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 A. L. Halberstadt / Behavioural Brain Research xxx (2014) xxx-xxx 9 does not evoke tolerance in man, even after an intramuscular (IM) dosage regimen of 0. 7 mg/kg twice daily for ﬁve days [227]. More recently, Strassman et al. [228] found there was no toler-ance to the subjective effects of DMT in volunteers who received four intravenous (i. v. ) injections of 0. 3 mg/kg at 30 min inter-vals. In vitro experiments have shown that exposure to LSD or DOI desensitizes 5-HT 2Aand 5-HT 2Creceptors in transfected cell lines [108,229]. However, after exposure to DMT, 5-HT 2Creceptors showed desensitization but there was no change in the response to 5-HT 2Aactivation [108]. These observations suggest that DMT fails to induce tolerance because it does not desensitize the 5-HT 2A receptor. 5. Hallucinogen effects on neuronal activity 5. 1. Locus coeruleus The locus coeruleus (LC), located in the dorsal pons, is the source of almost all noradrenergic projections in the CNS. LC neurons are responsive to sensory stimuli, especially of a novel or arousing nature, and the ﬁring of LC neurons is markedly increased by nox-ious stimulation (reviewed by: [230] ). Intravenous administration of mescaline (2 mg/kg), LSD (5-10 /H9262g/kg), DOM (20-80 /H9262g/kg), DOB (50-100 /H9262g/kg), or DOI (16-50 /H9262g/kg) profoundly enhances the responses of LC neurons to sensory stimuli while simultaneously depressing their spontaneous ﬁring [231-234]. After administra-tion of hallucinogens, the enhancement of responsiveness is so pronounced that even innocuous sensory stimuli normally inef-fective at driving LC cell ﬁring will evoke a response [231]. The ability to produce opposite effects upon spontaneous and sensory-evoked LC ﬁring is a speciﬁc property of LSD-like drugs, as other pharmacological agents that alter the basal activity of LC cells (e. g., (+)-amphetamine, clonidine, desipramine, or idazoxan) do not alter evoked LC ﬁring [231,232,234]. The observation that hallucinogens decrease the spontaneous activity of LC cells is supported by the work of Done and Sharp [235] who found that DOI and DOB lower the concentration of NE in hippocampal dialysates, which indicates those compounds decrease tonic NE release from LC projections. The effects of hallucinogens upon LC unit activity appear to be mediated by 5 HT2Areceptors. The 5-HT 2antagonists ketanserin and ritanserin have been shown to block the actions of hallucino-gens in the LC [232,233]. Furthermore, Szabo and Blier [236] found that the ability of DOI to alter the activity of LC neurons is abol-ished by M100907. Nonetheless, 5-HT 2Areceptors are sparsely distributed within the LC (e. g., [237] ), and application of the 5-HT2A/5-HT 3agonist quipazine or hallucinogens such as DOI directly into the LC does not mimic the effects of their systemic administra-tion [232-234,238]. Intravenous administration of mescaline and LSD also had no effect on the ability of locally applied acetylcholine, glutamate (Glu), or substance P to excite LC neuronal activity [231]. Presumably then, hallucinogens act upon LC afferents, altering the ﬁring of LC cells indirectly by modulating the activity of one or more input pathways. Chiang and Aston-Jones [234] reported that the decrease in LC spontaneous ﬁring induced by DOI could be blocked by the GABA Areceptor antagonists bicuculline and picrotoxin, whereas the ability of DOI to enhance sensory-evoked LC responses was blocked by the NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid but not by the AMPA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Thus, hallucino-gens appear to tonically activate GABAergic input to LC and concomitantly facilitate glutamatergic sensory input. It is likely that the nucleus prepositus hypoglossi (Pr H), an area known to provide direct GABAergic inhibitory input into the LC [239,240], mediates the hallucinogen-induced inhibition of spontaneous LC activity. Although one group reported that microinjection of quipazine directly into the Pr H did not alter LC unit activity in the rat [238], subsequent work conﬁrmed that DOI depolarizes Pr H neurons [241]. Moreover, electrolytic lesions of Pr H signiﬁcantly attenuate the ability of systemic quipazine injections to reduce the frequency of LC unit discharge [238]. This strongly implicates the Pr H or one of its afferents as the site through which 5-HT 2Aagonists modulate spontaneous LC ﬁring. The identity of the speciﬁc LC afferent(s) responsible for the hallucinogen-induced facilitation of LC gluta-matergic sensory input is currently unknown. Although the nucleus paragigantocellularis in the ventrolateral rostral medulla is a major source of excitatory input into the LC [234,242], the ability of somatosensory stimuli to excite the LC is unaffected by lesions of nucleus paragigantocellularis [243]. The LC also receives excitatory input from the prefrontal cortex (PFC), both directly and indirectly [244-246], and the excitatory effects of hallucinogens on the LC may be mediated by those pathways. As will be discussed below in Section 5. 2, hallucinogens increase the ﬁring of PFC projection neurons. The LC projects heavily to cortex, where there is overlap between the distribution of /H92511-adrenoceptors and 5-HT 2Arecep-tors [247]. Interestingly, in the PFC, /H92511-adrenoceptors and 5-HT 2A receptors have similar effects on the activity of layer V pyrami-dal neurons [248]. Hallucinogens increase the intensity of sensory experiences and affective responses, and it is tempting to speculate that the LC may contribute to these effects. Indeed, the ability of LSD to potentiate neophobia in rats in the Behavioral Pattern Monitor is diminished by depletion of norepinephrine from LC projections [249]. 5. 2. Prefrontal cortex (PFC) 5. 2. 1. Effects on PFC network activity in vitro It is now recognized that the PFC is an important site of action for hallucinogens. The 5-HT 2Areceptor is expressed heavily in the PFC and adjacent cortical regions, particularly in lamina V [237,250-252]. In situ hybridization histochemistry has conﬁrmed that most of the cells in monkey and human PFC express 5-HT 2A m RNA [253]. Likewise, in rats, a large percentage of the cells in the superﬁcial, middle, and deep layers of the secondary motor, anterior cingulate (ACA), prelimbic (Pr L), and infralimbic (IL) areas express 5-HT 2Am RNA [254,255]. Almost all prefrontal pyramidal neurons express the 5-HT 2Areceptor, with the receptor localized primarily to the proximal apical dendrites [237,252,256,257]. In addition to pyramidal neurons, 5-HT 2Areceptors are also expressed by subsets of parvalbumin- and calbindin-positive interneurons [253,255,256,258-260]. Approximately 20-25% of the glutamic acid decarboxylase-positive cells in PFC express 5-HT 2Am RNA [253]. From their morphology these interneurons appear to be basket cells and chandelier cells [258]. GABAergic interneurons expressing parvalbumin and calbindin are sources of perisomatic inhibition that synchronize the oscillatory ﬁring of large ensembles of pyramidal neurons [261-263]. Therefore, 5-HT 2Areceptors are likely to have direct and indirect effects on the activity of pyramidal cells (see Fig. 8). Electrophysiological studies have shown that 5-HT 2Aactivation (with DOB or DOI) produces several effects on the membrane properties of layer V pyramidal neurons: there is a moderate depolarization, spike-frequency accommodation is reduced, and the afterhyperpolarization (AHP) that normally follows a burst of spikes is replaced by a slow depolarizing afterpotential (s ADP) [264-266]. The effect on AHP is mediated by activation of PLC/H9252 signaling, which inhibits one of the currents (Is AHP) underlying the AHP [267,268] ; the induction of s ADP is probably a conse-quence of activating a Ca2+-dependent nonselective cation channel (ICAN). 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