Showing papers in "Psychopharmacology in 2008"

Affective neuroscience of pleasure: reward in humans and animals.

Abstract: Introduction Pleasure and reward are generated by brain circuits that are largely shared between humans and other animals.

The role of impulsive behavior in drug abuse.

Abstract: Impulsivity is a multifaceted construct that has recently been recognized as a factor contributing to enhanced vulnerability to drug abuse. In the present review, we focus on two facets of impulsivity (and tasks that measure them): (1) impulsive choice (delay discounting task) and (2) inhibitory failure (go/no-go, stop signal reaction time, and five-choice serial reaction time tasks). We also describe how performance on each of these tasks is associated with drug-related behavior during phases of drug abuse that capture the essential features of addiction (acquisition, escalation, and reinstatement of drug-seeking after drug access has terminated). Three hypotheses (H) regarding the relationship between impulsivity and drug abuse are discussed: (1) increased levels of impulsivity lead to drug abuse (H1), (2) drugs of abuse increase impulsivity (H2), and (3) impulsivity and drug abuse are associated through a common third factor (H3). Impulsivity expressed as impulsive choice or inhibitory failure plays a role in several key transition phases of drug abuse. There is evidence to support all three nonexclusive hypotheses. Increased levels of impulsivity lead to acquisition of drug abuse (H1) and subsequent escalation or dysregulation of drug intake. Drugs of abuse may increase impulsivity (H2), which is an additional contributor to escalation/dysregulation. Abstinence, relapse, and treatment may be influenced by both H1 and H2. In addition, there is a relationship between impulsivity and other drug abuse vulnerability factors, such as sex, hormonal status, reactivity to nondrug rewards, and early environmental experiences that may impact drug intake during all phases of addiction (H3). Relating drug abuse and impulsivity in phases of addiction via these three hypotheses provides a heuristic model from which future experimental questions can be addressed.

Realistic expectations of prepulse inhibition in translational models for schizophrenia research

Abstract: Under specific conditions, a weak lead stimulus, or “prepulse”, can inhibit the startling effects of a subsequent intense abrupt stimulus. This startle-inhibiting effect of the prepulse, termed “prepulse inhibition” (PPI), is widely used in translational models to understand the biology of brain‑based inhibitory mechanisms and their deficiency in neuropsychiatric disorders. In 1981, four published reports with “prepulse inhibition” as an index term were listed on Medline; over the past 5 years, new published Medline reports with “prepulse inhibition” as an index term have appeared at a rate exceeding once every 2.7 days (n = 678). Most of these reports focus on the use of PPI in translational models of impaired sensorimotor gating in schizophrenia. This rapid expansion and broad application of PPI as a tool for understanding schizophrenia has, at times, outpaced critical thinking and falsifiable hypotheses about the relative strengths vs. limitations of this measure. This review enumerates the realistic expectations for PPI in translational models for schizophrenia research, and provides cautionary notes for the future applications of this important research tool. In humans, PPI is not “diagnostic”; levels of PPI do not predict clinical course, specific symptoms, or individual medication responses. In preclinical studies, PPI is valuable for evaluating models or model organisms relevant to schizophrenia, “mapping” neural substrates of deficient PPI in schizophrenia, and advancing the discovery and development of novel therapeutics. Across species, PPI is a reliable, robust quantitative phenotype that is useful for probing the neurobiology and genetics of gating deficits in schizophrenia.

The neuropsychopharmacology of action inhibition: cross-species translation of the stop-signal and go/no-go tasks.

Abstract: Background and rationale The term ‘action inhibition’ encapsulates the ability to prevent any form of planned physical response. Growing evidence suggests that different ‘stages’ or even subtypes of action inhibition activate subtly different neuropharmacological and neuroanatomical processes.

