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Selegiline and rasagiline are two selective monoamine oxidase B (MAO-B) inhibitors used in the treatment of Parkinson's disease. In their clinical application, however, differences in L-dopa-sparing potencies have been observed. The aim of this study was to find neurochemical and behavioral explanations for the antiparkinsonian effects of these drugs. We found that selegiline possesses a dopaminergic enhancer effect: it stimulated the electrically induced [3H]dopamine release without influencing the resting [3H]dopamine release from rat striatal slices in 10−10–10−9 mol/L concentrations. Rasagiline added in 10−13 to 10−5 mol/L concentrations did not alter the resting or electrically stimulated [3H]dopamine release. Rasagiline (10−9 mol/L), however, suspended the stimulatory effect of selegiline on the electrically induced [3H]dopamine release. The trace amine-associated receptor 1 (TAAR1) antagonist EPPTB (10−8–10−7 mol/L) also inhibited the stimulatory effect of selegiline on [3H]dopamine release. The effect of selegiline in its enhancer dose (5.33 nmol/kg) against tetrabenazine-induced learning deficit measured in a shuttle box apparatus was abolished by a 5.84 nmol/kg dose of rasagiline. The selegiline metabolite (−)methamphetamine (10−9 mol/L) also exhibited enhancer activity on [3H]dopamine release. We have concluded that selegiline acts as an MAO-B inhibitor and a dopaminergic enhancer drug, and the latter relates to an agonist effect on TAAR1. In contrast, rasagiline is devoid of enhancer activity but may act as an antagonist on TAAR1. [ABSTRACT FROM AUTHOR]

Schizophrenia, the most serious among psychoses, has negative symptoms such as anhedonia, avolition and apathy, and cognitive defects in addition to positive symptoms such as hallucinations and delusions characterising all psychotic disorders. Traditional antipsychotics had dopamine D2 receptor antagonism as their principal mechanism of action, with disabling extrapyramidal symptoms as corollary. Newer atypical agents with diverse receptor actions introduced to circumvent this issue, nevertheless, had varied side effects such as agranulocytosis, insulin resistance, seizures, and cardiac events. Also, symptoms in cognitive and negative domains do not respond well even to newer agents creating an unmet need. Designing a valid animal model with translational relevance for a complex disease such as schizophrenia is a tedious process. Induction or suppression of certain animal behaviours by test compounds (behavioural models) and antagonising effects induced by compounds with psychotic potential (pharmacological models) are the conventional models used. One among the major disadvantages with conventional models is that these paradigms are induced acutely and relate to aberration of a single neurotransmitter system, which is in sharp contrast to the chronic nature and interplay of multiple neurotransmitter systems in psychotic diseases. However, with progress in elucidation of disease mechanisms, novel models are generated utilising developmental, genetic, and environmental factors (neurodevelopmental models) to effectively reflect the human disease pathogenesis and clinical manifestations, but with paucity of studies assessing the impact of drugs on them. This review presents an overview of schizophrenia hypotheses, requisites of a valid animal model, available animal models with their advantages and disadvantages. [ABSTRACT FROM AUTHOR]

The nitric oxide (NO)-donor, sodium nitroprusside (SNP) has been proposed as an adjunct treatment to enhance the effect of antipsychotic drugs (APDs). As NO constitutes an important downstream signaling molecule of N -methyl-D-aspartate receptors, SNP may alleviate symptoms of schizophrenia by modulating glutamatergic signaling. We previously showed that SNP enhances the antipsychotic-like effect of a sub-effective dose of risperidone in the conditioned avoidance response (CAR) test, indicating that adjunct SNP may be used to lower the dose of risperidone and in this way reduce the risk of side effects. By using the CAR test, we here investigated if SNP also enhances the antipsychotic-like effect of olanzapine or clozapine. Importantly, SNP (1.5 mg/kg) significantly enhanced the antipsychotic-like effect of olanzapine (1.25 and 2.5mg/kg) to a clinically relevant level, supporting the potential clinical use of SNP as an adjunct treatment to improve the effect of APDs. However, SNP (1.5 mg/kg) did not increase the antipsychotic-like effect of clozapine (5 and 6 mg/kg). Moreover, we found that the rats developed tolerance towards clozapine after repeated administrations. Thus, our study motivates further investigation using different preclinical models to assess the effect of adjunct treatment of SNP to APDs, also targeting the negative symptoms and cognitive deficits seen in schizophrenia. [ABSTRACT FROM AUTHOR]

One of the major discoveries in recent research on antipsychotic drugs is that antipsychotic treatment in adolescence could induce robust long-term alterations in antipsychotic sensitivity that persist into adulthood. These long-term impacts are likely influenced by various factors, including the "diseased" state of animals, sex, type of drugs, mode of drug administration, and age of treatment onset. In this study we compared the short- and long-term behavioral effects of 21-day continuous oral olanzapine (7.5 mg/kg/day) or clozapine (30.0 mg/kg/day) administration in heathy or maternal immune activated adolescent (33–53 days old) or adult (80–100 days old) rats of both sexes. We used a conditioned avoidance response model to assess the drug-induced alterations in antipsychotic sensitivity. Here, we report that while under the chronic drug treatment period, olanzapine progressively increased its suppression of avoidance responding over time, especially when treatment was initiated in adulthood. Clozapine's suppression depended on the age of drug exposure, with treatment initiated in adulthood showing a suppression while that initiated in adolescent did not. After a 17-day drug-free interval, in a drug challenge test, olanzapine treatment initiated in adolescence caused a decrease in drug sensitivity, as reflected by less avoidance suppression (a tolerance effect); whereas that initiated in adulthood appeared to cause an increase (more avoidance suppression, a sensitization effect). Clozapine treatments initiated in both adolescence and adulthood caused a similar tolerance effect. Our findings indicate that the same chronic antipsychotic treatment regimen initiated in adolescence or adulthood can have differential short- and long-term impacts on drug sensitivity. • In adolescent and adult rats, continuous olanzapine treatment increased the suppression of avoidance responding. • Continuous clozapine treatment suppressed avoidance responding only in adult rats, to in adolescents. • Olanzapine treatment caused a long-term decease in drug efficacy in adolescent rats. • Olanzapine treatment caused a long-term increase in drug efficacy in adult rats. • Clozapine treatment caused a long-term decrease in drug efficacy in both adolescent and adult rats. [ABSTRACT FROM AUTHOR]

Background: Antipsychotic treatment is effective in the treatment of psychosis, although it also brings with it some unwanted side effects and is associated with low compliance. Finding a non-pharmacological alternative for antipsychotic treatment is highly desirable.Aims: This preclinical study examined the 'antipsychotic' efficacy of such a behavioral technique using a conditioned avoidance response model. This technique, termed reinforcement attenuation (RA), is to administer a brief footshock (0.1-2.0 s, 0.8 mA) at the end of each trial regardless of whether a well-trained rat makes an avoidance response or not.Results: RA achieved the same avoidance suppressing effect as olanzapine (an atypical antipsychotic drug), including both acute suppression and sensitized suppression of avoidance response in well-trained Sprague-Dawley adult male rats. Interestingly, the RA-induced sensitization (an enhanced disruption of avoidance responding) enhanced subsequent olanzapine sensitivity, whereas the olanzapine (1.0 mg/kg)-induced sensitization had little impact on later RA treatment. When RA and olanzapine (0.5 mg/kg, subcutaneously) were used together, the RA-induced sensitization was still detectable in the RA challenge test, although its magnitude was reduced by olanzapine. Finally, we showed that the RA-induced sensitization in avoidance suppression persisted from adolescence into adulthood, long after such a treatment was terminated.Conclusions: These findings demonstrate that the RA is functionally equivalent (if not superior) to antipsychotic treatment in the avoidance suppression effect (both acute and sensitization effects) in both adolescent and adult animals. Behavioral therapies that specifically target the reinforcer of psychotic thoughts might be a viable strategy for the treatment of psychosis. [ABSTRACT FROM AUTHOR]

