Psychopharmacology (v.218, #4)

Inhibition of cerebral type 1 cannabinoid receptors is associated with impaired auditory mismatch negativity generation in the ketamine model of schizophrenia by Patrik Roser; Ida S. Haussleiter; Hee-Jeong Chong; Christoph Maier; Wolfram Kawohl; Christine Norra; Georg Juckel (611-620).
Preclinical and clinical research suggests that the endogenous cannabinoid system is involved in cognitive impairments related to schizophrenia. In particular, the deficient generation of mismatch negativity (MMN) indicating auditory sensory memory is a characteristic finding in schizophrenic patients. Experimental studies implicate deficient N-methyl-d-aspartate (NMDA) receptor functioning in such abnormalities.The primary aim of this study was to investigate the effects of the cannabinoid CB1 receptor antagonist rimonabant on MMN deficits in the NMDA receptor antagonist model of schizophrenia by using ketamine.Twenty-four healthy male subjects participated in a randomized, double-blind, placebo-controlled cross-over study with subanesthetic doses of intravenous ketamine. The MMNs to frequency and duration deviants were elicited within an auditory oddball paradigm and recorded by a 32-channel EEG. Psychopathology was assessed using the Psychotomimetic States Inventory.Twenty subjects completed both experimental sessions. Ketamine infusion had no significant effect on MMN amplitudes in both deviance conditions. In contrast to placebo, co-administration of rimonabant produced significant deficits in MMN amplitudes to duration deviants at electrode position Fz.The results point to the involvement of the endogenous cannabinoid system in auditory sensory memory as a cognitive key feature in schizophrenia. They particularly suggest that CB1 receptor antagonism may impair cognitive performance by a disturbed interaction between endocannabinergic activity and glutamatergic neurotransmission implied in schizophrenia.
Keywords: Mismatch negativity; Ketamine; NMDA; Rimonabant; CB1 receptor; Schizophrenia

Antidepressant-like properties of sarizotan in experimental Parkinsonism by Xiaoqun Zhang; Martin Egeland; Per Svenningsson (621-634).
Depression and anxiety are common symptoms in Parkinson's disease for which there are no optimal treatments. Sarizotan, an agonist at serotonin receptors and partial agonist at dopamine D2-like receptors, has shown antidyskinetic effects in Parkinson's disease. Based on its pharmacological profile, we hypothesized that sarizotan could also have antidepressant-like properties.Examine effects of sarizotan on behavioral and histological measures known to be regulated by established antidepressants in normal and unilaterally 6-hydroxydopamine-lesioned rats.Sarizotan was found to significantly reduce immobility in the modified forced swim test, a measure of antidepressant-like activity, but had no effects on thigmotaxis or corner time, measures of anxiety-like behavior, in the unilaterally 6-hydroxydopamine-lesioned rats. At the same dose, sarizotan counteracted l-DOPA/benserazide-induced supersentitized rotational behavior and dyskinesias without significantly affecting l-DOPA/benserazide-induced locomotion. At the histological level, sarizotan alone or in combination with l-DOPA/benserazide stimulated cell proliferation, measured by bromodeoxyuridine incorporation or Ki-67 staining, both in the subgranular zone of the dentate gyrus and in the subventricular zone of the striatum in the 6-hydroxydopamine-lesioned hemisphere. Likewise, combined sarizotan and l-DOPA/benserazide treatment stimulated doublecortin levels in the subgranular zone of the dentate gyrus.These significant effects of sarizotan in the modified forced swim test and on cell proliferation are reminiscent of those found after various antidepressant therapies. These data suggest that sarizotan may have some antidepressant-like and restorative properties in Parkinsonism.
Keywords: 6-hydroxydopamine; Parkinson's disease; Bromodeoxyuridine; Ki-67; Doublecortin; Serotonin; Modified forced swim test