Models and mechanisms of anxiety: evidence from startle studies

Abstract: Rationale Preclinical data indicates that threat stimuli elicit two classes of defensive behaviors, those that are associated with imminent danger and are characterized by flight or fight (fear), and those that are associated with temporally uncertain danger and are characterized by sustained apprehension and hypervigilance (anxiety). Objective The objectives of the study are to (1) review evidence for a distinction between fear and anxiety in animal and human experimental models using the startle reflex as an operational measure of aversive states, (2) describe experimental models of anxiety, as opposed to fear, in humans, (3) examine the relevance of these models to clinical anxiety. Results The distinction between phasic fear to imminent threat and sustained anxiety to temporally uncertain danger is suggested by psychopharmacological and behavioral evidence from ethological studies and can be traced back to distinct neuroanatomical systems, the amygdala and the bed nucleus of the stria terminalis. Experimental models of anxiety, not fear, are relevant to non-phobic anxiety disorders. Conclusions Progress in our understanding of normal and abnormal anxiety is critically dependent on our ability to model sustainedaversivestates to temporallyuncertain threat.

Antidepressant activity of curcumin: involvement of serotonin and dopamine system

Abstract: Rationale Curcumin is a major active principle of Curcuma longa, one of the widely used preparations in the Indian system of medicine. It is known for its diverse biological actions.

Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats.

Abstract: Cannabidiol (CBD) is a non-psychotomimetic constituent of Cannabis sativa plant that induces anxiolytic effects. However, the brain sites and mechanisms of these effects remain poorly understood. The dorsolateral periaqueductal gray (dlPAG) is a midbrain structure related to anxiety that contains receptors proposed to interact with CBD such as 5HT1A. In addition, since CBD has been shown to inhibit anandamide metabolism, CB1 receptors could also be involved in the effects of this cannabinoid. To investigate if the dlPAG could be a possible site of the anxiolytic effects induced by CBD and if these effects depend on CB1 or 5HT1A receptors. Male Wistar rats with cannulae aimed at the dlPAG were tested in the elevated plus maze (EPM) and the Vogel conflict test (VCT). CBD injected into the dlPAG produced anxiolytic-like effects in the EPM with a bell-shaped dose–response curve. The anxiolytic effect of CBD was confirmed in the VCT. These effects were prevented by WAY100635, a 5HT1A receptor antagonist, but not by AM251, an antagonist of CB1 receptors. These results suggest the CBD interacts with 5HT1A receptors to produce anxiolytic effects in the dlPAG.

Controversies in translational research: drug self-administration

Abstract: Rationale Laboratory animal and human models of drug self-administration are used to evaluate potential pharmacotherapies for drug abuse, yet the utility of these models in predicting clinically useful medications is variable.

Chronic cocaine but not chronic amphetamine use is associated with perseverative responding in humans

Abstract: Rationale Chronic drug use has been associated with increased impulsivity and maladaptive behaviour, but the underlying mechanisms of this impairment remain unclear. We investigated the ability to adapt behaviour according to changes in reward contingencies, using a probabilistic reversal-learning task, in chronic drug users and controls.

Inhibition of orexin-1/hypocretin-1 receptors inhibits yohimbine-induced reinstatement of ethanol and sucrose seeking in Long-Evans rats

Abstract: Rationale Previous studies have shown that orexin-1/hypocretin-1 receptors play a role in self-administration and cue-induced reinstatement of food, drug, and ethanol seeking. In the current study, we examined the role of orexin-1/hypocretin-1 receptors in operant self-administration of ethanol and sucrose and in yohimbine-induced reinstatement of ethanol and sucrose seeking.

Single dose of a dopamine agonist impairs reinforcement learning in humans : Behavioral evidence from a laboratory-based measure of reward responsiveness

Abstract: Rationale The dopaminergic system, particularly D2-like dopamine receptors, has been strongly implicated in reward processing. Animal studies have emphasized the role of phasic dopamine (DA) signaling in reward-related learning, but these processes remain largely unexplored in humans.

Stress-induced reinstatement of cocaine seeking is mediated by the kappa opioid system

Abstract: Introduction Prior activation of the kappa opioid system by repeated stress or agonist administration has been previously shown to potentiate the rewarding properties of subsequently administered cocaine. In the present study, intermittent and uncontrollable footshock, a single session of forced swim, or acute administration of the kappa agonist U50,488 (5 mg/kg) were found to reinstate place preference in mice previously conditioned with cocaine (15 mg/kg) and subsequently extinguished by repeated training sessions without drug.

Reward system activation in schizophrenic patients switched from typical neuroleptics to olanzapine.