The present study aims to evaluate antistress and neuropharmacological parameters of ethanolic, ethyl acetate and hexane flower extracts of Tecoma gaudichaudi. Forced swim stress was used to evaluate antistress activity. The 24 h urinary excretion of vanillylmandelic acid (VMA) and ascorbic acid were determined by spectrophotometric methods in all groups under normal and stressed conditions. In the present study, the extracts (200 and 400 mg/kg, p.o.) were investigated for nootropic activity in rats with and without stress. Cook's pole climbing apparatus measures conditioned avoidance response, elevated plus maze determines transfer latency and staircase test calculates the number of steps climbed and rearings in normal and stress induced rats to assess cognitive-improving activities. Cognition was enhanced by daily administration of Tecoma gaudichaudi extracts at doses of 200 and 400 mg/kg, p.o. in dose dependent manner in normal rats. Tecomine and its derivatives were isolated from alkaloidal fraction. [ABSTRACT FROM AUTHOR]

Schizophrenic (SCH) patients show cognitive impairment in attentional performance. Positive allosteric modulators (PAMs) of α7 nicotinic acetylcholine receptors (nAChRs) such as the Alzheimer’s drug galantamine (GAL) and PAM-2 are documented to have pro-cognitive properties. However, it is not well established if these properties would be lost, or may hamper antipsychotic efficacy, when given as an adjunct to an antipsychotic which is needed for managing psychotic symptoms. Using adult male Wistar rats, we here investigated the effects of: a) GAL, alone or co-administered with the antipsychotic risperidone (RISP), on acute phencyclidine (PCP)-induced deficits in the attentional set-shifting (ASST) test; b) PAM-2, alone and co-administered with RISP, in the conditioned avoidance response (CAR) test for antipsychotic activity. Acute PCP produced selective and significant SCH-like impairment in extra dimensional shift (EDS) performance, which was completely reversed by GAL. The ability of GAL to reverse PCP-induced EDS impairment was not prevented when co-administered with RISP, suggesting that the combination of GAL and low doses of RISP may be used to improve the cognitive impairment in SCH. Pretreatment with methyllycaconitine (MLA), a selective α7 nAChR antagonist, completely prevented the reversal elicited by GAL, supporting the concept that α7 nAChRs are involved in this process. On the other hand, PAM-2 alone had no effects on CAR, but enhanced, although not significantly, the antipsychotic-like effect of RISP when administered together. In conclusion, α7 PAMs, in addition to alleviate the cognitive impairments observed in SCH patients, may enhance the antipsychotic efficacy of atypical antipsychotics. [ABSTRACT FROM AUTHOR]

The effects of antipsychotic drugs (APDs) on the adolescent brain are poorly understood despite a dramatic increase in prescription of these drugs in adolescents over the past twenty years. Neuronal systems continue to be remodeled during adolescence. Therefore, when given in adolescence, antipsychotic drugs (APDs) have the potential to affect this remodeling. In this study we investigated the effects of chronic 22-day risperidone treatment (1.3 mg/kg/day) in both adolescent and adult rats. We examined short- and long-term changes in behaviour (catalepsy, locomotion and conditioned avoidance response (CAR)), and dopaminergic and serotonergic neurochemistry in the striatum and the nucleus accumbens. Here, we report that, both during chronic treatment and after a lengthy drug-free interval, risperidone induced a sensitised cataleptic response regardless of the age of exposure. Selectively in adolescents, risperidone-induced catalepsy was inversely correlated with striatal dopamine turnover immediately after chronic treatment. After a drug-free interval, a significant proportion of rats with prior adolescent risperidone treatment also failed to acquire CAR to a defined criterion. Our data provide evidence that the same chronic risperidone treatment regimen can induce contrasting short- and long-term neural outcomes in the adolescent and adult brains. [ABSTRACT FROM AUTHOR]

Many behavioral and biological effects of a psychoactive drug often undergo time-dependent change following even one single drug exposure. The present study examined whether one or two exposures of haloperidol, olanzapine or clozapine would also induce a time-dependent change in their behavioral effects in adolescent rats, and whether such a change vary between sexes. Adolescent Sprague-Dawley rats (<40 days old) were first treated with one single injection of haloperidol (0.05 and 0.1 mg/kg, sc), clozapine (10.0 and 20.0 mg/kg, sc), 2 injections of olanzapine (1.0 and 2.0 mg/kg, sc) or vehicle, and tested in a conditioned avoidance response (CAR) model or a PCP (3.20 mg/kg, sc)-induced hyperlocomotion model to assess the drug’s antipsychotic-like behavioral effects. One or three weeks later, rats were challenged with the drug and their avoidance responses and the PCP-induced hyperlocomotion were re-assessed. One-trial haloperidol and 2-trial olanzapine induced a sensitization, while 1-trial clozapine induced a tolerance effect. The 1-trial haloperidol sensitization was significantly higher at the 3-week time point than at 1-week point, especially in the females. Clozapine tolerance in the conditioned avoidance response model also exhibited the time-dependent increase in both sex groups. Olanzapine sensitization in the PCP model showed a time-dependent change in a sex-dependent fashion. Overall, the time-dependent antipsychotic sensitization and tolerance can be demonstrated in adolescent animals. Many pharmacological (e.g. specific drugs, drug doses), individual (e.g. male versus female) and environmental (e.g. specific behavioral models) factors play a role in the modulation of the strength of antipsychotic sensitization and tolerance. [ABSTRACT FROM AUTHOR]

The present study investigated the potential sex differences in repeated aripiprazole (ARI) treatment-induced behavioral sensitization from adolescence to adulthood, and to determine whether ARI sensitization can be transferred to olanzapine (OLZ) and/or clozapine (CLZ) using the conditioned avoidance response (CAR) and phencyclidine-induced (PCP) hyperlocomotion tests of antipsychotic activity. Male and female Sprague-Dawley adolescence rats (P46) were first treated with ARI (10 mg/kg) for 5 consecutive days (P46–50) and tested for avoidance response and ARI-induced inhibition of PCP-induced hyperlocomotion. After they became adults (> P68), rats were challenged with ARI (1.5 mg/kg, sc) (P70), OLZ (0.5 mg/kg, sc; P73), CLZ (5 mg/kg, sc; P76) and again with ARI (1.5 mg/kg, sc; P84) and tested for avoidance response and ARI-induced inhibition of PCP-induced hyperlocomotion again. During the drug treatment period in adolescence, repeated ARI treatment suppressed avoidance response, inhibited the PCP-induced hyperlocomotion, and these effects were progressively increased across the 5-day period in both males and females, confirming the induction of ARI sensitization. On the challenge days, rats previously treated with ARI in adolescence also had significantly lower avoidance and lower PCP-induced hyperlocomotion than the previous vehicle rats, confirming the expression of ARI sensitization and its persistence into adulthood. More importantly, female rats made significantly more avoidances than males in both ARI and vehicle groups, indicating higher sensitivity to the acute and long-term effects of ARI. Further, on the OLZ and CLZ challenge days, prior ARI treatment seemed to increase sensitivity to OLZ exposure, however, this increase was not significant. Similarly, rats also showed an ARI sensitization to OLZ and CLZ on challenge days. Collectively, results from this experiment demonstrated a sex difference in response to ARI and enhanced inhibition of PCP-induced hyperlocomotion in animals that were pretreated with ARI as compared to controls. [ABSTRACT FROM AUTHOR]