Preclinical assessment of an adjunctive treatment approach for cognitive impairment associated with schizophrenia using the alpha7 nicotinic acetylcholine receptor agonist WYE-103914/SEN34625 by Karen L. Marquis; Thomas A. Comery; Flora Jow; Rachel L. Navarra; Steven M. Grauer; Claudine Pulicicchio; Cody Kelley; Julie A. Brennan; Renza Roncarati; Carla Scali; Simon Haydar; Chiara Ghiron; Georg C. Terstappen; John Dunlop (635-647).
α7 nicotinic acetylcholine receptor (nAChR) agonists are proposed as candidate agents for the adjunctive treatment of cognitive deficits associated with schizophrenia. Despite the pursuit of such an approach clinically, it is surprising that the preclinical profile of pro-cognitive agents in conjunction with antipsychotic drugs is currently unexplored.We determined if the memory-enhancing effects of the selective α7 nAChR agonist WYE-103914 were preserved in the presence of the atypical antipsychotic drug risperidone, and if the antipsychotic-like profile of risperidone was preserved in the presence of WYE-103914.Using the rat novel object recognition (NOR) paradigm, the maintenance of memory-enhancing activity of the α7 nAChR agonist WYE-103914 in the presence of risperidone was examined. Similarly, in the standard tests of antipsychotic-like activity, apomorphine-induced climbing (AIC) in mice and conditioned avoidance responding (CAR) in rats, the preservation of antipsychotic-like activity of risperidone was evaluated in the presence of WYE-103914.WYE-103914 exhibited memory-enhancing activity in rat NOR, and this effect of WYE-103914 was retained in the presence of risperidone. In AIC, the atypical antipsychotic profile of risperidone was not significantly altered by WYE-103914. In contrast, WYE-103914 moderately potentiated the efficacy profile of risperidone in CAR, an effect that did not appear to be convincingly linked to a pharmacokinetic interaction.These data underscore the value of a preclinical evaluation of the adjunctive profile of a memory-enhancing agent in combination with antipsychotics and provide further support to augmentation with α7 nAChR agonists to address the cognitive deficits associated with schizophrenia.
Keywords: Nicotinic; Acetylcholine; Schizophrenia; Cognition; Adjunctive; Alpha7

Psilocybin occasioned mystical-type experiences: immediate and persisting dose-related effects by Roland R. Griffiths; Matthew W. Johnson; William A. Richards; Brian D. Richards; Una McCann; Robert Jesse (649-665).
This dose-effect study extends previous observations showing that psilocybin can occasion mystical-type experiences having persisting positive effects on attitudes, mood, and behavior.This double-blind study evaluated psilocybin (0, 5, 10, 20, 30 mg/70 kg, p.o.) administered under supportive conditions.Participants were 18 adults (17 hallucinogen-naïve). Five 8-h sessions were conducted individually for each participant at 1-month intervals. Participants were randomized to receive the four active doses in either ascending or descending order (nine participants each). Placebo was scheduled quasi-randomly. During sessions, volunteers used eyeshades and were instructed to direct their attention inward. Volunteers completed questionnaires assessing effects immediately after and 1 month after each session, and at 14 months follow-up.Psilocybin produced acute perceptual and subjective effects including, at 20 and/or 30 mg/70 kg, extreme anxiety/fear (39% of volunteers) and/or mystical-type experience (72% of volunteers). One month after sessions at the two highest doses, volunteers rated the psilocybin experience as having substantial personal and spiritual significance, and attributed to the experience sustained positive changes in attitudes, mood, and behavior, with the ascending dose sequence showing greater positive effects. At 14 months, ratings were undiminished and were consistent with changes rated by community observers. Both the acute and persisting effects of psilocybin were generally a monotonically increasing function of dose, with the lowest dose showing significant effects.Under supportive conditions, 20 and 30 mg/70 kg psilocybin occasioned mystical-type experiences having persisting positive effects on attitudes, mood, and behavior. Implications for therapeutic trials are discussed.
Keywords: Psilocybin; Dose effects; Hallucinogen; Entheogen; Psychedelic; Mystical experience; Fear; Spiritual; Religion; Positive psychology; Humans