Abstract: High blockade of dopamine D2 receptors in the ventral striatum including the nucleus accumbens may interfere with reward anticipation and cause secondary negative symptoms such as apathy or anhedonia. This may not be the case with newer neuroleptics such as olanzapine, which show less dopamine D2 receptor blockade and a faster off-rate from the receptor. We used functional magnetic resonance imaging to assess the blood oxygenation level dependent response in the ventral striatum of schizophrenics medicated with typical neuroleptics (T1) and after switching them to olanzapine (T2) and of healthy control subjects at corresponding time points during reward anticipation. Ten schizophrenics, while medicated with typical neuroleptics (T1) and after having been switched to olanzapine (T2), and ten matched healthy volunteers participated in a monetary incentive delay task, in which visual cues predicted that a rapid response to a subsequent target stimulus would either result in monetary gain or have no consequence. During reward anticipation, healthy volunteers showed significantly higher ventral striatal activation compared to schizophrenic patients treated with typical neuroleptics but not olanzapine, which was reflected in a significant interaction between group and session. In patients treated with typical neuroleptics, but not with olanzapine, decreased left ventral striatal activation was correlated with negative symptoms. Failure to activate the ventral striatum during reward anticipation was pharmacologically state-dependent and observed only in patients treated with typical neuroleptics but not with olanzapine, which may indicate that this drug did not induce secondary negative symptoms via interference with reward anticipation.

Cortical activation during delay discounting in abstinent methamphetamine dependent individuals

Abstract: Background Methamphetamine (MA)-dependent individuals prefer smaller immediate over larger delayed rewards in delay discounting (DD) tasks. Human and animal data implicate ventral (amygdala, ventral striatum, ventrolateral prefrontal cortex insula) and dorsal (dorsolateral prefrontal cortex, dorsal anterior cingulate cortex and posterior parietal cortex) systems in DD decisions. The ventral system is hypothesized to respond to the salience and immediacy of rewards while the dorsal system is implicated in the process of comparison and choice.

The mGlu2 but not the mGlu3 receptor mediates the actions of the mGluR2/3 agonist, LY379268, in mouse models predictive of antipsychotic activity

Abstract: Group II metabotropic glutamate receptors (mGluRs) comprise the mGluR2 and mGluR3 subtypes, the activation and modulation of which has been suggested to be beneficial for treating schizophrenia. Genetic association studies suggest limited association between mGluR2 and schizophrenia but some association between mGluR3 and schizophrenia. Conversely, pre-clinical studies suggest that mGluR2 may be responsible for mediating the antipsychotic activity of mGluR2/3 agonists, although to date, the role of mGluR3 has not been specifically assessed. The aim of this study is to use recently generated mGluR3 and mGluR2 knockout mice to investigate which of the group II mGluRs mediates the actions of the mGluR2/3 agonist, LY379268, in two mouse models predictive of antipsychotic activity. LY379268 (0.3–10 mg/kg SC), phencyclidine (PCP; 1–5 mg/kg IP), and amphetamine 1–10 mg/kg IP) were assessed on locomotor activity and behaviour in C57Bl/6J and transgenic mice. LY379268 was then assessed on PCP (5 mg/kg IP)- and amphetamine (2.5 mg/kg IP)-induced hyperactivity and behaviour in C57Bl/6J and transgenic mice. PCP (5 mg/kg)-evoked hyperactivity and behavioural alterations, i.e. circling, falling, stereotypy and ataxia, as well as amphetamine (2.5 mg/kg)-evoked hyperactivity, were dose-dependently attenuated by LY379268 (0.3–3 mg/kg) in C57Bl/6J mice. One milligram per kilogram of LY379268 reversed PCP-evoked hyperactivity and behavioural alterations in wild-type (WT) and mGluR3 knockout mice but not in mice lacking mGluR2. Similarly, 3 mg/kg LY379268 reversed amphetamine-evoked hyperactivity in WT and mGluR3 knockout mice but not in mice lacking mGluR2. The mGlu2 but not the mGlu3 receptor subtype mediates the actions of the mGluR2/3 agonist, LY379268, in mouse models predictive of antipsychotic activity.

Effect of varenicline and bupropion SR on craving, nicotine withdrawal symptoms, and rewarding effects of smoking during a quit attempt.