Clinical studies indicate a reciprocal impact between nicotine use and antipsychotic medications in patients with schizophrenia. The present study used a conditioned avoidance response (CAR) test (a behavioral test of antipsychotic effect) and examined the specific drug-drug interactions between nicotine and haloperidol or clozapine. Following acquisition of the avoidance response, rats were first tested under either vehicle, nicotine (0.2, 0.4 mg/kg, sc), haloperidol (0.025, 0.05 mg/kg, sc), clozapine (5.0, 10.0 mg/kg, sc), or a combination of nicotine and haloperidol or nicotine and clozapine for seven consecutive days. Afterward, they were challenged with nicotine (0.2 mg/kg), haloperidol (0.025 mg/kg), or clozapine (5.0 mg/kg) in the CAR to assess if haloperidol or clozapine affected the behavioral effect of nicotine on avoidance response and if nicotine altered the avoidance suppressive effect of haloperidol and clozapine. During the seven avoidance drug test days, nicotine did not alter the avoidance suppressive effect of haloperidol or clozapine. However, in the challenge test, prior nicotine treatment (0.2 mg/kg) attenuated haloperidol's (0.05 mg/kg) sensitized effect on avoidance response. On the other hand, prior haloperidol treatment increased nicotine's (0.2 mg/kg) avoidance disruptive effect, and even engendered nicotine 0.4 mg/kg to exhibit an "acquired" avoidance suppressive effect. The combined nicotine and clozapine treatment did not produce any detectable interactive effects on avoidance response and motor activity. These findings suggest that nicotine is capable of altering the long-term antipsychotic efficacy of haloperidol, while haloperidol can alter the behavioral effects of nicotine. Clozapine and nicotine are less likely to influence each other. [ABSTRACT FROM AUTHOR]

5-Hydroxytryptamine 2C (5-HT2C) receptor agonists have been suggested to possess an antipsychotic activity in several acute preclinical tests of antipsychotic drugs with low extra-pyramidal side effect liability. However, little is known about the long-term effect associated with chronic use of 5-HT2C receptor agonists. The present study examined whether repeated activation of 5-HT2C receptor with a highly selective 5-HT2C receptor agonist MK212 would induce a long-term change in its antipsychotic-like activity (either a sensitization or tolerance) in the conditioned avoidance response and MK801-induced hyperlocomotion tests. Sprague-Dawley rats were first tested under the intraperitoneal (i.p.) treatment of MK212 (0.25, 0.5, 1.0 mg/kg) for 5 consecutive days. Three days later, when all rats were injected with a low dose of MK 212 (0.25 mg/kg) and tested for avoidance responding, rats that had been pretreated with 1.0 and 0.5 mg/kg MK212 made significantly fewer avoidance responses than those that had been treated with vehicle (0.9% saline). However, this past drug exposure-induced group difference was not significant in the MK801-induced hyperlocomotion test. Overall, results from this study suggest that repeated treatment of MK212 is capable of inducing a dose-dependent sensitization of antipsychotic activity in conditioned avoidance response. The discrepancy in sensitization of MK212 in CAR and MK801-induce hyperlocomotion may be related to the different mechanism underlying the effect of MK212 in these two tests. © 2016 IUBMB Life, 68(12):985-993, 2016 [ABSTRACT FROM AUTHOR]

Adolescence is a period of dynamic remodeling and maturation in the brain. Exposure to psychotropic drugs during adolescence can potentially alter neural maturation in the adolescent brain subsequently altering neural function at maturity. In this regard, antipsychotic drugs (APDs) are important given a notable global increase in prescription of these APDs to adolescents for a variety of behavioural symptoms and conditions over the past twenty years. However, there is a paucity of data on the long-term consequences of APDs on the adolescent brain. In this preclinical study, we have examined whether the adolescent brain is more susceptible than the adult brain to long-term neural changes induced by risperidone, which is the APD most frequently prescribed to adolescents. Rats were chronically treated (21 days) with 1.3 mg/kg/day risperidone or vehicle either as adolescents (postnatal day (PND) 36–56)) or adults (PND80-100). Behaviour was assessed using the well-described suppression of the conditioned avoidance response (CAR) by APDs. We examined CAR after all animals had reached maturity (PND127). We show that mature rats treated with risperidone as adolescents had increased CAR suppression compared to adults when rechallenged with this same drug. In the nucleus accumbens, significant downregulation of serotonergic 5HT 2A receptors and catechol-o-methyl transferase mRNA levels was observed only in the adolescent treated animals. Impaired 5HT 2A receptor signaling may explain the increased CAR suppression observed in rats treated with risperidone as adolescents. Magnetic resonance imaging (MRI), however, did not detect any risperidone-induced long-term brain structural change at maturity. These findings confirm that APD administration during adolescence may produce long-term behavioural and neurochemical alterations. [ABSTRACT FROM AUTHOR]

Rationale: Therapeutic agents for memory enhancement in psychiatric disorders, such as schizophrenia, are urgently needed. Objective: The aim of this study is to characterize the preclinical profile of ITI-214, a potent inhibitor of phosphodiesterase 1 (PDE1). Methods: ITI-214 was assayed for inhibition of PDE1 versus other PDE enzyme families using recombinant human PDE enzymes and for off-target binding to 70 substrates (General SEP II diversity panel; Caliper Life Sciences). Effects of ITI-214 (0.1-10 mg/kg, po) on memory performance were assayed in rats using the novel object recognition (NOR) paradigm, with drug given at specified time points prior to or following exposure to objects in an open field. ITI-214 was evaluated for potential drug-drug interaction with risperidone in rats using conditioned avoidance response (CAR) and pharmacokinetic assessments. Results: ITI-214 inhibited PDE1A ( K = 33 pmol) with >1000-fold selectivity for the nearest other PDE family (PDE4D) and displayed minimal off-target binding interactions in a 70-substrate selectivity profile. By using specific timing of oral ITI-214 administration, it was demonstrated in the NOR that ITI-214 is able to enhance acquisition, consolidation, and retrieval memory processes. All memory effects were in the absence of effects on exploratory behavior. ITI-214 did not disrupt the risperidone pharmacokinetic profile or effects in CAR. Conclusions: ITI-214 improved the memory processes of acquisition, consolidation, and retrieval across a broad dose range (0.1-10 mg/kg, po) without disrupting the antipsychotic-like activity of a clinical antipsychotic medication, specifically risperidone. Clinical development of ITI-214 is currently in progress. [ABSTRACT FROM AUTHOR]

Rationale: Recently, we showed that 2-bromoterguride acted as a dopamine D receptor partial agonist, a serotonin 5-HT and α-adrenergic receptor antagonist, and exhibited antidopaminergic efficacy in amphetamine-induced locomotion (AIL) in rats without inducing catalepsy. Objective: To extend our knowledge on the antipsychotic effects of 2-bromoterguride, we used convergent preclinical animal models and tests; i.e., conditioned avoidance response (CAR), predictive of antipsychotic-like effects; Fos protein expression, a molecular marker for (atypical) antipsychotic activity; wet dog shake behavior, a test for the in vivo effects of drugs acting on central 5-HT receptors; and investigated metabolic changes as a common side effect of atypical antipsychotic drugs (APDs). Results: Acute treatment with 2-bromoterguride (0.1 and 0.3 mg/kg) decreased the CAR at 30, 90, and 270 min post-injection in rats without inducing escape failures at any time. Fos protein expression, as shown by Western blotting, was enhanced by 2-bromoterguride in the nucleus accumbens (NAc), the dorsolateral striatum (dStr), and the medial prefrontal cortex (mPFC). (±)-2,5-Dimethoxy-4-iodoamphetamine (DOI)-induced wet dog shakes in rats were reduced by 2-bromoterguride. Chronic treatment with 2-bromoterguride did not affect metabolic parameters such as body weight development and body fat composition as well as behavioral parameters such as food intake and locomotor activity. Conclusions: Our data suggest that 2-bromoterguride is a promising candidate in the treatment of schizophrenia due to its atypical antipsychotic-like activity and its inability to induce weight gain. [ABSTRACT FROM AUTHOR]