Prompt but inefficient: nicotine differentially modulates discrete components of attention by Signe Vangkilde; Claus Bundesen; Jennifer T. Coull (667-680).
Nicotine has been shown to improve both memory and attention when assessed through speeded motor responses. Since very few studies have assessed effects of nicotine on visual attention using measures that are uncontaminated by motoric effects, nicotine’s attentional effects may, at least partially, be due to speeding of motor function.Using an unspeeded, accuracy-based test, the CombiTVA paradigm, we examined whether nicotine enhances attention when it is measured independently of motor processing.We modelled data with a computational theory of visual attention (TVA; Bundesen 1990) so as to derive independent estimates of several distinct components of attention from performance of the single task: threshold of visual perception, perceptual processing speed, visual short-term memory storage capacity and top–down controlled selectivity. Acute effects of nicotine (2 mg gum) on performance were assessed in 24 healthy young non-smokers in a placebo-controlled counterbalanced, crossover design. Chronic effects of nicotine were investigated in 24 age- and education-matched minimally deprived smokers.Both an acute dose of nicotine in non-smokers and chronic nicotine use in temporarily abstaining smokers improved perceptual thresholds but slowed subsequent perceptual speed. Moreover, both acute and chronic nicotine use reduced attentional selectivity though visual short-term memory capacity was unimpaired.Nicotine differentially affected discrete components of visual attention, with acute and chronic doses revealing identical patterns of performance. We challenge prior reports of nicotine-induced speeding of information processing by showing, for the first time, that nicotine slows down perceptual processing speed when assessed using accuracy-based measures of cognitive performance.
Keywords: Nicotine; Attention; Cognition; Perceptual processing speed; Selectivity; Memory; Smoker; Non-smoker; Human

Elevated gray and white matter densities in cocaine abstainers compared to current users by Colleen A. Hanlon; Darin L. Dufault; Michael J. Wesley; Linda J. Porrino (681-692).
Numerous neuroimaging studies have demonstrated lower neural tissue density in chronic cocaine users, which may be linked to cognitive dysfunction.The goal of this study was to determine whether neural tissue density was also impaired in individuals abstinent from cocaine and whether any observed changes were associated with cognitive performance.A total of 73 participants were included: 24 active cocaine users, 24 abstainers (abstinent for at least 1 month), and 25 nondrug-abusing controls rigorously matched for age, gender, and IQ. All participants performed a cognitive assessment battery and received an MRI which was analyzed using voxel-based morphometry.The abstainers had significantly higher gray matter density than the current cocaine users in neocortical areas including the frontal and temporal cortex. In contrast to the users, there was no difference in white matter density in the abstainers relative to the controls. The abstainers performed better than current users on several behavioral tasks. Within users and abstainers, cortical density was correlated with performance on memory and reaction time tasks. Subcortical gray matter density was lower in both the users and abstainers relative to the controls. Within abstainers, subcortical tissue density was correlated with the ability to set-shift.These data suggest that individuals able to remain abstinent from cocaine for at least 1 month have elevated neocortical tissue density and perform better on multiple cognitive tests, relative to current cocaine users. Larger, longitudinal studies are needed to address this interaction between abstinence, cognition, and cortical tissue density directly.
Keywords: Addiction; Neuroimaging; Cocaine; Cognition; Substance abuse; Myelin; Abstinence

Neuropeptide Y (NPY), an orexigenic peptide that is released during periods of food restriction, has been shown to have a significant modulatory impact on drug-related behaviors. We have previously reported that both acute food deprivation (FD) and NPY injections can reinstate extinguished drug-seeking behavior, a proposed animal model of relapse to drug abuse. However, it is not clear whether the FD effect on drug seeking is dependent on NPY transmission. Here, we used the reinstatement model to assess the role of NPY Y1 and Y5-receptor-mediated transmission in FD-induced reinstatement of heroin seeking.Rats were trained to self-administer heroin for 10–12 days (0.1 mg/kg/infusion/intravenous). Animals then underwent extinction training followed by drug-seeking reinstatement tests under 21 h of FD and sated conditions.Injections of a novel NPY Y5-receptor antagonist, Lu AA33810 (0.0, 1.0, or 30.0 mg/kg/IP), resulted in a significant attenuation of FD-induced reinstatement of extinguished heroin seeking. However, no significant effects on reinstatement were found for the Y1-receptor antagonist, BIBO 3304 (0.0, 5.0, or 10.0 nmol/intracerebroventricular).These results suggest that while signals mediated through NPY Y1 receptors play a modest role in reinstatement, activation of Y5 receptors has a critical function in FD-induced reinstatement of heroin-seeking behavior.
Keywords: Neuropeptide Y (NPY); Reinstatement; Drug seeking; Heroin; Y1 receptors; Y5 receptors; Food deprivation

