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Experiments were carried out in mice to investigate the influence of diazepam (DZP) on dexamphetamine, para-chloro-N-methylamphetamine (pCMA), cocaine, morphine, trihexyphenidyl or (in MAOIs pretreated) reserpine induced motor hyperactivity. The interaction of DZP with these hyperactivities in which probably different biochemical central mechanisms are involved allows to construct a profile of action of DZP and to approach its mechanism of action. The locomotor hyperactivities induced by dexamphetamine, pCMA, morphine, cocaine were not reduced by DZP even by doses which decrease spontaneous locomotor activity; low doses of DZP enhance the hyperactivity induced by these compounds. Those induced by trihexyphenidyle or by reserpine (after MAOI) were reduced by DZP at doses which produce no decrease in spontaneous motor activity. Inasmuch as DZP at low doses potentiates the effects of 4 different substances, the results can hardly be satisfactorily explained neither by an interference of the benzodiazepine on the metabolism of the drugs or by a depression of the anxiogenic action of dexamphetamine. Even though it may be difficult to relate the antagonism of DZP on trihexyphenidyl- or on reserpine- (after MAOI) induced motor hyperactivity to the suggested anticholinergic and dopaminergic actions of DZP, these effects may partly be involved in the increase in locomotor hyperactivity induced by dexamphetamine, morphine or cocaine. The observed effect of DZP on pCMA induced locomotor hyperactivity does not support a possible antiserotonine action often suggested to explain the effects of benzodiazepines in conflict situations. [ABSTRACT FROM AUTHOR]

Various minor tranquilizers (benzodiazepines, barbiturates and meprobamate) induced an increase in the food intake of rats or mice. Drugs were injected i.p. 30 min before testing and the amount of food consumed during 30 min was recorded. The enhanced food consumption occurred when the animals were in a novel situation, in a situation which they had previously experienced, or in their home cage, in which they were used to eating in the daytime within 30 min. Studies with two benzodiazepines showed this effect to be maximal between 10 to 30 min after injection and to disappear 4 hrs after injection. Moreover, minor tranquilizers reduce the latency before eating of rats and mice tested in a new situation. These results and the observation of anti-anxiety drugs-induced hyperphagia in satiated animals suggest that: [ABSTRACT FROM AUTHOR]

The 'staircase' is a simple and rapid test and was used to study two components of exploratory behaviour in the rat. The scores of rearing and the number of steps climbed during three minutes were recorded. Various psychotropic drugs were tested, which modified these two parameters. Neuroleptic induced a parallel decrease of both, while benzodiazepines, meprobamate, amobarbitone and ethanol decreased the rearing at doses which left the steps climbed unchanged. At high doses, there was a parallel decrease of both parameters. Amphetamine, at lower doses, increased the rearing score alone. The comparison of the studied psychotropic drug effects with those of two muscle relaxants (by a comparison of the slopes of regression lines) suggests that either the observed benzodiazepine effects were only partly due to their myorelaxant action, or, that both myorelaxants have some anxiolytic action. The effect of amphetamine at low doses can be viewed as a demonstration of increased anxiety. [ABSTRACT FROM AUTHOR]

Rats were tested in a Lashley III maze, the floor of which was heated. The animals had to learn to negotiate it in order to gain access to the unheated goal box. In the early period of training the animals were able to find the goal box rapidly and without error. Their performance then deteriorated, in a particular way which strongly evoked a conflict behavior. This deterioration in performance was progressively reduced by oxazepam administration (8 mg/kg/day). [ABSTRACT FROM AUTHOR]

Rationale: The 5-HT2A receptor is the major target of classic hallucinogens. Both DOI (2,5-dimethoxy-4-iodoamphetamine) and lisuride act at 5-HT2A receptors, and lisuride shares comparable affinity with DOI and acts as a partial agonist at 5-HT2A receptors. However, not like DOI, lisuride lacks hallucinogenic properties. Impulsive decision-making refers to the preference for an immediate small reinforcer (SR) over a delayed large reinforcer (LR). Objectives: The current study aims to compare the effects of DOI and lisuride on impulsive decision-making and further to investigate the possible receptor mechanisms responsible for the actions of the two drugs. Methods: Impulsive decision-making was evaluated in male Sprague–Dawley rats by the percentage of choice for the LR in delay discounting task (DDT). Delay to the LR changed in an ascending order (0, 4, 8, 16, and 32 s) across one session. Results: DOI (0.5 and 1.0 mg/kg) increased impulsive decision-making, and the effects of DOI (1.0 mg/kg) were blocked by the 5-HT2A receptor antagonist ketanserin (1.0 mg/kg) rather than the 5-HT2C receptor antagonist SB-242084 (1.0 mg/kg). Contrarily, lisuride (0.1, 0.3, and 0.5 mg/kg) decreased impulsive decision-making. The effects of lisuride (0.3 mg/kg) were not antagonized by ketanserin (1.0 mg/kg), selective 5-HT1A antagonist WAY-100635 (1.0 mg/kg), or selective dopamine D4 receptor antagonist L-745870 (1.0 mg/kg) but were attenuated by the selective dopamine D2/D3 receptor antagonist tiapride (40 mg/kg). Conclusions: DOI and lisuride have contrasting effects on impulsive decision-making via distinct receptorsDOI-induced increase of impulsivity is mediated by the 5-HT2A receptor, while lisuride-induced inhibition of impulsivity is regulated by the dopamine D2/D3 receptor. [ABSTRACT FROM AUTHOR]