Phosphodiesterase 10A (PDE10A) inhibitors increase the functionality of striatal medium spiny neurons and produce antipsychotic-like effects in rodents by blocking PDE10A mediated hydrolysis of cAMP and/or cGMP. In the current study, we characterized a radiolabeled PDE10A inhibitor, [ 3 H]BMS-843496, and developed an ex vivo PDE10 binding autoradiographic assay to explore the relationship between PDE10 binding site occupancy and the observed biochemical and behavioral effects of PDE10 inhibitors in mice. [ 3 H]BMS-843496 is a potent PDE10A inhibitor with a binding affinity (K D ) of 0.15 nM and a functional selectivity of >100-fold over other PDE subtypes tested. Specific [ 3 H]BMS-843496 binding sites were dominant in the basal ganglia, especially the striatum, with low to moderate binding in the cortical and hippocampal areas, of the mouse and monkey brain. Systemic administration of PDE10 inhibitors produced a dose- and plasma/brain concentration-dependent increase in PDE10A occupancy measured in the striatum. PDE10A occupancy was positively correlated with striatal pCREB expression levels. PDE10A occupancy was also correlated with antipsychotic-like effects measured using the conditioned avoidance response model; a minimum of ∼40% occupancy was typically required to achieve efficacy. In contrast, a clear relationship between PDE10A occupancy and catalepsy scores, a potential extrapyramidal symptom readout in rodent, was not evident. [ABSTRACT FROM AUTHOR]

The present study characterized the behavioral mechanisms of avoidance–disruptive effect of quetiapine in the conditioned avoidance response test under two behavioral testing (2 warning signals vs . 1 warning signal) and two drug administration conditions (subcutaneous vs . intravenous). In Experiments 1 and 2, well-trained adult male Sprague-Dawley rats were tested under the subcutaneous (s.c.) quetiapine treatment (5.0, 15.0, 25.0, 50.0 mg/kg) for 7 days in a novel procedure consisting of two conditioned stimuli (CS) (white noise serving as CS1 and pure tone as CS2). Only the highest dose (50.0 mg/kg) produced a persistent suppression of the avoidance response without impairing the escape response. The magnitude of suppression of the CS1 avoidance was similar to that of CS2 avoidance. No significant group difference was found in the quetiapine (15.0 mg/kg, s.c.) challenge test, indicating a lack of a long-term quetiapine effect. In Experiment 3, well-trained rats were tested under the intravenous (i.v.) quetiapine treatment (3.0, 9.0, 15.0 mg/kg) for 5 days and challenged with quetiapine (6.0 mg/kg, i.v. followed by 9.0 mg/kg, s.c.). Only the white noise was used as the CS. Similar to what was being observed in Experiments 1 and 2, intravenously administered quetiapine dose-dependently suppressed avoidance responding during the drug test days, but did not alter drug sensitivity in the challenge days. Thus, quetiapine does not appear to show a preferential inhibition of the avoidance response to a less salient stimulus; and prior quetiapine treatment (s.c. and i.v.) does not cause a sensitization or tolerance to quetiapine. [ABSTRACT FROM AUTHOR]

Previous work established that repeated olanzapine (OLZ) administration in normal adolescent rats induces a sensitization effect (i.e. increased behavioral responsiveness to drug re-exposure) in the conditioned avoidance response (CAR) model. However, it is unclear whether the same phenomenon can be detected in animal models of schizophrenia. The present study explored the generalizability of OLZ sensitization from healthy animals to a preclinical neuroinflammatory model of schizophrenia in the CAR. Maternal immune activation (MIA) was induced via polyinosinic:polycytidylic acid (PolyI:C) administration into pregnant dams. Behavioral assessments of offspring first identified decreased maternal separation-induced pup ultrasonic vocalizations and increased amphetamine-induced hyperlocomotion in animals prenatally exposed to PolyI:C. In addition, repeated adolescent OLZ administration confirmed the generalizability of the sensitization phenomenon. Using the CAR test, adolescent MIA animals displayed a similar increase in behavioral responsiveness after repeated OLZ exposure during both the repeated drug test days as well as a subsequent challenge test. Neurobiologically, few studies examining the relationship between hippocampal cell proliferation and survival and either antipsychotic exposure or MIA have incorporated concurrent behavioral changes. Thus, the current study also sought to reveal the correlation between OLZ behavioral sensitization in the CAR and hippocampal cell proliferation and survival. 5′-bromodeoxyuridine immunohistochemistry identified a positive correlation between the magnitude of OLZ sensitization (i.e. change in avoidance suppression induced by OLZ across days) and hippocampal cell proliferation. The implications of the relationship between behavioral and neurobiological results are discussed. [ABSTRACT FROM AUTHOR]

The present study investigated how repeated administration of aripiprazole (a novel antipsychotic drug) alters its behavioral effects in two behavioral tests of antipsychotic activity and whether this alteration is correlated with an increase in dopamine D2 receptor function. Male adult Sprague-Dawley rats were first repeatedly tested with aripiprazole (3, 10 and 30 mg/kg, subcutaneously (sc)) or vehicle in a conditioned avoidance response (CAR) test or a phencyclidine (PCP) (3.20 mg/kg, sc)-induced hyperlocomotion test daily for five consecutive days. After 2–3 days of drug-free retraining or resting, all rats were then challenged with aripiprazole (1.5 or 3.0 mg/kg, sc). Repeated administration of aripiprazole progressively increased its inhibition of avoidance responding and PCP-induced hyperlocomotion. More importantly, rats previously treated with aripiprazole showed significantly lower avoidance response and lower PCP-induced hyperlocomotion than those previously treated with vehicle in the challenge tests. An increased sensitivity to quinpirole (a selective D2/3 agonist) in prior aripiprazole-treated rats was also found in the quinpirole-induced hyperlocomotion test, suggesting an enhanced D2/3-mediated function. These findings suggest that aripiprazole, despite its distinct receptor mechanisms of action, induces a sensitization effect similar to those induced by other antipsychotic drugs and this effect may be partially mediated by brain plasticity involving D2/3 receptor systems. [ABSTRACT FROM AUTHOR]

Rationale: Acute administration of clozapine (a gold standard of atypical antipsychotics) disrupts avoidance response in rodents, while repeated administration often causes a tolerance effect. Objective: The present study investigated the neuroanatomical basis and receptor mechanisms of acute and repeated effects of clozapine treatment in the conditioned avoidance response test in male Sprague-Dawley rats. Methods: 2,5-dimethoxy-4-iodo-amphetamine (DOI, a preferential 5-HT agonist) or quinpirole (a preferential dopamine D agonist) was microinjected into the medial prefrontal cortex (mPFC) or nucleus accumbens shell (NAs), and their effects on the acute and long-term avoidance disruptive effect of clozapine were tested. Results: Intra-mPFC microinjection of quinpirole enhanced the acute avoidance disruptive effect of clozapine (10 mg/kg, sc), while DOI microinjections reduced it marginally. Repeated administration of clozapine (10 mg/kg, sc) daily for 5 days caused a progressive decrease in its inhibition of avoidance responding, indicating tolerance development. Intra-mPFC microinjection of DOI at 25.0 (but not 5.0) μg/side during this period completely abolished the expression of clozapine tolerance. This was indicated by the finding that clozapine-treated rats centrally infused with 25.0 μg/side DOI did not show higher levels of avoidance responses than the vehicle-treated rats in the clozapine challenge test. Microinjection of DOI into the mPFC immediately before the challenge test also decreased the expression of clozapine tolerance. Conclusions: Acute behavioral effect of clozapine can be enhanced by activation of the D receptors in the mPFC. Clozapine tolerance expression relies on the neuroplasticity initiated by its antagonist action against 5-HT receptors in the mPFC. [ABSTRACT FROM AUTHOR]