Abstract: Aims To examine the effect of varenicline, a selective alpha4-beta2 nicotinic acetylcholine receptor (nAChR) partial agonist, on craving and withdrawal symptoms in smokers making a quit attempt and the rewarding effects of smoking during a lapse after the target quit date (TQD).

Escitalopram effects on insula and amygdala BOLD activation during emotional processing

Abstract: Rationale The amygdala and insular cortex are integral to the processing of emotionally salient stimuli. We have shown in healthy volunteers that an anxiolytic agent, lorazepam, dose-dependently attenuates activation of limbic structures.

Long-lasting behavioral effects and recognition memory deficit induced by chronic mild stress in mice: effect of antidepressant treatment

Abstract: Rationale Many studies support the validity of the chronic mild stress (CMS) model of depression in rodents. However, most of them focus on analysis of reactivity to rewards during the CMS and/or depressive-like behavior shortly after stress. In this study, we investigate acute and long-term effects of CMS and antidepressant treatment on depressive, anxiety-like behavior and learning.

Effects of a low dose of alcohol on cognitive biases and craving in heavy drinkers

Abstract: Rationale Heavy alcohol drinking increases the incentive salience of alcohol-related cues. This leads to increased appetitive motivation to drink alcohol as measured by subjective craving and cognitive biases such as attentional bias and approach bias. Although these measures relate to the same construct, correlations between these variables are often very low. Alcohol consumption might not only increase different aspects of appetitive motivation, but also correlations between those aspects.

The rewarding effect of aggression is reduced by nucleus accumbens dopamine receptor antagonism in mice

Abstract: Dopamine (DA) receptors within the nucleus accumbens (NAc) are implicated in the rewarding properties of stimuli. Aggressive behavior can be reinforcing but the involvement of NAc DA in the reinforcing effects of aggression has yet to be demonstrated. To microinject DA receptor antagonists into the NAc to dissociate their effects on reinforcement from their effects on aggressive behavior and general movement. Male Swiss Webster mice were implanted with guide cannulae aimed for the NAc and tested for aggressive behavior in a resident–intruder procedure. Aggressive mice were then conditioned on a variable-ratio 5 (VR-5) schedule with presentation of the intruder as the reinforcing event. The D1- and D2-like receptor antagonists SCH-23390 and sulpiride were microinfused (12–50 ng) before the mice responded on the VR-5 schedule and attacked the intruder. Open-field activity was also determined following the highest doses of these drugs. SCH-23390 and sulpiride dose-dependently reduced VR responding but did not affect open-field activity. The 50-ng SCH-23390 dose suppressed response rates by 40% and biting behaviors by 10%; other aggressive behaviors were not affected. The 25 and 50 ng sulpiride doses almost completely inhibited VR responding; the 50-ng dose suppressed biting by 50%. These results suggest that both D1- and D2-like receptors in the ventral striatum are involved in the rewarding properties of aggression, but that D1-like receptors may be related to the motivation to earn reinforcement as opposed to aggressive behavior.

Positron emission tomographic studies of brain dopamine and serotonin transporters in abstinent (±)3,4-methylenedioxymethamphetamine (“ecstasy”) users: relationship to cognitive performance

Abstract: (±)3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) is a recreational drug and brain serotonin (5-HT) neurotoxin Under certain conditions, MDMA can also damage brain dopamine (DA) neurons, at least in rodents Human MDMA users have been found to have reduced brain 5-HT transporter (SERT) density and cognitive deficits, although it is not known whether these are related This study sought to determine whether MDMA users who take closely spaced sequential doses, which engender high plasma MDMA concentrations, develop DA transporter (DAT) deficits, in addition to SERT deficits, and whether there is a relationship between transporter binding and cognitive performance Sixteen abstinent MDMA users with a history of using sequential MDMA doses (two or more doses over a 3- to 12-h period) and 16 age-, gender-, and education-matched controls participated Subjects underwent positron emission tomography with the DAT and SERT radioligands, [11C]WIN 35,428 and [11C]DASB, respectively Subjects also underwent formal neuropsychiatric testing MDMA users had reductions in SERT binding in multiple brain regions but no reductions in striatal DAT binding Memory performance in the aggregate subject population was correlated with SERT binding in the dorsolateral prefrontal cortex, orbitofrontal cortex, and parietal cortex, brain regions implicated in memory function Prior exposure to MDMA significantly diminished the strength of this relationship Use of sequential MDMA doses is associated with lasting decreases in brain SERT, but not DAT Memory performance is associated with SERT binding in brain regions involved in memory function Prior MDMA exposure appears to disrupt this relationship These data are the first to directly relate memory performance to brain SERT density

Individual differences in acute alcohol impairment of inhibitory control predict ad libitum alcohol consumption.

