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 11 Table 3 Receptor agonists and antagonists that modulate the electrophysiological effects of 5-HT 2Aactivation in the m PFC also alter the head twitch response in rats and mice. Receptor Ligandpharmacology5-HT 2A-induced s EPSCs in layer V pyramidal neuronsa DOI-induced head twitch responsea 5-HT 2A Antagonist ↓ M100907 [272] Beique et al., 2007 [290]↓ M100907 [160] 5-HT 2C Antagonist Ø SB242084 [248] Beique et al., 2007Ø SB242084 [170] [171] AMPA Antagonist ↓ LY293558 [272][274] ↓ LY300164 [274] ↓ CNQX [273] Beique et al., 2007 [290]↓ LY293558 [274] ↓ GYKI 52466 [274] ↓ DNQX [451] ↓ NBQX [452] /H9262-opioid Agonist ↓ DAMGO [286] ↓ endomorphin-1 [286]↓ morphine [453] ↓ buprenorphine [454] ↓ fentanyl [454] m Glu 2/3 Agonist ↓ LY354740 [287] ↓ LY379268 [287] [273]↓ LY354740 [455][273] ↓ LY379268 [273] Antagonist ↑ LY341495 [287]↑ LY341495 [455] Adenosine A1 Agonist ↓ N6-cyclopentyladenosine [288]↓ N6-cyclohexyladenosine Marek et al., 2009 CNQX, 6-cyano-7-nitroquinoxaline-2,3-dione; DAMGO, [d-Ala2, N-Me Phe4, Gly-ol5]-enkephalin; DNQX, 6,7-dinitroquinoxaline-2,3-dione; NBQX, 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[ f]quinoxaline-7-sulfonamide; s EPSCs, spontaneous excitatory postsynaptic currents. a The speciﬁed ligand reduces the response (↓), has no effect (Ø), or enhances the response (↑). the gamma range (30-80 Hz) that play a putative role in a multi-tude of perceptual and cognitive functions [310-314]. Recordings of local ﬁeld potentials (LFPs) from the PFC have shown DOI reduces low-frequency oscillations in anesthetized rats [315], and dampens gamma oscillations in freely moving rats [306]. DOI also desynchro-nizes the ﬁring of pyramidal neurons so that their activity is no longer coupled to LFPs [306,315]. 5-Me O-DMT has similar effects on low-frequency PFC network activity in anesthetized rats [305]. Taken together, these ﬁndings demonstrate that hallucinogens dis-rupt the oscillatory activity of cortical networks and reduce the likelihood that individual pyramidal neurons will ﬁre in synchrony. Similar to the LFP data in rats, magnetoencephalographic (MEG) recordings in humans have shown that psilocybin (2 mg, i. v. ) pro-duces broadband reductions in cortical oscillatory power [316]. Dynamic causal modeling of the MEG data indicates that psilo-cybin reduces cortical synchrony by increasing the excitability of deep-layer pyramidal neurons. Likewise, electroencephalographic studies have reported that ayahuasca (containing the equivalent of 0. 85 mg/kg DMT) reduces cortical oscillatory power across multiple frequency bands [317,318]. Since cortical oscillations play a funda-mental role in a diverse set of mental processes and are required for the coordination of neural processing [319-324], it is tempting to speculate that the reduction of neuronal synchrony by hallu-cinogens could be responsible for mediating many of their effects on perception and cognition. Along these lines, there is evidence that schizophrenia patients show deﬁcits of gamma oscillations and synchrony [325-328] and reductions in slow-wave sleep [329], and it has been hypothesized that these abnormalities play an impor-tant role in the pathophysiology of psychosis. As was noted earlier, neuroimaging studies have demonstrated that hallucinogens alter activity in the frontal cortex. Studies using PET and single-photon emission computed tomography(SPECT) have consistently found that hallucinogens produce frontal hyperactivity. Administration of mescaline sulfate (500 mg, p. o. ) produces a hyperfrontal metabolic pattern, especially in the right hemisphere [53]. PET studies with [18F]ﬂuorodeoxyglucose ([18F]FDG) have shown that psilocybin (0. 20-0. 36 mg/kg, p. o. ) also produces a hyperfrontal pattern, with robust metabolic increases in frontolateral and frontomedial cortical regions and ACA [54,330]. Similar patterns of brain activation were found in subjects administered ayahuasca as part of a SPECT study [331]. By contrast, it has been argued, based on functional MRI (f MRI) data, that psilocybin reduces resting-state brain activity [332]. In that study, volunteers received 2 mg i. v. psilocybin and regional blood ﬂow and venous oxygenation were assessed using arterial spin labeling and blood-oxygen level-dependent (BOLD) f MRI scans. Psilocybin reduced blood ﬂow and BOLD signal in ACA and m PFC, and there was evidence of reduced coupling between m PFC and the posterior cingulate cortex. Based on those results, Carhart-Harris, Nutt, and colleagues concluded that psilocybin reduces activity and connectivity in core nodes of the default-mode network, brain regions that are active during the resting state and potentially involved in introspective processes (for more information, see: [333-335] ). It remains to be determined why psilocybin produces such discrepant effects in PET and f MRI studies. One potential explanation is that the hemodynamic responses measured by f MRI are actually better correlated with cortical oscillatory activity than with neuronal ﬁring [336-340]. Indeed, recent work by Artigas and co-workers conﬁrms the decoupling of BOLD measures and spiking in rats [305]. According to their report, 5-Me O-DMT (0. 1 mg/kg, i. v. ) increased the ﬁring rate of m PFC pyramidal cells by 215%, but signiﬁcantly reduced the BOLD signal (measured by f MRI) and the power of low-frequency oscillations (measured by LFP recordings). Therefore, PET and f MRI studies may be assessing different types883 884885886887888889890891892893894895896897898899900901902903904905906907908909910911912913914915 916917918919920921922923924925926927928929930931932933934935936937938939940941942943944945946