Effects of acute administration of nicotine, amphetamine, diazepam, morphine, and ethanol on risky decision-making in rats by Marci R. Mitchell; Colin M. Vokes; Amy L. Blankenship; Nicholas W. Simon; Barry Setlow (703-712).
Most individuals can accurately assess the risks and rewards associated with choice alternatives and decide accordingly; however, drug users often display maladaptive decision-making, such that choices are biased toward excessively risky options.The purpose of this study was to investigate the effects of a range of drugs of abuse on risky decision-making.Male Long–Evans rats were trained in the Risky Decision-Making Task, in which they chose between two levers, one which produced a small, “safe” food reward and the other which produced a large, “risky” food reward. The large reward was accompanied by the risk of a mild footshock, the probability of which increased over the course of each test session (0%, 25%, 50%, 75%, and 100%).Nicotine (0.6 mg/kg) and amphetamine (1.5 mg/kg) caused a significant decrease in choice of the large risky reward (decreased risk taking). Diazepam (1.0 mg/kg) caused a significant increase in choice of the large risky reward (increased risk taking), whereas morphine (3.0 mg/kg) caused only a trend toward increased choice of the large risky reward. Ethanol had no effect on choice behavior.These results show that acute administration of drugs of abuse can modulate risk taking in a drug-specific manner, either increasing or decreasing preference for highly rewarding, but risky, options.
Keywords: Decision-making; Risk; Punishment; Amphetamine; Ethanol; Morphine; Nicotine; Diazepam

Translational PK–PD modelling of molecular target modulation for the AMPA receptor positive allosteric modulator Org 26576 by Roberta Bursi; Gul Erdemli; Robert Campbell; Matthew M. Hutmacher; Thomas Kerbusch; David Spanswick; Ross Jeggo; Kari R. Nations; Peter Dogterom; Jacques Schipper; Mohammed Shahid (713-724).
The α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor potentiator Org 26576 represents an interesting pharmacological tool to evaluate the utility of glutamatergic enhancement towards the treatment of psychiatric disorders. In this study, a rat–human translational pharmacokinetic–pharmacodynamic (PK–PD) model of AMPA receptor modulation was used to predict human target engagement and inform dose selection in efficacy clinical trials.Modelling and simulation was applied to rat plasma and cerebrospinal fluid (CSF) pharmacokinetic and pharmacodynamic measurements to identify a target concentration (EC80) for AMPA receptor modulation. Human plasma pharmacokinetics was determined from 33 healthy volunteers and eight major depressive disorder patients. From four out of these eight patients, CSF PK was also determined. Simulations of human CSF levels were performed for several doses of Org 26576.Org 26576 (0.1–10 mg/kg, i.v.) potentiated rat hippocampal AMPA receptor responses in an exposure-dependant manner. The rat plasma and CSF PK data were fitted by one-compartment model each. The rat CSF PK–PD model yielded an EC80 value of 593 ng/ml (90% confidence interval 406.8, 1,264.1). The human plasma and CSF PK data were simultaneously well described by a two-compartment model. Simulations showed that in humans at 100 mg QD, CSF levels of Org 26576 would exceed the EC80 target concentration for about 2 h and that 400 mg BID would engage AMPA receptors for 24 h.The modelling approach provided useful insight on the likely human dose–molecular target engagement relationship for Org 26576. Based on the current analysis, 100 and 400 mg BID would be suitable to provide ‘phasic’ and ‘continuous’ AMPA receptor engagement, respectively.
Keywords: Org 26576; AMPA receptor positive allosteric modulator; Translational pharmacometrics; PK–PD modelling and simulation; Depression; ADHD; Schizophrenia

Serotonin-2A receptor regulation of panic-like behavior in the rat dorsal periaqueductal gray matter: the role of GABA by Thatiane de Oliveira Sergio; Valquiria Camin de Bortoli; Helio Zangrossi Jr. (725-732).
Electrical stimulation of the dorsal periaqueductal gray (dPAG) evokes escape, a defensive response associated with panic attacks. Stimulation of 5-HT1A or 5-HT2A receptors in this midbrain area equally inhibits escape performance, even though at the molecular level these receptors cause opposite effects, i.e., activation of the former hyperpolarizes the cell membrane, while the latter excites it. A proposal has been made that 5-HT2A receptor agonists exert their inhibitory effect on escape by activating GABAergic interneurons located in the dPAG.In the present study, we evaluated this hypothesis by investigating whether previous intra-dPAG administration of the GABAA receptor antagonist bicuculline blocks the anti-escape effect caused by the local injection of different 5-HT2A/2C receptor agonists.Intra-dPAG administration of 5-HT, the preferential 5-HT2A receptor agonist DOI, the nonselective 5-HT2C receptor agonist mCPP or the 5-HT2C receptor agonist RO 60–0175 significantly inhibited the escape reaction induced by electrical stimulation of the same brain area. In all cases, this panicolytic-like effect was blocked by previous microinjection of bicuculline. This GABAA antagonist, however, failed to antagonize the anti-escape effect caused by the 5-HT1A receptor agonist 8-OH-DPAT. The inhibitory effect caused by DOI, RO 60–0175, and mCPP was also blocked by previous intra-dPAG injection of the preferential 5-HT2A receptor antagonist ketanserin. Pre-administration of the 5-HT2C receptor antagonist SB-242084 in the dPAG did not block the anti-escape effect of RO 60–0175.Stimulation of 5-HT2A but not 5-HT2C receptors in the dPAG causes a panicolytic-like effect that is mediated by facilitation of GABAergic neurotransmission.
Keywords: Dorsal periaqueductal gray matter; Serotonin; GABA; 5-HT2A receptors; Panic