Neurotensin is an endogenous neuropeptide closely associated with the mesolimbic dopaminergic system and shown to possess antipsychotic-like effects. In particular, acute neurotensin receptor activation can inhibit conditioned avoidance response (CAR), attenuate phencyclidine (PCP)-induced prepulse inhibition (PPI) disruptions, and reverse PCP-induced hyperlocomotion. However, few studies have examined the long term effects of repeated neurotensin receptor activation and results are inconsistent. Since clinical administration of antipsychotic therapy often requires a prolonged treatment schedule, here we assessed the effects of repeated activation of neurotensin receptors using an NTS1 receptor selective agonist, PD149163, in 3 behavioral tests of antipsychotic activity. We also investigated whether reactivity to the atypical antipsychotic clozapine was altered following prior PD149163 treatment. Using both normal and prenatally immune activated rats generated through maternal immune activation with polyinosinic:polycytidylic acid, we tested PD149163 in CAR, PCP (1.5 mg/kg)-induced PPI disruption, and PCP (3.2 mg/kg)-induced hyperlocomotion. For each paradigm, rats were first repeatedly tested with vehicle or PD149163 (1.0, 4.0, 8.0 mg/kg, sc) along with vehicle or PCP for PPI and hyperlocomotion tests, then challenged with PD149163 after 2 drug-free days. All rats were then challenged with clozapine (5.0 mg/kg, sc). During the repeated test period, PD149163 exhibited antipsychotic-like effects in all three models. On the PD149163 challenge day, prior drug treatment only caused a tolerance effect in CAR. This tolerance in CAR was transferrable to clozapine, as it enhanced clozapine tolerance in the same group of animals. Although no tolerance effect was seen in the PD149163 challenge for the PCP-induced hyperlocomotion test, the clozapine challenge showed increased sensitivity in groups previously exposed to repeated PD149163 treatment. Our findings suggest that repeated exposure to NTS1 receptor agonists can induce a dose-dependent tolerance and cross-tolerance to clozapine to some of its behavioral effects but not others. [ABSTRACT FROM AUTHOR]

Asenapine is a new antipsychotic drug that induces a long-lasting behavioral sensitization in adult rats. The present study investigated the developmental impacts of adolescent asenapine treatment on drug sensitivity and on 3 proteins implicated in the action of antipsychotic drugs (i.e. brain-derived neurotrophic factor (BDNF), dopamine D 2 receptor, and ΔFosB) in adulthood. Male adolescent Sprague–Dawley rats (postnatal days, P 43–48) were first treated with asenapine (0.05, 0.10 or 0.20 mg/kg, sc) and tested in the conditioned avoidance or PCP (2.0 mg/kg, sc)-induced hyperlocomotion tasks for 5 days. After they became adults (∼P 76), asenapine sensitization was assessed in a single avoidance or PCP-induced hyperlocomotion challenge test with all rats being injected with asenapine (0.10 mg/kg, sc). Rats were then sacrificed 1 day later and BDNF, D 2 and ΔFosB in the prefrontal cortex, striatum and hippocampus were examined using Western blotting. In adolescence, repeated asenapine treatment produced a persistent and dose-dependent inhibition of avoidance response, spontaneous motor activity and PCP-induced hyperlocomotion. In the asenapine challenge test, adult rats treated with asenapine (0.10 and 0.20 mg/kg) in adolescence made significantly fewer avoidance responses and showed a stronger inhibition of spontaneous motor activity than those previously treated with saline. However, no group difference in the levels of BDNF, D 2 and ΔFosB expression was found. These findings suggest that although adolescent asenapine treatment for a short period of time induces a robust behavioral sensitization that persists into adulthood, such a long-term effect is not likely to be mediated by BDNF, D 2 and ΔFosB. [ABSTRACT FROM AUTHOR]

Animal work on the behavioral effects of antipsychotic treatment suggests that different dosing regimens could affect drug sensitivity differently, with an intermittent treatment regimen tending to cause a sensitization effect, while a continuous treatment causing a tolerance. In this study, we explored how haloperidol (HAL) sensitization induced throughout adolescence and tested in adulthood was differentially impacted by these two dosing regimens in the conditioned avoidance response (CAR) test. We also examined how these two dosing regiments affected social interaction and social memory in adulthood. Male adolescent Sprague-Dawley rats were treated with HAL via either osmotic minipump (HAL-0.25 CONT; 0.25 mgkg− 1day− 1, n = 14) or daily injection (HAL-0.05 INT; 0.05 mgkg− 1day− 1 injection, sc, n = 14), or sterile water (n = 14) from postnatal days (PND) 44 to 71. HAL sensitization was assessed in a challenge test in which all rats were injected with HAL (0.025 and 0.05 mg/kg, sc) on PND 80 and PND 82. Two days later, half of the rats from each group (n = 7/group) were assayed in two 4-trial social interaction tests in which a subject rat was given four 5-min social encounters with a familiar or novel juvenile rat (PND 35-40) at 10 min intervals. Another half were tested in a quinpirole-induced hyperlocomotion assay to assess the potential HAL-induced change in D2-mediated function. Results show that only the intermittent dosing group under the HAL 0.05 mg/kg challenge showed a robust sensitization effect as rats in this group made significantly fewer avoidance responses than those in the vehicle and HAL-0.25 CONT groups. Adolescent HAL treatment did not affect social behavior and social memory, as rats from all 3 groups exhibited a similar level of social interaction and showed a similar level of sensitivity to the change of social stimuli. Similarly, adolescent HAL treatment also did not produce a long-lasting change in D2 function, as all 3 groups exhibited a similar level of increase in motor activity under quinpirole challenge. These findings suggest that HAL sensitization is a dosing-specific phenomenon. It is more likely to be seen under an intermittent dosing regimen than under a continuous dosing one. The findings that the intermittent HAL treatment did not impair social functioning and did not alter D2 function suggest a dissociation between drug-induced alterations in drug sensitivity and those in social function and neuroreceptors. [ABSTRACT FROM AUTHOR]

Rationale: Risperidone use in children and adolescents for the treatment of various neuropsychiatric disorders (e.g., schizophrenia, autism, disruptive behavior, etc.) has increased substantially in recent decades. However, its long-term effect on the brain and behavioral functions is not well understood. Objective: The present study investigated how a short-term risperidone treatment in adolescence impacts antipsychotic response in adulthood in the conditioned avoidance response and phencyclidine (PCP)-induced hyperlocomotion tests. Methods: Male adolescent Sprague-Dawley rats (postnatal days [P] 40-44 or 43-48) were first treated with risperidone (0.3, 0.5, or 1.0 mg/kg, subcutaneously (sc)) and tested in the conditioned avoidance or PCP (3.2 mg/kg, sc)-induced hyperlocomotion model daily for five consecutive days. After they became adults (~P 76-80), they were challenged with risperidone (0.3 mg/kg, sc) to assess their sensitivity to risperidone reexposure. A quinpirole (a D receptor agonist, 1.0 mg/kg, sc)-induced hyperlocomotion test was later conducted to assess the risperidone-induced functional changes in D receptor. Results: In the risperidone challenge test in adulthood, adult rats previously treated with risperidone in adolescence made significantly fewer avoidance responses and exhibited significantly lower PCP-induced hyperlocomotion than those previously treated with vehicle. They also appeared to be more hyperactive than the vehicle-pretreated ones in the quinpirole-induced hyperlocomotion test. Prepulse inhibition of acoustic startle or fear-induced 22 kHz ultrasonic vocalizations in adulthood was not altered by adolescence risperidone treatment. Conclusions: Adolescent risperidone exposure induces a long-term increase in behavioral sensitivity to risperidone that persists into adulthood. This long-lasting change might be due to functional upregulation of D-mediated neurotransmission. [ABSTRACT FROM AUTHOR]