The serotonin (5-HT) system, particularly the 5-HT2C receptor, has consistently been implicated in behavioural control. However, while some studies have focused on the role 5-HT2C receptors play in regulating motivation to work for reward, others have highlighted its importance in response restraint. To date, it is unclear how 5-HT transmission at this receptor regulates the balance of response invigoration and restraint in anticipation of future reward. In addition, it remains to be established how 5-HT2C receptors gate the influence of internal versus cue-driven processes over reward-guided actions. To elucidate these issues, we investigated the effects of administering the 5-HT2C receptor antagonist SB242084, both systemically and directly into the nucleus accumbens core (NAcC), in rats performing a Go/No-Go task for small or large rewards. The results were compared to the administration of d-amphetamine into the NAcC, which has previously been shown to promote behavioural activation. Systemic perturbation of 5-HT2C receptors—but crucially not intra-NAcC infusions—consistently boosted rats' performance and instrumental vigour on Go trials when they were required to act. Concomitantly, systemic administration also reduced their ability to withhold responding for rewards on No-Go trials, particularly late in the holding period. Notably, these effects were often apparent only when the reward on offer was small. By contrast, inducing a hyperdopaminergic state in the NAcC with d-amphetamine strongly impaired response restraint on No-Go trials both early and late in the holding period, as well as speeding action initiation. Together, these findings suggest that 5-HT2C receptor transmission, outside the NAcC, shapes the vigour of ongoing goal-directed action as well as the likelihood of responding as a function of expected reward. [ABSTRACT FROM AUTHOR]

Rationale: Stress is a well-known risk factor for anhedonia, and its impacts on social reward functions may be mitigated by its controllability. Moreover, there are questions about the effectiveness of selective serotonin reuptake inhibitors (SSRIs) on improving social hedonic functioning deficits characteristic of major depression. Objectives: The current study in male Sprague–Dawley rats investigated the effects of uncontrollable stress on responses to social incentive stimuli and possible modulation by the SSRI escitalopram (ESC). Methods: The effects of inescapable foot-shocks on preferential responses to a conspecific, and to a compartment that was previously paired with the presence of a conspecific, were assessed in a Y-apparatus in rats that received 0, 5, or 10 mg/kg ESC. Results: Although inescapable foot-shock exposure did not significantly alter the investigation of the conspecific, it did impair the response to the social-paired compartment and, importantly, this impairment was reversed by ESC. Conclusion: These results indicate that psychophysical stress can negatively impact reactivity to learned social rewards and that SSRI administration can have positive therapeutic effects. [ABSTRACT FROM AUTHOR]

Rationale: Cannabis use is typically initiated during adolescence, and different studies suggest that adolescent cannabinoid exposure may increase the risk for drug addiction in adulthood. Objectives: This study investigated the effects of adolescent exposure to the main psychoactive component of cannabis, ∆9-tetrahydrocannabinol (THC), in the reinforcing properties of nicotine in adult male mice. Possible alterations in relapse to nicotine-seeking behaviour in adult animals due to THC adolescent exposure were also evaluated. Methods: Adolescent mice were exposed to escalating doses of THC from PND35 to PND49. When mice reached adulthood (PND70), surgical procedures were applied for further behavioural evaluation. Nicotine self-administration sessions were conducted consecutively for 10 days. Following extinction, mice were tested for cue- and stress-induced reinstatement of nicotine-seeking behaviour. Results: Adolescent THC treatment did not modify acquisition and extinction of nicotine self-administration in adulthood. Moreover, THC exposure did not alter relapse to nicotine seeking induced by stress or nicotine-associated cues. Conclusions: These results suggest that a history of exposure to THC during adolescence under these particular conditions does not modify the reinforcing effects and seeking behaviour of nicotine in the adult period. [ABSTRACT FROM AUTHOR]

