produce profound effects on visual perception. This includes visual distortions such as micropsia or macropsia, kinetopsia, pareidolias, hyperchromatopsia, dysmorphopsia, and polyopia-like trailing phenomena; elementary imagery composed of multicolored geometric patterns; and complex imagery with947 948949950951952953954955 956 9579589599609619629639649659669679689699709719729739749759769779789799809819829839849859869879889899909919929939949959969979989991000100110021003100410051006100710081009101010111012 10131014101510161017101810191020102110221023102410251026102710281029103010311032 1033 10341035103610371038103910401041104210431044104510461047104810491050105110521053105410551056105710581059106010611062106310641065106610671068 1069 1070 1071107210731074