Abstract: This preclinical study investigated how a short-term risperidone treatment in adolescence impacts antipsychotic response to olanzapine and clozapine in adulthood. Antipsychotic effect was indexed by a drug's suppressive effect on avoidance responding in a rat conditioned avoidance response (CAR) model. Male adolescent Sprague–Dawley rats were first treated with risperidone (1.0mg/kg, sc) or sterile water and tested in the CAR model for 5 consecutive days from postnatal days P 40 to 44. After they became adults (~P 80–84), they were switched to olanzapine (0.5mg/kg, sc), clozapine (5.0mg/kg, sc) or vehicle treatment and tested for avoidance for 5days. During the adolescent period, repeated risperidone treatment produced a persistent inhibition of avoidance response. Throughout the 5days of adulthood drug testing, rats previously treated with risperidone in adolescence made significantly fewer avoidance responses than the vehicle ones when they all were switched to olanzapine, indicating a risperidone-induced enhancement of behavioral sensitivity to olanzapine. In contrast, when switched to clozapine, rats previously treated with risperidone made significantly more avoidance responses than the vehicle rats, indicating a risperidone-induced decrease of behavioral sensitivity to clozapine. Performance in the prepulse inhibition of acoustic startle response in adulthood was not altered by adolescent risperidone treatment. Collectively, adolescent risperidone exposure induced a long-term change in behavioral sensitivity to other atypical antipsychotic drugs, with the specific direction of change (i.e., increase or decrease) dependent on the drug to be switched to. These long-lasting changes are likely mediated by drug-induced neuroplastic changes and may also have significant clinical implications for antipsychotic treatment of chronic patients with an early onset of psychotic symptoms. [Copyright &y& Elsevier]

Abstract: The design, synthesis and structure activity relationship studies of a series of compounds from benzo[d]imidazo[5,1-b]thiazole scaffold as phosphodiesterase 10A (PDE10A) inhibitors are discussed. Several potent analogs with heteroaromatic substitutions (9a–d) were identified. The anticipated binding mode of these analogs was confirmed by performing the in silico docking experiments. Later, the heteroaromatics were substituted with saturated heteroalkyl groups which provided a tool compound 9e with excellent PDE10A activity, PDE selectivity, CNS penetrability and with favorable pharmacokinetic profile in rats. Furthermore, the compound 9e was shown to be efficacious in the MK-801 induced psychosis model and in the CAR model of psychosis. [Copyright &y& Elsevier]

Abstract: Among several commonly used atypical antipsychotic drugs, olanzapine and risperidone cause a sensitization effect in the conditioned avoidance response (CAR) and phencyclidine (PCP)-induced hyperlocomotion paradigms – two well established animal tests of antipsychotic drugs, whereas clozapine causes a tolerance effect. Asenapine is a novel antipsychotic drug recently approved for the treatment of schizophrenia and manic disorders. It shares several receptor binding sites and behavioral features with other atypical antipsychotic drugs. However, it is not clear what type of repeated effect (sensitization or tolerance) asenapine would induce, and whether such an effect is transferrable to other atypicals. In this study, male adult Sprague-Dawley rats were first repeatedly tested with asenapine (0.05, 0.10 or 0.20 mg/kg, sc) for avoidance response or PCP (3.20 mg/kg, sc)-induced hyperlocomotion daily for 5 consecutive days. After 2–3 days of retraining/drug-free recovery, they were then challenged with asenapine (0.10 mg/kg, sc), followed by olanzapine (0.50 mg/kg, sc) and clozapine (2.50 mg/kg, sc). During the 5-day drug test period (the induction phase), repeated asenapine treatment progressively increased its inhibition of avoidance response and PCP-induced hyperlocomotion in a dose-dependent fashion. On the asenapine and olanzapine challenge tests (the expression phase), rats previously treated with asenapine still showed significantly lower avoidance response and lower PCP-induced hyperlocomotion than those previously treated with vehicle. An increased reactivity to clozapine challenge in prior asenapine-treated rats was also found in the PCP-induced hyperlocomotion test. These findings suggest that asenapine is capable of inducing a sensitization effect and a cross-sensitization to olanzapine and clozapine (to a lesser extent). Because the behavioral profile of asenapine in both tests is similar to that of olanzapine, but different from that of clozapine, we suggest that asenapine resembles olanzapine to a greater extent than clozapine in its therapeutic and side effect profiles. [Copyright &y& Elsevier]

Highlights: [•] Repeated risperidone and asenapine treatment enhanced acute effect of these drugs in the conditioned avoidance model. [•] Risperidone and asenapine sensitization lasted up to 40 days. [•] Risperidone and asenapine sensitization increased with the passage of time. [•] Repeated risperidone treatment caused a functional upregulation of dopamine D2/3 receptors. [ABSTRACT FROM AUTHOR]

Abstract: Repeated administration of antipsychotic drugs induces a sensitization-like or tolerance-like effect in many behavioral tasks, including the conditioned avoidance response (CAR) and the phencyclidine (PCP)-induced hyperlocomotion, two rodent models with high predictive validity for antipsychotic activity. This study investigated the impacts of contextual and behavioral variables on the expression of clozapine tolerance using a recently validated across-model transfer paradigm (Zhang and Li, 2012 [1]). Male Sprague-Dawley rats were first repeatedly treated with clozapine (2.5–10.0mg/kg, sc) in the CAR model or PCP (1.6mg/kg, sc)-induced hyperlocomotion model for five consecutive days. They were then tested for the expression of clozapine tolerance in another model for another 5 days. Finally, all rats were switched back to the original model and tested again for the expression of clozapine tolerance. When tested in the PCP model, rats previously treated with clozapine in the CAR model did not show an immediate weaker inhibition of PCP-induced hyperlocomotion than those treated with clozapine for the first time, but showed a significantly weaker inhibition over time. In contrast, when tested in the CAR model, rats previously treated with clozapine in the PCP model showed an immediate weaker disruption of avoidance response than those treated with clozapine for the first time, but this weaker effect diminished over time. These results suggest that the expression of clozapine tolerance is strongly modulated by the test environment and/or selected behavioral response. Clozapine tolerance and its situational specificity may be related to the drug''s low extrapyramidal motor side effect, its superior therapeutic efficacy and/or emergence of clozapine withdrawal syndrome. [Copyright &y& Elsevier]

Abstract: Antipsychotic drugs suppress animals'' ability to avoid an aversive stimulus in the conditioned avoidance response model (CAR). This behavioral effect is thought to reflect antipsychotic activity and is suggested to be mediated by a drug''s action in attenuating the motivational salience of a conditioned stimulus (CS). In the present study, we tested whether atypical antipsychotic drugs clozapine and olanzapine act through this behavioral mechanism by manipulating the number of avoidance test trials. We reasoned that more CS trials in the presence of clozapine or olanzapine would afford the drug more opportunities to decrease the motivational salience of the CS, thus avoidance decline would be greater with the increase of CS trials in each test session. In two separate experiments, adult male Sprague–Dawley rats were tested under clozapine (5.0mg/kg, sc), olanzapine (0.5mg/kg, sc) or vehicle (sterile water) for 6 consecutive days in three CS trial conditions (i.e. 3, 10, and 40 CS trials per session). Two days later, all rats were tested under the same 40-trial session after receiving clozapine (5.0mg/kg, sc) or olanzapine (0.5mg/kg, sc). Results show that repeated clozapine and olanzapine treatment persistently decreased avoidance response, and this effect was potentiated by the increase of number of CS trials in the test sessions, as the clozapine-treated or olanzapine-treated rats tested under the 40-trial or 10-trial condition had significantly lower avoidance and faster decline across-sessions than those tested under the 3-trial condition. This potentiated effect was not only seen in the total avoidance percentage, but also observed in the within-session decline pattern in the last three drug test sessions and in the final 40-trial test session. These findings suggest that the clinical efficacy of a drug can be enhanced by increasing the exposure of symptoms in the presence of the drug. [Copyright &y& Elsevier]