Abstract: Rationale Research has begun to examine how acute cognitive impairment from alcohol could contribute to alcohol abuse. Specifically, alcohol-induced impairment of inhibitory control could compromise the drinker’s ability to stop the self-administration of alcohol, increasing the risk of binge drinking.

Effects of THC and lofexidine in a human laboratory model of marijuana withdrawal and relapse

Abstract: Individuals seeking treatment for their marijuana use rarely achieve sustained abstinence. The objectives of the study are to determine if THC, a cannabinoid agonist, and lofexidine, an α2-adrenergic receptor agonist, given alone and in combination, decreased symptoms of marijuana withdrawal and relapse, defined as a return to marijuana use after a period of abstinence. Nontreatment-seeking, male volunteers (n = 8), averaging 12 marijuana cigarettes/day, were maintained on each of four medication conditions for 7 days: placebo, tetrahydrocannabinol (THC) (60 mg/day), lofexidine (2.4 mg/day), and THC (60 mg/day) combined with lofexidine (2.4 mg/day); each inpatient phase was separated by an outpatient washout phase. During the first three inpatient days, placebo marijuana was available for self-administration (withdrawal). For the next 4 days, active marijuana was available for self-administration (relapse). Participants paid for self-administered marijuana using study earnings. Self-administration, mood, task performance, food intake, and sleep were measured. THC reversed the anorexia and weight loss associated with marijuana withdrawal, and decreased a subset of withdrawal symptoms, but increased sleep onset latency, and did not decrease marijuana relapse. Lofexidine was sedating, worsened abstinence-related anorexia, and did not robustly attenuate withdrawal, but improved sleep and decreased marijuana relapse. The combination of lofexidine and THC produced the most robust improvements in sleep and decreased marijuana withdrawal, craving, and relapse in daily marijuana smokers relative to either medication alone. These data suggest the combination of lofexidine and THC warrant further testing as a potential treatment for marijuana dependence.

Predicting response to opiate antagonists and placebo in the treatment of pathological gambling

Abstract: Although opiate antagonists have shown promise in the treatment of pathological gambling (PG), individual responses vary. No studies have systematically examined predictors of medication treatment outcome in PG. Understanding clinical variables related to treatment outcome should help generate treatment algorithms for PG. We sought to identify clinical variables associated with treatment outcome in PG subjects receiving opiate antagonists. Two hundred eighty-four subjects [137 (48.2%) women] with DSM-IV PG were treated in one of two double-blind placebo-controlled trials (16 weeks of nalmefene or 18 weeks of naltrexone). Gambling severity was assessed with the Yale Brown Obsessive Compulsive Scale Modified for Pathological Gambling (PG-YBOCS) with positive response defined as ≥35% reduction in PG-YBOCS score for at least 1 month by study endpoint. Depression, anxiety, and psychosocial functioning were included in stepwise logistic regression analyses designed to identify clinical factors independently associated with treatment response. The clinical variable most strongly associated with a positive response to an opiate antagonist was a positive family history of alcoholism (p = 0.006). Among individuals receiving higher doses of opiate antagonists (i.e., nalmefene 50 or 100 mg/day or naltrexone 100 or 150 mg/day), intensity of gambling urges (PG-YBOCS urge subscale) was associated with a positive response on a trend level (p = 0.036). Among individuals receiving placebo, younger age was associated, on a trend level, with positive treatment outcome (p = 0.012). A family history of alcoholism appears to predict response to an opiate antagonist in PG. Future research is needed to identify specific factors (e.g., genetic) mediating favorable responses.