Effects of antipsychotic treatment on psychopathology and motor symptoms. A placebo-controlled study in healthy volunteers by Tanja Veselinović; Holger Schorn; Ingo Vernaleken; Katharina Schiffl; Christoph Hiemke; Gerald Zernig; Ruben Gur; Gerhard Gründer (733-748).
There is increased interest in elucidating the range of symptoms of schizophrenia and their response to treatment with medications. Particularly negative and cognitive symptoms are often resistant to the therapy with currently available antipsychotics. There are even similarities between negative symptoms in psychosis and the side effects of antidopaminergic antipsychotic drugs.The aim of this randomized, single-blinded, placebo-controlled study was to investigate the influence of a subchronic, prolonged neuroleptic-induced dopamine deficit on psychopathology and subjective well-being in healthy subjects.Seventy-two healthy volunteers without history of psychiatric diseases were included. A 7-day antidopaminergic intervention was provided with aripiprazole, haloperidol, and reserpine. For the clinical assessment, structured interviews and psychopathology and extrapyramidal symptom scales were used.Seven out of 18 participants (38.9%) randomized to the haloperidol group terminated the study ahead of schedule. In the reserpine and the haloperidol group, significantly higher levels of negative and positive symptoms (PANSS scale) were documented. Depressive symptoms predominantly occurred in the reserpine group. Among all participants experiencing the antidopaminergic intervention, the subgroup with positive family history among first and second-generation relatives developed more pronounced depressive symptoms. Concerning extrapyramidal motor symptoms, the haloperidol group had significantly more severe manifestations than all three other groups.Antidopaminergic modulation in healthy subjects induced substantial impairments in several domains of subjective well-being. In particular an association between hypodopaminergic states and depressive symptoms was observed which may be amplified by a genetic predisposition.
Keywords: Dopamine; Antipsychotics; Psychopathology; Healthy volunteers; Aripiprazole; Reserpine; Haloperidol

Repeated administrations of the D2/D3 agonist quinpirole (QNP) to rats elicit an antieconomical pattern of drinking called “contrafreeloading” (CFL), a putative model of compulsive-like behavior.We tested the sensitivity of QNP-induced CFL to haloperidol (HAL), aripiprazole (ARI), and clomipramine (CIM), the latter proven effective in the treatment of obsessive–compulsive disorder (OCD).Rats were trained under a schedule of reinforcement (FR3) for water. On days 1–6, water was only available through lever pressing. On days 7–15, a choice between operant and free access was provided. QNP 0.5 mg/kg was administered alone or in combination with HAL (0.1 or 0.2 mg/kg), ARI (0.3 or 1 mg/kg), or CIM (5 or 10 mg/kg).Acutely QNP suppressed operant behavior and, therefore, water intake; upon repeated administrations, tolerance developed to this suppressant effect on responding but only to a lesser extent to the antidipsic effect. In choice conditions, QNP induced a progressive preference for the operant access (CFL). HAL per se, but not CIM and ARI, significantly reduced both responding and drinking (operant phase). In the choice phase, HAL and CIM inhibited CFL, but only the latter reinstated total water intake. ARI, in combination with QNP, increased responding.CIM reinstates control patterns of drinking, while HAL and ARI where partially or not effective at all, respectively. As far as CIM is considered a first line treatment in OCD, these results further strengthen the notion that QNP-induced CFL belongs to the realm of dopaminergic drug-induced compulsive behaviors.
Keywords: Contrafreeloading; Obsessive–compulsive disorder; Quinpirole; Haloperidol; Clomipramine; Aripiprazole