Abstract: SYA013, a homopiperazine analog of haloperidol, was further evaluated for antipsychotic potential using additional animal models. Previously, SYA013 was tested in mice with an antipsychotic screening model in which it inhibited apomorphine induced climbing behavior, indicating antagonism of the dopaminergic system and the potential for use in the treatment of schizophrenia. In this study, SYA013 was shown to inhibit both d-amphetamine-induced locomotor activity in rats and conditioned avoidance response (CAR) in rats in a dose dependent manner and in the case of CAR, without producing any escape failure responses (EFRs), two tests predictive of antipsychotic action. The selective 5HT1A antagonist WAY100,635 was used to determine if binding of SYA013 to the 5HT1A receptor contributed to suppression of CAR. The results indicated that 0.63mg/kg WAY100,635 did not have a significant effect on the inhibition of CAR by SYA013. Pharmacokinetic parameters in brain and plasma were determined for SYA013. A log brain/plasma concentration ratio at a tmax of 1.48 suggests that SYA013 readily crosses the blood brain barrier (BBB). The hypothesis that binding of SYA013 to the 5HT1A receptor contributed to the lack of significant catalepsy was investigated using the 5HT1A antagonist WAY100,635. The results of acute and semi-chronic tests suggest that binding to the 5HT1A receptor alone did not significantly account for the lack of catalepsy. Lack of catalepsy was preserved after the semi-chronic challenge with SYA013. These tests further indicate that SYA013 has a pharmacological profile with the potential for use in the treatment of neuropsychiatric diseases. In addition, the 5HT1A receptor does not appear to play a significant role in the pharmacological profile of SYA013. [Copyright &y& Elsevier]

Although plant-derived essential oils (EOs) have been used to treat various mental disorders, their central nervous system (CNS) acting effects have not been clarified. The present study compared the effects of 20 kinds of EOs with the effects of already-known CNS acting drugs to examine whether the EOs exhibited CNS stimulant-like effects, CNS depressant-like effects, or neither. All agents were tested using a discrete shuttle-type conditioned avoidance task in mice. Essential oils of peppermint and chamomile exhibited CNS stimulant-like effects; that is, they increased the response rate (number of shuttlings/min) of the avoidance response. Linden also increased the response rate, however, the effect was not dose-dependent. In contrast, EOs of orange, grapefruit, and cypress exhibited CNS depressant-like effects; that is, they decreased the response rate of the avoidance response. Essential oils of eucalyptus and rose decreased the avoidance rate (number of avoidance responses/number of avoidance trials) without affecting the response rate, indicating that they may exhibit some CNS acting effects. Essential oils of 12 other plants, including juniper, patchouli, geranium, jasmine, clary sage, neroli, lavender, lemon, ylang-ylang, niaouli, vetivert and frankincense had no effect on the avoidance response in mice. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The present study was designed to assess the role of 5-HT receptors in the acute and repeated effect of clozapine and olanzapine in a rat conditioned avoidance response model, a validated model of antipsychotic activity. Male Sprague-Dawley rats that were previously treated with either phencyclidine (0.5-2.0 mg/kg, sc), amphetamine (1.25-5.0 mg/kg, sc), or saline and tested in a prepulse inhibition of acoustic startle study were used. They were first trained to acquire avoidance response to a white noise (CS1) and a pure tone (CS2) that differed in their ability to predict the occurrence of footshock. Those who acquired avoidance response were administered with clozapine (10.0 mg/kg, sc) or olanzapine (1.0 mg/kg, sc) together with either saline or 1-2,5-dimethoxy-4-iodo-amphetamine (DOI, a selective 5-HT agonist, 1.0 or 2.5 mg/kg, sc), and their conditioned avoidance responses were tested for four consecutive days. After two drug-free retraining days, the long-term repeated effect was assessed in a challenge test during which all rats were injected with a low dose of clozapine (5 mg/kg, sc) or olanzapine (0.5 mg/kg). Results show that pretreatment of DOI dose-dependently reversed the acute disruptive effect of clozapine on both CS1 and CS2 avoidance responses, whereas it had little effect in reversing the acute effect of olanzapine. On the challenge test, pretreatment of DOI did not alter the clozapine-induced tolerance or the olanzapine-induced sensitization effect. These results confirmed our previous findings and suggest that clozapine, but not olanzapine, acts on through 5-HT receptors to achieve its acute avoidance disruptive effect and likely its therapeutic effects. The long-term clozapine tolerance and olanzapine sensitization effects appear to be mediated by non-5-HT receptors. [ABSTRACT FROM AUTHOR]

Abstract: The role of dopamine (DA) in rewarding motivated actions is well established but its role in learning how to avoid aversive events is still controversial. Here we tested the role of D2-like DA receptors in the nucleus accumbens (NAc) and the dorsolateral striatum (DLS) of rats in the learning and performance of conditioned avoidance responses (CAR). Adult male Wistar rats received systemic, intra-NAc or intra-DLS (pre- or post-training) administration of a D2-like receptor agonist (quinpirole) or antagonist ((−)sulpiride) and were given two sessions in the two-way active avoidance task. The main effects observed were: (i) sulpiride and lower (likely pre-synaptic) doses of quinpirole decreased the number of CARs and increased the number of escape failures; (ii) higher doses of quinpirole (likely post-synaptic) increased inter-trial crossings and failures; (iii) pre-training administration of sulpiride decreased the number of CARs in both training and test sessions when infused into the NAc, but this effect was observed only in the test session when it was infused into the DLS; (iv) post-training administration of sulpiride decreased CARs in the test session when infused into the NAc but not DLS. These findings suggest that activation of D2 receptors in the NAc is critical for fast adaptation to responding to unconditioned and conditioned aversive stimuli while activation of these receptors in the DLS is needed for a slower learning of how to respond to the same stimuli based on previous experiences. [Copyright &y& Elsevier]

Abstract: Agonists for neurotensin (NT)-1 receptors have produced antipsychotic-like effects in many animals, including reversal of prepulse inhibition deficits and psychostimulant-induced increases in spontaneous activity. The present study sought to provide a basic assessment of the putative antipsychotic effects of PD149163 in rats using a two way conditioned avoidance response task, which is highly validated for screening antipsychotic drugs, and an inclined grid assessment, which is used to assess extrapyramidal side effect liability. PD149163 (0.0625–8.0mg/kg) significantly suppressed conditioned avoidance responding (CAR) following administration of a 1.0 or 8.0mg/kg dose. PD149163 failed to significantly increase catalepsy scores. The typical antipsychotic drug haloperidol (0.01–1.0mg/kg) significantly suppressed CAR at a 0.1, 0.3, and 1.0mg/kg dose, and a significant increase in catalepsy scores was found at the 1.0mg/kg dose. The atypical antipsychotic drug clozapine (2.5–10.0mg/kg) also produced a significant inhibition of CAR, which occurred following administration of a 10.0mg/kg dose. Clozapine failed to significantly increase catalepsy scores. Finally, d-amphetamine (1.0mg/kg), serving as a negative control, failed to suppress CAR or increase catalepsy scores. These data further suggest that PD149163 may have atypical antipsychotic-like properties. [Copyright &y& Elsevier]