Bidirectional cannabinoid modulation of social behavior in adolescent rats

Abstract: Marijuana use in adolescents is a highly social activity, and interacting endocannabinoid and opioid systems may modulate social reward. However, cannabinoid exposure has been reported to reduce social behavior. The aim of this study was to elucidate the mechanisms underlying the paradoxical relationship between cannabinoid exposure and sociability. We investigated the effect of cannabinoid agonists with a different mechanism of action on social play behavior in adolescent rats. In addition, we examined whether endocannabinoid neurotransmission interacts with opioid and dopaminergic neurotransmission in the modulation of social play behavior. The direct CB1 cannabinoid receptor agonist WIN55,212-2 reduced social play. However, the indirect cannabinoid agonist URB597, which inhibits the hydrolysis of the endocannabinoid anandamide, enhanced social play. This effect of URB597 depended upon stimulation of opioid and dopamine receptors. The well-known stimulatory effect of morphine on social play was attenuated by the CB1 cannabinoid receptor antagonist SR141716A, but independent of dopamine receptor stimulation. Combined treatment with ineffective doses of URB597 and morphine increased social play. Cannabinoid neurotransmission can both enhance and inhibit social interaction in adolescent rats depending on how the endocannabinoid system is stimulated. Activation of cannabinoid receptors throughout the brain, which occurs during cannabis use, inhibits sociability. In contrast, on-demand release of endocannabinoids facilitates social interaction, which is magnified by indirect cannabinoid agonists through an interaction with opioid and dopaminergic neurotransmission. These results shed light on the paradoxical relationship between cannabis exposure and sociability and suggest that endocannabinoid degradation inhibitors hold promise for the treatment of social dysfunctions.

Nesfatin-1 increases anxiety- and fear-related behaviors in the rat

Abstract: Nesfatin-1, derived from the protein NEFA/nucleobindin2 (NUCB2), is a newly identified peptide that acts as a potent satiety agent. It has been reported that peptides involved in the regulation of ingestive behavior are also involved in the regulation of the stress response. However, the relation between nesfatin-1 and stressor-related behaviors like anxiety and/or fear has not yet been investigated. The effects of intracerebroventricular (ICV) injection of nesfatin-1 (0, 5, and 25 pmol/3 μl) were assessed in several paradigms that are thought to reflect anxiety and/or fear in rats. Consistent with an anxiogenic effect, nesfatin-1 dose-dependently decreased the percentage of time spent on the open arms of the elevated plus maze, increased latency to approach, and decreased consumption of a palatable snack in an anxiogenic (unfamiliar) environment. Moreover, ICV nesfatin-1 increased the fear-potentiated startle response and the time spent freezing to both context and conditioned cues in a conditioned emotional response test. These findings suggest that in addition to its role as a satiety peptide, nesfatin-1 may also be involved in the mediation of anxiety- and/or fear-related responses.

Pharmacology of neuropeptide S in mice: therapeutic relevance to anxiety disorders.

Abstract: Neuropeptide S (NPS) and its receptor (NPSR) comprise a recently deorphaned G protein-coupled receptor system. Recent reports implicate NPS in the mediation of anxiolytic-like activity in rodents. To extend the characterization of NPS, the present studies examined the in vitro pharmacology of mouse NPSR and the in vivo pharmacology of NPS in three preclinical mouse models predictive of anxiolytic action: the four-plate test (FPT), elevated zero maze (EZM), and stress-induced hyperthermia (SIH). The ability of NPS to produce antidepressant-like effects in the tail suspension test (TST) was also investigated. In vitro, mouse NPS1–20 (mNPS1–20) and the C-terminal glutamine-truncated mouse NPS1–19 bound mNPSR with high affinity (K i = 0.203 ± 0.060, 0.635 ± 0.141 nM, respectively) and potently activated intracellular calcium release (EC50 = 3.73 ± 1.08, 4.10 ± 1.25 nM). NPS produced effects in vivo consistent with anxiolytic-like activity. In FPT, NPS increased punished crossings (minimal effective dose [MED]: mNPS1–20 = 0.2 μg, mNPS1–19 = 0.02 μg), similar to the reference anxiolytic, alprazolam (MED 0.5 μg). NPS increased the percentage of time spent in the open quadrants of EZM (MED: mNPS1–20 = 0.1 μg, mNPS1–19 = 1.0 μg), like the reference anxiolytic, chlordiazepoxide (MED 56 μg). In SIH, NPS attenuated stress-induced increases in body temperature similar to alprazolam but with a large potency difference between the NPS peptides (MED: mNPS1–20 = 2.0 μg, mNPS1–19 = 0.0002 μg) and mNPS1–20 increased baseline temperature. Unlike fluoxetine, NPS did not effect immobility time in TST, indicating a lack of antidepressant-like activity. These data provide an important confirmation and expansion of the anxiolytic-like effects of NPS and implicate the NPS system as a novel target for anxiolytic drug discovery.