Rationale: Social withdrawal is a core feature of the negative symptoms of schizophrenia. Currently available pharmacotherapies have only limited efficacy towards the negative symptoms, i.e., there is a significant unmet medical need in the treatment of these symptoms. Objective: We wanted to confirm whether selective adrenergic α2C receptor (AR) antagonist therapy could ameliorate acute phencyclidine (PCP)-induced schizophrenia-like social interaction deficits in rats, and to compare the effects of an α2C AR antagonist to another putative therapeutic alternative, an α7 nicotinic acetylcholine receptor (nAChR) partial agonist, as well against three commonly used atypical antipsychotics. Methods: Here, we used acute PCP administration and modified a protocol for testing social interaction deficits in male Wistar rats and then used this model to compare the effects of an α2C AR antagonist (ORM-13070 0.3 and 1.0 mg/kg s.c.) with an α7 nAChR partial agonist (EVP-6124 0.3 mg/kg s.c.) and three atypical antipsychotics (clozapine 2.5 mg/kg i.p., risperidone 0.04 and 0.08 mg/kg s.c., olanzapine 0.125 and 0.5 mg/kg s.c.) on social interaction behavior. Results: Acute PCP (1.5 mg/kg s.c.) produced robust and reproducible deficits in social interaction behavior without affecting locomotor activity. The selective α2C AR antagonist significantly ameliorated PCP-induced social interaction deficits. In contrast, neither the partial α7 nAChR agonist nor any of the three atypical antipsychotics were able to reverse the behavioral deficits at the selected doses. Conclusion: Our findings confirm that α2C AR antagonism is a potential mechanism for the treatment of the negative symptoms of schizophrenia. [ABSTRACT FROM AUTHOR]

Rationale: Lower lip retraction (LLR) in rats has been described as a distinctive effect of 5-HT1A agonists. In the course of evaluating behavioral effects of cannabinoid agonists in rats, LLR effects were evident following injection of several cannabinoid agonists. Objectives: To pharmacologically characterize cannabinoid-induced LLR in rats. Methods: Lower lip retraction was scored using a 3-point scale for up to 6 h after injection of the cannabinoid agonists Δ9-tetrahydrocannabinol (Δ9-THC, 1–10 mg/kg), AM7499 (0.01–1.0 mg/kg), or AM2389 (0.003–0.1 mg/kg), or, for comparison, the 5-HT1A agonist 8-OH-DPAT (0.01–0.3 mg/kg). Next, antagonist effects of rimonabant (1–10 mg/kg) and WAY100635 (0.3 mg/kg) on LLR produced by cannabinoid or 5-HT1A agonists were evaluated. Lastly, effects of 8-OH-DPAT were determined following pretreatment with AM2389 (0.003–0.01 mg/kg) or Δ9-THC (1 mg/kg). Results: All three cannabinoid agonists produced LLR. Effects of AM2389 were attenuated by both rimonabant and WAY100635 whereas effects of 8-OH-DPAT were antagonized by WAY 100635 but not by rimonabant. Pretreatment with 1 mg/kg Δ9-THC or 0.01 mg/kg AM2389 shifted the 8-OH-DPAT dose-effect function for LLR to the left and isobolographic analysis of the data indicates CB1 and 5-HT1A interactions can be supraadditive. Conclusions: Cannabinoid agonists produce LLR in rats, an effect heretofore ascribed only to activity at 5-HT1A receptors, via CB1 receptor-mediated actions. Co-administration of a cannabinoid agonist and the 5-HT1A agonist 8-OH-DPAT results in a synergistic effect on LLR. [ABSTRACT FROM AUTHOR]

Rationale: Across species, effort-related motivation can be assessed by testing behaviour under a progressive ratio (PR) schedule of reinforcement. However, to date, PR tasks for rodents have been available using traditional operant response systems only.Objectives: Touchscreen operant response systems allow the assessment of behaviour in laboratory rodents, using tasks that share high face validity with the computerised assessments used in humans. Here, we sought to optimise a rat touchscreen variant of PR and validate it by assessing the effects of a number of manipulations known to affect PR performance in non-touchscreen paradigms.Methods: Separate groups of male Sprague-Dawley rats were trained on PR schedules with either linear (PR4) or exponential (PREXP) schedules of reinforcement. PR performance was assessed in response to manipulations in reward outcome. Animals were tested under conditions of increased reward magnitude and following reward devaluation through a prefeeding procedure. Subsequently, the effects of systemic administration of the dopamine D2/D3 receptor antagonist raclopride and the psychostimulant d-amphetamine were examined as traditional pharmacological methods for manipulating motivation.Results: Rats reinforced under PR4 and PREXP schedules consistently showed differential patterns of response rates within sessions. Furthermore, both PR4 and PREXP schedules were sensitive to suppression by prefeeding or raclopride administration. Performance under both schedules was facilitated by increasing reward magnitude or d-amphetamine administration.Conclusions: Taken together, these findings mirror those observed in lever-based PR paradigms in rats. This study therefore demonstrates the successful validation of the rat touchscreen PR task. This will allow for the assessment of motivation in rats, within the same touchscreen apparatus used for the assessment of complex cognitive processes in this species. [ABSTRACT FROM AUTHOR]

