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 10 A. L. Halberstadt / Behavioural Brain Research xxx (2014) xxx-xxx Fig. 8. Distribution of 5-HT 2Areceptors in neurons in layer V of the prefrontal cortex. 5-HT 2Areceptors are expressed by glutamatergic pyramidal neurons and GABAergic basket cells and chandelier cells. Hallucinogens increase the frequency of spontaneous EPSCs and IPSCs in layer V pyramidal neurons by enhancing recurrent glutamatergic and GABAergic network activity. neurons [269]. DOI also produces a 5-HT 2A-dependent inhibition of voltage-dependent Na+-currents and L-type Ca2+-currents in PFC pyramidal cells via the PLC/H9252-IP3-protein kinase C and PLC/H9252-IP3-calcineurin signaling cascades, respectively, effects that would likely inﬂuence dendritic integration [270,271]. Hallucinogens have profound effects on excitatory and inhibitory transmission in medial PFC (m PFC) in vitro. Recordings from brain slices have shown that DOI and other 5-HT 2Aagonists produce a marked enhancement of the frequency and ampli-tude of spontaneous excitatory postsynaptic potentials/currents (EPSPs/EPSCs) in most layer V pyramidal neurons in m PFC [272,273] (Zhou and Hablitz, 1999). These effects are mediated Q2 by an increase in Glu release and subsequent activation of post-synaptic AMPA receptors [272,274]. Because these studies failed to locate any glutamatergic m PFC neurons that were driven to ﬁre action potentials by 5-HT 2Aactivation, it was initially thought that the increase in Glu release was caused by local activation of the terminals of glutamatergic thalamocortical afferents [275,276]. However, although the ability of 5-HT to induce EPSCs is lost after deletion of the 5-HT 2Agene (htr2A-/-mice), the effect can be res-cued by selective restoration of 5-HT 2Areceptors to pyramidal neurons in the forebrain [277]. The htr2A-/-mice used by Weis-staub et al. were generated by inserting a ﬂoxed Neo-stop cassette between the promoter and the coding region, so the gene could be rescued by crossing the mice with Emx1-Cre+/-mice (which selectively expresses Cre recombinase in the forebrain). The fact that the EPSCs were rescued in htr2A-/-× Emx1-Cre+/-mice shows that projections from thalamus and other subcortical structures are not being directly excited by 5-HT 2Areceptors. More recent work has identiﬁed a subpopulation of pyramidal neurons in m PFC deep layer V that are depolarized and excited by DOI [278], indicating hallucinogens induce spontaneous EPSCs by increasing recurrentglutamatergic network activity. 5-HT 2Areceptor activation also increases the frequency of spontaneous IPSCs in pyramidal neurons (Zhou and Hablitz, 1999), an effect that is mediated by activa-tion of neighboring GABAergic interneurons [260,279]. Therefore, it appears hallucinogens recruit glutamatergic and GABAergic neu-rons, which produces a marked enhancement of excitatory and inhibitory recurrent network activity in m PFC [280,281]. This conclusion is supported by microdialysis data showing that hallu-cinogens increase extracellular levels of Glu [282-284] and GABA [285] in m PFC. There is evidence that enhancement of glutamatergic activ-ity in m PFC plays an important role in mediating the effects of hallucinogens. Manipulations that suppress the facilitation of recurrent glutamatergic network activity, including the use of m Glu 2/3agonists, /H9262-opioid agonists, adenosine A1agonists, and AMPA antagonists [273,286-290], block many of the neurochemi-cal and behavioral effects of hallucinogens. These interactions have been demonstrated most extensively for the HTR (see Table 3), a 5-HT 2A-mediated behavior that can be provoked by infusion of DOI directly into the m PFC [291,292]. Likewise, the discrimina-tive stimulus effects of LSD are attenuated by the m Glu 2/3agonist LY379268 and augmented by the m Glu 2/3antagonist LY341495 [112], and there is evidence that the LSD stimulus cue is mediated by activation of 5-HT 2Areceptors in the ACA [114]. Another exam-ple is the ability of DOI to increase impulsive responding in rats, which is attenuated by administration of LY379268 systemically or directly into m PFC [293,294]. In addition to 5-HT 2Aantagonists, m Glu 2/3agonists and AMPA antagonists also block the ability of DOI to increase cortical expression of BDNF and the immediate-early genes c-fos, erg-2, and Arc [289,294-298]. Evidence has emerged that m Glu 2and 5-HT 2Areceptors can form heteromeric com-plexes in cortex [298,299], and these complexes may mediate the crosstalk that occurs between these receptors. It is important to note, however, that it has not been conclusively demonstrated that the heterodimers are responsible for the interactions between 5-HT2Aand m Glu 2[300,301], and it is possible the crosstalk is purely functional and occurs at the circuit level. m Glu 2receptors func-tion predominantly as presynaptic autoreceptors [302], so m Glu 2 activation could potentially suppress 5-HT 2A-induced spontaneous EPSCs by reducing Glu release from axon terminals. 5. 2. 2. Effects on PFC network activity in vivo Recent studies have examined the effects of hallucinogens on PFC activity in vivo. Extracellular recordings from anesthetized rats have shown that DOI (0. 05-0. 8 mg/kg, i. v. ) and 5-Me O-DMT (0. 1 mg/kg, i. v., in combination with the monoamine oxidase inhibitor clorgyline) produce a net excitatory effect on pyrami-dal neurons in the Pr L, IL, and ACA regions of m PFC [303-305]. Individual pyramidal neurons are either excited (38-53%), inhib-ited (27-35%), or show no response. It appears that these effects are mediated by recruitment of glutamatergic and GABAergic neurons because the excitatory response to DOI is blocked by LY379268 and the inhibitory response is blocked by the GABA A antagonist picrotoxinin [303,304]. These effects are also blocked by 5-HT 2Aantagonists. In contrast to those ﬁndings, another group has reported that higher doses of DOI (3-5 mg/kg, i. p. ) tend to inhibit the ﬁring of pyramidal cells in ACA and the ventral, dorsolateral, and lateral orbitofrontal cortices of behaving rats [306]. Despite the discrepant ﬁndings outlined above, hallucinogens produce strikingly similar effects on cortical network activity in anesthetized and freely moving rats. Under anesthesia or dur-ing slow-wave sleep, cortical networks display slow (0. 5-1 Hz) and delta (1-4 Hz) oscillations [307-309] that reﬂect alternations between periods of silence (DOWN states) and periods of depo-larization with repetitive spiking (UP states). This contrasts with the active waking state, which is characterized by fast rhythms in786 787788789790791792793794795796797798799800801802803804805806807808809810811812813814815816817818 819820821822823824825826827828829830831832833834835836837838839840841842843844845846847848849850851852853854855856857 858 859860861862863864865866867868869870871872873874875876877878879880881882