Mismatch negativity generation in the human 5HT2A agonist and NMDA antagonist model of psychosis.

Abstract: Rationale Many studies have reported deficits of mismatch negativity (MMN) in schizophrenic patients. Pharmacological challenges with hallucinogens in healthy humans are used as models for psychotic states. Previous studies reported a significant reduction of MMN after ketamine (N-methyl-d-aspartate acid [NMDA] antagonist model) but not after psilocybin (5HT2A agonist model).

An extract of Salvia (sage) with anticholinesterase properties improves memory and attention in healthy older volunteers

Abstract: Species of Salvia (sage) have a long-standing reputation in European medical herbalism, including for memory enhancement. In recent controlled trials, administration of sage extracts with established cholinergic properties improved cognitive function in young adults. This randomised, placebo-controlled, double-blind, balanced, five-period crossover study investigated the acute effects on cognitive performance of a standardised extract of Salvia officinalis in older adults. Twenty volunteers (>65 years of age, mean = 72.95) received four active doses of extract (167, 333, 666 and 1332 mg) and a placebo with a 7-day wash-out period between visits. Assessment involved completion of the Cognitive Drug Research computerised assessment battery. On study days, treatments were administered immediately following a baseline assessment with further assessment at 1, 2.5, 4 and 6 h post treatment. Compared with the placebo condition (which exhibited the characteristic performance decline over the day), the 333-mg dose was associated with significant enhancement of secondary memory performance at all testing times. The same measure benefited to a lesser extent from other doses. There also were significant improvements to accuracy of attention following the 333-mg dose. In vitro analysis confirmed cholinesterase inhibiting properties for the extract. The overall pattern of results is consistent with a dose-related benefit to processes involved in efficient stimulus processing and/or memory consolidation rather than retrieval or working memory efficiency. These findings extend those of the memory-enhancing effects of Salvia extracts in younger populations and warrant further investigation in larger series, in other populations and with different dosing regimes.

Mice with reduced NMDA receptor glycine affinity model some of the negative and cognitive symptoms of schizophrenia.

Abstract: Schizophrenic patients demonstrate prominent negative and cognitive symptoms that are poorly responsive to antipsychotic treatment. Abnormal glutamatergic neurotransmission may contribute to these pathophysiological dimensions of schizophrenia. We examined the involvement of the glycine coagonist site on the N-methyl-d-aspartate receptor (NMDAR) glycine coagonist site in the modulation of negative and cognitive endophenotypes in mice. Behavioral phenotypes relevant to schizophrenia were assessed in Grin1D481N mice that have reduced NMDAR glycine affinity. Grin1D481N mutant mice showed abnormally persistent latent inhibition (LI) that was reversed by two agents that enhance NMDAR glycine site function, d-serine (600 mg/kg) and ALX-5407 (1 mg/kg), and by the classical atypical antipsychotic clozapine (3 mg/kg). Similarly, blockade of the NMDAR glycine site with the antagonist L-701,324 (5 mg/kg) induced persistent LI in C57BL6/J mice. In a social affiliations task, Grin1D481N mutant animals showed reduced social approach behaviors that were normalized by d-serine (600 mg/kg). During a nonassociative spatial object recognition task, mutant mice demonstrated impaired reactivity to a spatial change that was reversible by d-serine (300 and 600 mg/kg) and clozapine (0.75 mg/kg). In contrast, responses to social novelty and nonspatial change remained unaffected, indicating that the Grin1D481N mutation induces selective deficits in sociability and spatial discrimination, while leaving intact the ability to react to novelty. Genetic and pharmacologically induced deficiencies in glycine binding appear to model the impairments in behavioral flexibility, sociability, and spatial recognition related to the negative and cognitive symptoms of schizophrenia. Antipsychotics that target the NMDAR glycine site may be beneficial in treating such psychiatric symptoms.