Rationale: Adding reward-concurrent cues to a rat gambling task (rGT) increases risky choice. This cued version of the task may reflect an 'addiction-like' cognitive process, more similar to human gambling than the uncued task. Serotonergic drugs that target 5-HT receptors alter mechanisms linked to impulse control. However, relatively little is known regarding the impact of such agents on either risky decision making, or the ability of conditioned stimuli to bias the choice process, despite potential relevance to addiction development and treatment. Objectives: The aim of this study was to determine the effects of SB 242,084 and M100907, selective antagonists at the 5-HT and 5-HT receptors respectively, as well as the selective 5-HT receptor agonist Ro-60-0175, on performance of both cued and uncued versions of the rGT. Results: SB 242,084 significantly and dose-dependently increased choice of the most optimal option in the cued rGT only, despite concurrently increasing impulsive responses made prematurely on both the cued and uncued rGT. M100907 and Ro-60-0175 did not alter risky decision making, but nevertheless produced the expected decrease in premature responses on both task variants. Conclusions: These findings demonstrate that the 5-HT receptor-mediated regulation of risky decision making and motor impulsivity can be pharmacologically dissociated and further show that the presence of highly salient reward-paired cues critically alters the neurochemical regulation of the choice process. Importantly, these results suggest that 5-HT receptor antagonists may be of use in disrupting maladaptive patterns of decision making. [ABSTRACT FROM AUTHOR]

Rationale: Cannabinoid CB1 inverse agonists hold therapeutic promise as appetite suppressants but have produced suicidal behaviors among a small subpopulation in clinical trials. Anatomical and pharmacological evidence implicate the 5HT serotonin receptor in suicide in humans and impulsivity in humans and animals. Objective: The objective of the study is to assess whether 5HT blockade is necessary for CB1 ligands to produce impulsivity. Methods: Sprague Dawley rats were administered the CB1 inverse agonist AM 251, the CB1 antagonist AM 6527, or the peripherally restricted antagonist AM 6545, with or without pretreatment with the 5HT antagonist WAY 100,635 (WAY) on the paced fixed consecutive number (FCN) task, which measures choice to terminate a chain of responses prematurely. As FCN is sensitive to changes in time perception, which have been demonstrated with CB1 blockade, a novel variable consecutive number task with discriminative stimulus (VCN-S) was also performed and proposed to be less sensitive to changes in timing. Results: Pretreatment with WAY enabled mild but significant reductions in FCN accuracy for AM 251 and AM 6527. No effects were found for AM 6545. On the VCN-S task, substantial impairments were found for the combination of WAY and AM 251. Conclusions: AM 251, but not the antagonists AM 6527 or AM 6545, produced impulsivity only following systemic 5HT blockade. Although preliminary, the results may indicate that disrupted serotonin signaling produces a vulnerability to undesirable effects of CB1 inverse agonists, which is not evident in the general population. Furthermore, neutral CB1 antagonists do not produce this effect and therefore may have greater safety. [ABSTRACT FROM AUTHOR]

Rationale: Novel cannabinoid compounds continue to be marketed as 'legal' marijuana substitutes, even though little is known about their molecular and behavioral effects. Objectives: Six of these compounds (ADBICA, ADB-PINACA, THJ-2201, RCS-4, JWH-122, JWH-210) were tested for in vitro and in vivo cannabinoid-like effects to determine their abuse liability. Methods: Binding to and functional activity at CB1 cannabinoid receptors was tested. Locomotor activity in mice was tested to screen for behavioral activity and to identify behaviorally active dose ranges and times of peak effect. Discriminative stimulus effects of the six compounds were tested in rats trained to discriminate Δ-tetrahydrocannabinol (Δ-THC). Results: ADBICA, ADB-PINACA, THJ-2201, RCS-4, JWH-122, and JWH-210 showed high affinity binding at the CB1 receptor at nanomolar affinities (0.59 to 22.5 nM), and all acted as full agonists with nanomolar potencies (0.024 to 111 nM) when compared to the CB1 receptor full agonist CP 55940. All compounds depressed locomotor activity below 50 % of vehicle responding, with depressant effects lasting 1.5 to nearly 4 h. All compounds fully substituted (<80 % Δ-THC-appropriate responding) for the discriminative stimulus effects of Δ-THC. 3,4-Methylenedioxy-methamphetamine (MDMA) was tested as a negative control and did not substitute for Δ-THC (11 % Δ-THC-appropriate responding). Conclusions: All six of the compounds acted at the CB1 receptor and produced behavioral effects common to abused cannabinoid compounds, which suggest that these compounds have substantial abuse liability common to controlled synthetic cannabinoid compounds. [ABSTRACT FROM AUTHOR]

The validity of spontaneous hypertensive rat (SHR) as a model of attention deficit hyperactivity disorder (ADHD) has been explored by comparing SHR with Wistar rats in a test of attention, the two-choice visual discrimination task (2-CVDT). Animals were 4-5 weeks old during the training phase of the experiment and 6-7 weeks old during the testing phase in which they were tested with D-amphetamine, a stimulant drug used for the treatment of ADHD. As compared to Wistar, SHR showed a slightly better attention performance, a slightly lower impulsivity level, and a lower general activity during the training phase, but these differences disappeared or lessened thereafter, during the testing phase. D-amphetamine (0.5, 1 mg/kg) improved attention performance in Wistar, but not in SHR, and did not modify impulsivity and activity in the two strains. In conclusion, the present study did not demonstrate that SHR represents a valid model of ADHD, since it did not show face validity regarding the behavioral symptoms of ADHD and predictive validity regarding the effect of a compound used for the treatment of ADHD. On the other hand, this study showed that the 2-CVDT may represent a suitable tool for evaluating in adolescent Wistar rats the effect on attention of compounds intended for the treatment of ADHD. [ABSTRACT FROM AUTHOR]

Rationale: Since the hypofunction of the N-methyl-D-aspartate (NMDA) receptor is known to be involved in the pathophysiology of schizophrenia, the enhancement of NMDA receptor function through glycine modulatory sites is expected to be a useful approach for the treatment of schizophrenia. Objectives: We investigated the efficacy of a glycine transporter 1 (GlyT1) inhibitor that potentiates NMDA receptor function by increasing synaptic glycine levels in animal models for cognitive dysfunction and negative symptoms, both of which are poorly managed by current antipsychotics. Results: A newly synthesized GlyT1 inhibitor, 3-chloro-N-{(S)-[3-(1-ethyl-1H-pyrazol-4-yl)phenyl][(2S)-piperidin-2-yl]methyl}-4-(trifluoromethyl)pyridine-2-carboxamide (TASP0315003) significantly improved cognitive deficit induced by MK-801 in the object recognition test in rats. Likewise, TASP0315003 significantly improved MK-801 impaired cognition in the social recognition test in rats and also enhanced social memory in treatment-naïve rats. In addition, repeated phencyclidine (PCP) treatment reduced the social interaction of paired mice, which may reflect negative symptoms such as social withdrawal, and both acute and sub-chronic treatment with TASP0315003 reversed the reduction in social interaction induced by PCP. Moreover, TASP0315003 additionally exhibited an antidepressant effect in the forced swimming test in rats. In contrast, TASP0315003 did not affect spontaneous locomotor activity or rotarod performance and did not induce catalepsy, indicating that TASP0315003 does not cause sedation or motor dysfunction, which is sometimes observed with the use of current antipsychotics. Conclusions: These results suggest that GlyT1 inhibitors including TASP0315003 may be useful for the treatment of cognitive dysfunction and the negative symptoms of schizophrenia without having undesirable central nervous system side effects. [ABSTRACT FROM AUTHOR]

Rationale: Oxytocin (OT), vasopressin (AVP) and 3,4 methylenedioxymethamphetamine (MDMA, 'Ecstasy') all increase social interaction in rats, perhaps by enhancing the rewarding value of social encounters. Objectives: Here, we used the conditioned place preference (CPP) paradigm to assess the intrinsic rewarding effects of OT, AVP and MDMA, and whether these effects are enhanced by the presence of a conspecific, or a dynamic, tactile object (a tennis ball). Methods: Adult male rats received conditioning sessions in a CPP apparatus twice a day (vehicle at 10 a.m., drug at 3 p.m.). Experiment 1 involved conditioning with OT (0.5 mg/kg, intraperitoneal (i.p.)), AVP (0.005 mg/kg, i.p.) or MDMA (5 mg/kg, i.p.). Experiments 2 and 3 involved conditioning with the same treatments but in the presence of a conspecific receiving the same treatment (social-CPP) or in the presence of a tennis ball (object-CPP), respectively. Conditioned place preference was assessed 24 h, 2 weeks and 4 weeks later. Results: OT, AVP and MDMA did not produce a conventional CPP. However, when the conditioning environment also contained a conspecific both OT and MDMA induced a significant CPP lasting for at least 4 weeks. Rats given OT and MDMA also developed a more modest yet significant CPP for the environment where they encountered a tennis ball. Conclusions: These results indicate that OT and MDMA can augment the rewarding effects of social interaction, but also interaction with a dynamic and tactile non-social object. AVP does not condition social- or object-CPPs and may promote social proximity by inducing generalized anxiety and defensive aggregation. [ABSTRACT FROM AUTHOR]

Background: Animal models that allow concurrent access to drug and nondrug reinforcers provide unique insight into the etiology, maintenance, and treatment of drug use. Objectives: We sought to develop and utilize a concurrent access procedure with nicotine and sucrose in rats. Methods: Pressing one lever delivered intravenous nicotine, and pressing another lever delivered sucrose pellets, with both reinforcers freely available throughout daily sessions. Results: Rats that had been pretrained with nicotine on some days and sucrose on other days responded on both levers when subsequently given concurrent access, but almost all responded at substantially higher rates on the sucrose lever. In contrast, rats pretrained exclusively with nicotine before being given concurrent access showed individual differences, with about half responding more on the nicotine lever. Treatment with the nicotinic receptor partial agonist varenicline selectively decreased nicotine self-administration. Food restriction and removal of the sucrose lever both increased nicotine self-administration. Conclusions: The finding that rats continue to take nicotine when sucrose is concurrently available-and in many cases take it more frequently than sucrose-demonstrates that nicotine self-administration does not only occur in the absence of alternative reinforcement options. As a model of human nicotine use, concurrent access is more naturalistic and has higher face validity than procedures in which only one reinforcer is available or choosing one reinforcer precludes access to other reinforcers. As such, this procedure could be useful for evaluating therapeutic agents and improving our understanding of environmental conditions that promote or discourage nicotine use. [ABSTRACT FROM AUTHOR]

Rationale: Human motivation and decision-making is influenced by the interaction of Pavlovian and instrumental systems. The neurotransmitters dopamine and serotonin have been suggested to play a major role in motivation and decision-making, but how they affect this interaction in humans is largely unknown. Objective: We investigated the effect of these neurotransmitters in a general Pavlovian-to-instrumental transfer (PIT) task which measured the nonspecific effect of appetitive and aversive Pavlovian cues on instrumental responses. Methods: For that purpose, we used selective dietary depletion of the amino acid precursors of serotonin and dopamine: tryptophan ( n = 34) and tyrosine/phenylalanine ( n = 35), respectively, and compared the performance of these groups to a control group ( n = 34) receiving a nondepleted (balanced) amino acid drink. Results: We found that PIT differed between groups: Relative to the control group that exhibited only appetitive PIT, we found reduced appetitive PIT in the tyrosine/phenylalanine-depleted group and enhanced aversive PIT in the tryptophan-depleted group. Conclusions: These results demonstrate a differential involvement of serotonin and dopamine in motivated behavior. They suggest that reductions in serotonin enhance the motivational influence of aversive stimuli on instrumental behavior and do not affect the influence of appetitive stimuli, while reductions in dopamine diminish the influence of appetitive stimuli. No conclusions could be drawn about how dopamine affects the influence of aversive stimuli. The interplay of both neurotransmitter systems allows for flexible and adaptive responses depending on the behavioral context. [ABSTRACT FROM AUTHOR]

Rationale: Diverse preclinical studies suggest the potential therapeutic utility of the modulation of the glutamatergic system in brain via metabotropic glutamate (mGlu) receptors. Lu AF21934, a positive allosteric modulator of the mGlu4 receptor, was previously shown to reverse behavioral phenotypes in animal models thought to mimic positive, negative, and cognitive symptoms of schizophrenia. Objectives: To begin elucidating the brain circuitry involved in mGlu4 receptor pharmacology and add mechanistic support to Lu AF21934-induced phenotypic responses, the potential involvement of 5-HT receptors in these antipsychotic-like effects was explored. The tests used were the following: MK-801-induced hyperactivity and 2,5-dimethoxy-4-iodoamphetamine (DOI)-induced head twitches in mice, for positive symptoms; MK-801-induced disruptions of social interactions for negative symptoms; and novel object recognition and spatial delayed alteration test for cognitive symptoms. The microdialysis studies in which the effect of Lu AF21934 on MK-801-induced dopamine and serotonin release was investigated. Results: The effects caused by Lu AF2193 were inhibited by administration of the selective 5-HT receptor antagonist WAY100635 (0.1 mg/kg). That inhibition was observed across all models used. Moreover, the concomitant administration of sub-effective doses of Lu AF21934 and a sub-effective dose of the selective 5-HT receptor agonist tool compound ( R)-(+)-8-hydroxy-DPAT hydrobromide (0.01 mg/kg) induced a clear antipsychotic-like effect in all the procedures used. Lu AF21934 (5 mg/kg) also inhibited MK-801-induced increase in dopamine and 5-HT release. Conclusions: The actions of Lu AF21934 are 5-HT receptor-dependent. Activation of the mGlu4 receptor may be a promising mechanism for the development of novel antipsychotic drugs, efficacious toward positive, negative, and cognitive symptoms. [ABSTRACT FROM AUTHOR]

Rationale: The serotonin (5-HT) system has been reported to be involved in decision-making. A key component of this neurotransmitter system is the 5-HT receptor, and research is beginning to show how this receptor can influence decision-making. However, this relationship has rarely been studied in humans. Objectives: This study assessed whether individual variability in 5-HT availability correlates with decision-making in healthy volunteers. Methods: We measured regional availability of the 5-HT receptor in the hippocampal complex and striatum using positron emission tomography and correlated this with performance on two decision-making tasks measuring sensitivity to probability, rewards and punishments and temporal discounting, respectively. Results: No relationship between decision-making behaviour and 5-HT availability in the striatum was found. However, a positive correlation was detected between participants' 5-HT availability in the hippocampal complex and their sensitivity to the probability of winning. Furthermore, there was a negative correlation between the degree to which participants discounted future rewards and 5-HT availability in the hippocampal complex. Conclusions: These data support a role for the 5-HT receptor in the aberrant decision-making that can occur in neuropsychiatric disorders such as depression. [ABSTRACT FROM AUTHOR]

Rationale: Cannabinoid antagonists purportedly have greater effects in reducing the intake of highly palatable food compared to less palatable food. However, this assertion is based on free-feeding studies in which the amount of palatable food eaten under baseline conditions is often confounded with other variables, such as unequal access to both food options and differences in qualitative features of the foods. Objective: We attempted to reduce these confounds by using a model of choice that programmed the delivery rates of sucrose and carrot-flavored pellets. Methods: Lever pressing of ten lean ( Fa/Fa or Fa/fa) and ten obese ( fa/fa) Zucker rats was placed under three conditions in which programmed ratios for food pellets on two levers were 5:1, 1:1, and 1:5. In phase 1, responses on the two levers produced one type of pellet (sucrose or carrot); in phase 2, responses on one lever produced sucrose pellets and on the other lever produced carrot pellets. After responses stabilized under each food ratio, acute doses of rimonabant (0, 3, and 10 mg/kg) were administered before experimental sessions. The number of reinforcers and responses earned per session under each ratio and from each lever was compared. Results and conclusions: Rimonabant reduced reinforcers in 1:5 and 5:1 food ratios in phase 1, and across all ratios in phase 2. Rimonabant reduced sucrose and carrot-flavored pellet consumption similarly; rimonabant did not affect bias toward sucrose, but increased sensitivity to amount differences in lean rats. This suggests that relative amount of food, not palatability, may be an important behavioral mechanism in the effects of rimonabant. [ABSTRACT FROM AUTHOR]

Rationale: The 'subjective high' from marijuana ingestion is likely due to Δ-tetrahydrocannabinol (THC) activating the central cannabinoid receptor type 1 (CBR) of the endocannabinoid signaling system. THC is a weak partial agonist according to in vitro assays, yet THC mimics the behavioral effects induced by more efficacious cannabinergics. This distinction may be important for understanding similarities and differences in the dose-effect spectra produced by marijuana/THC and designer cannabimimetics ('synthetic marijuana'). Objective: We evaluated if drug discrimination is able to functionally detect/differentiate between a full, high-efficacy CBR agonist [(±)AM5983] and the low-efficacy agonist THC in vivo. Materials and methods: Rats were trained to discriminate between four different doses of AM5983 (0.10 to 0.56 mg/kg), and vehicle and dose generalization curves were determined for both ligands at all four training doses of AM5983. The high-efficacy WIN55,212-2 and the lower-efficacy ( R)-(+)-methanandamide were examined at some AM5983 training conditions. Antagonism tests involved rimonabant and WIN55,212-2 and AM5983. The separate ( S)- and ( R)-isomers of (±)AM5983 were tested at one AM5983 training dose (0.30 mg/kg). The in vitro cyclic adenosine monophosphate (cAMP) assay examined AM5983 and the known CBR agonist CP55,940. Results: Dose generalization ed values increased as a function of the training dose of AM5983, but more so for the partial agonists. The order of potency was ( R)-isomer > (±)AM5983 > ( S)-isomer and AM5983 > WIN55,212-2 ≥ THC > ( R)-(+)-methanandamide. Surmountable antagonism of AM5983 and WIN55,212-2 occurred with rimonabant. The cAMP assay confirmed the cannabinergic nature of AM5983 and CP55,940. Conclusions: Drug discrimination using different training doses of a high-efficacy, full CBR agonist differentiated between low- and high-efficacy CBR agonists. [ABSTRACT FROM AUTHOR]

Rationale: Inhibition of glycine transporter 1 (GlyT1) elevates extracellular glycine and can thus increase N-methyl- d-aspartate receptor (NMDAR) excitability in the brain. The potent GlyT1 inhibitor, SSR504734, has also been shown to potentiate the behavioral effects of direct and indirect dopamine agonists. Thus, an acute systemic dose of SSR504734 was sufficient to exacerbate the motor-stimulant effect of the dopamine releaser amphetamine in C57BL/6 mice, even though SSR504734 alone exerted no significant effect on motor activity. Objectives: Here, we explore if SSR504734 might modulate dopamine-dependent sensory gating in the paradigm of prepulse inhibition (PPI) of the acoustic startle reflex. Methods: Experiment 1 characterized the effect of SSR504734 (10 and 30 mg/kg i.p.) on PPI expression when administered alone. Experiments 2 and 3 investigated the impact of SSR504734 when administered in conjunction with the dopamine receptor agonist, apomorphine (1 and 2 mg/kg s.c.), which is known to reliably disrupt PPI. Results: When administered alone, acute SSR504734 enhanced PPI only at 30 mg/kg-a dose that has been shown to improve cognitive functions including working memory, which has been linked to enhanced NMDAR function resulting from the elevation of extracellular glycine. However, this effect did not allow SSR504734 to antagonize the PPI-disruptive effect of apomorphine. At the lower dose of 10 mg/kg-that was insufficient to enhance PPI when administered alone-SSR504734 even exacerbated the deleterious effect of apomorphine on PPI. Conclusions: The therapeutic potential of GlyT1 inhibition against distinct behavioral/cognitive deficiency might require different magnitudes of GlyT1 inhibition. [ABSTRACT FROM AUTHOR]

Background: Numerous studies suggest (1) that a major physiological role of brain serotonin-containing neurons is to modulate sex steroid-driven behaviour such as sex and aggression, (2) that sex steroids influence brain serotonergic neurotransmission and (3) that brain serotonergic neurotransmission displays sexual dimorphism. Such observations indicate that an important task for brain serotonin is to either enhance or counteract sex differences in behaviour. Methods: To test this hypothesis, we explored the effect of short-term serotonin depletion on the behaviour of adult male and female rats in a behavioural paradigm in which males and females have been shown to behave differently, i.e. the elevated plus maze. Results: Two rounds of testing of untreated Wistar rats confirmed the previous observation that females make more entries into open arms (round 1, p = 0.001; round 2, p = 0.008) and spend more time on these arms (round 1, p ≤ 0.001; round 2, p = 0.006) than males; in addition, males displayed fewer entries into closed arms upon habituation, i.e. at the second round ( p ≤ 0.001) than did females. Administration of the tryptophan hydroxylase inhibitor para-chloro-phenylalanine, at a regimen (300 mg/kg/day for 3 days), markedly reducing brain content of serotonin, enhanced entries upon open arms ( p = 0.01) and time spent on open arms ( p = 0.004) in males but exerted no such effects in females ( p = 0.9 and p = 0.9, respectively); moreover, it reduced entries into closed arms in females ( p ≤ 0.001) but not in males ( p = 0.1). Conclusions: Serotonin depletion abolishing the sex differences observed at baseline supports the theory that serotonin aids to uphold certain sex differences in behaviour. [ABSTRACT FROM AUTHOR]

Rationale: Whereas cannabinoid CB receptors have long been known to contribute to the rewarding effects and dependence liability of many drugs of abuse, recent studies have implicated the involvement of cannabinoid CB receptors. Objective: Here, we evaluated the role of CB receptors in the rewarding properties of nicotine, as assessed in the conditioned place preference (CPP) paradigm and mecamylamine-precipitated withdrawal in nicotine dependent mice. Methods: Using complementary pharmacological and genetic approaches, we investigated the involvement of CB receptors in nicotine- and cocaine-induced CPP in mice and mecamylamine-precipitated withdrawal in nicotine-dependent mice. We also determined whether deletion of CB receptors affects nicotine-induced hypothermia and hypoalgesia. Results: Nicotine-induced (0.5 mg/kg) CPP was completely blocked by selective CB antagonist, SR144528 (3 mg/kg) in wild-type mice, and was absent in CB (−/−) mice. Conversely, the CB receptor agonist, O-1966 (1, 3, 5, 10, 20 mg/kg) given in combination with a subthreshold dose of nicotine (0.1 mg/kg) elicited a place preference. In contrast, O-1966 (20 mg/kg) blocked cocaine (10 mg/kg)-induced CPP in wild type mice, while CB (−/−) mice showed unaltered cocaine CPP. CB (+/+) and (−/−) nicotine-dependent mice showed almost identical precipitated withdrawal responses and deletion of CB receptor did not alter acute somatic effects of nicotine. Conclusions: Collectively, these results indicate that CB receptors are required for nicotine-induced CPP in the mouse, while it is not involved in nicotine withdrawal or acute effects of nicotine. Moreover, these results suggest that CB receptors play opposing roles in nicotine- and cocaine-induced CPP. [ABSTRACT FROM AUTHOR]