Abstract: Suppression of conditioned avoidance response is a preclinical behavioral index of antipsychotic activity. Previous work shows that olanzapine and risperidone disrupt avoidance response elicited by a less salient conditioned stimulus (CS2) to a greater extent than avoidance elicited by a more salient stimulus (CS1), suggesting that antipsychotic drugs may have a weakening action on motivational salience of stimuli. In the present study, we further examined this mechanism of antipsychotic action, focusing on the possible impact of baseline difference of CS1 and CS2 response rates on the avoidance-disruptive effect of olanzapine and risperidone. Rats were first trained to acquire avoidance responding in a procedure in which the number of CS2 trials (i.e. 20) was twice the number of CS1 trials (i.e. 10), but the percentage of CS2-shock pairing was set at 25% lower (15 trials out of 20) than the percentage of CS1-shock pairing (20 trials out of 20). They were then tested daily under olanzapine (0.5 and 1.0mg/kg, sc) or risperidone (0.33 and 1.0mg/kg, sc) for 5 consecutive days. Repeated olanzapine and risperidone treatment dose-dependently disrupted avoidance responding to both CS1 and CS2. Both drugs at the high dose disrupted the CS2 avoidance to a greater extent than the CS1 avoidance. In the final challenge test, rats previously treated with olanzapine were tested under risperidone (0.33mg/kg), whereas rats previously treated with risperidone were tested under olanzapine (0.5mg/kg). Results show that rats previously treated with risperidone 1.0mg/kg group made significantly fewer avoidance responses than the vehicles under olanzapine at 0.5mg/kg. These findings confirm that olanzapine and risperidone disrupt avoidance response primarily by selectively attenuating the motivational salience of the CS. The present study also suggests that there is a generality of antipsychotic drug experience that is mediated by a shared interoceptive drug state mechanism. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the nootropic and neuroprotective effects of aspirin in Sprague Dawley rats. Materials and Methods: Retention of conditioned avoidance response (CAR) and central 5-HT-mediated behavior (lithium-induced head twitches) were assessed using repeated electroconvulsive shock (ECS) in rats. Rats were divided into eight groups: control (pretreated with distilled water), scopolamine (0.5 mg/kg i.p.), ECS (150 V, 50 Hz sinusoidal with intensity of 210 mA for 0.5 s) pretreated, aspirin (6.75 mg/kg orally) pretreated, combined scopolamine and aspirin pretreated, ondansetron (0.36 mg/kg orally) pretreated, combined ECS and ondansetron pretreated and combined ECS and aspirin pretreated groups. Data was analyzed by the chi-square test and ANOVA. Results: Findings show that administration of single ECS daily for consecutive 8 days results in enhancement of 5-HT-mediated behavior (lithium-induced head twitches) and in disruption of the retention of CAR. Aspirin and ondansetron administration significantly increased the retention of conditioned avoidance response compared to control. Ondansetron and aspirin significantly prevented ECSinduced attenuation of the retention of conditioned avoidance response also. On the other hand, ondansetron and aspirin significantly retarded the ECS-induced enhancement of 5-HT-mediated behavior. Conclusion: Inhibition of the serotonergic transmission by aspirin is responsible for its nootropic and neuroprotective actions. [ABSTRACT FROM AUTHOR]

Acute antipsychotic treatment disrupts conditioned avoidance responding, and repeated treatment induces a sensitization- or tolerance-like effect. However, the neurochemical mechanisms underlying both acute and repeated antipsychotic effects remain to be determined. The present study examined the neuroreceptor mechanisms of haloperidol, clozapine, and olanzapine effect in a rat two-way conditioned avoidance model. Well-trained Sprague–Dawley rats were administered with haloperidol (0.05 mg/kg, sc), clozapine (10.0 mg/kg, sc), or olanzapine (1.0 mg/kg, sc) together with either saline, quinpirole (a selective dopamine D2/3 agonist, 1.0 mg/kg, sc), or 2,5-dimethoxy-4-iodo-amphetamine (DOI; a selective 5-HT2A/2C agonist, 2.5 mg/kg, sc), and their conditioned avoidance responses were tested over 3 days. After 2 days of drug-free retraining, the repeated treatment effect was assessed in a challenge test. Pretreatment of quinpirole, but not DOI, attenuated the acute haloperidol-induced disruption of avoidance responding and to a lesser extent, olanzapine-induced disruption. In contrast, pretreatment of DOI, but not quinpirole, attenuated the acute effect of clozapine. On the repeated effect, pretreatment of DOI, but not quinpirole, attenuated the potentiated disruption of haloperidol, whereas pretreatment of quinpirole attenuated the potentiated disruption of olanzapine but enhanced the tolerance-like effect of clozapine. These findings suggest that acute haloperidol and olanzapine disrupt avoidance responding primarily by blocking dopamine D2 receptors, whereas acute clozapine exerts its disruptive effect primarily by blocking the 5-HT2A receptors. The repeated haloperidol effect may be mediated by 5-HT2A/2C blockade-initiated neural processes, whereas the repeated clozapine and olanzapine effect may be mediated by D2/3 blockade-initiated neural processes. [ABSTRACT FROM AUTHOR]

Antipsychotic drugs selectively suppress conditioned avoidance response. Using a two-way active avoidance response paradigm, we examined the role of drug-induced interoceptive state in the mediation of avoidance suppressive effect. In Experiment 1, we found that rats intermittently treated with olanzapine (OLZ) (1.0 mg/kg, s.c.) or haloperidol (0.03 mg/kg, s.c.) on the 1st day of a 3-day cycle for seven cycles exhibited a progressive across-session decline in avoidance responding, despite the fact that they exhibited a comparable high level of avoidance responding on the 3rd day of each cycle during the drug-free retraining session. In Experiments 2 and 3, rats that were previously treated with OLZ (0.5-2.0 mg/kg, s.c.) or risperidone (0.2-1.0 mg/kg) during the acquisition phase of avoidance conditioning exhibited significantly fewer avoidance responses when they were retested 3 weeks later to the same drug in comparison to rats that were previously treated with nonantipsychotic drugs (chlordiazepoxide, 10 mg/kg, citalopram 10 mg/kg, or sterile water). Overall, these findings indicate a 'drug memory'-like mechanism that maintains the avoidance-suppressing effect of antipsychotics over time. This mechanism is likely driven by the interoceptive state caused by the antipsychotics, which may also be an important behavioral mechanism mediating the clinical effects of antipsychotic treatments. [ABSTRACT FROM AUTHOR]

Abstract: Iptakalim is a novel putative adenosine triphosphate (ATP)-sensitive potassium (KATP) channel opener. In the brain, iptakalim is thought to act on the neuronal and astrocytic plasma membrane and/or mitochondrial KATP channels. Because iptakalim demonstrates an action on the regulation of dopamine and glutamate release in the forebrain regions, we examined its potential antipsychotic efficacy in several preclinical tests. First, we show that iptakalim is effective in reducing amphetamine- and phencyclidine-induced hyperlocomotion as well as selectively disrupting conditioned avoidance responding. Next, we show that combined iptakalim and amphetamine treatment produces a reduction on prepulse inhibition of acoustic startle and this combined drug effect is also found with haloperidol, but not with clozapine. Finally, we show that iptakalim and clozapine preferentially increase c-Fos expression in the medial prefrontal cortex, nucleus accumbens and lateral septal nucleus, whereas haloperidol induces a greater increase in the nucleus accumbens, the dorsolateral striatum and lateral septal nucleus. Collectively, our findings indicate that iptakalim is likely to be a potential antipsychotic drug with distinct mechanisms of action. This study also suggests that neuronal and astrocytic plasma membrane and/or mitochondrial KATP channels may be a novel target that deserves attention for antipsychotic drug development. Future research using other sensitive tests is needed to confirm this property of iptakalim. [Copyright &y& Elsevier]

Abstract: Atypical antipsychotics are also used in the treatment of anxiety-related disorders. Clinical and preclinical evidence regarding their intrinsic anxiolytic efficacy has been mixed. In this study, we examined the potential anxiolytic-like effects of risperidone and olanzapine, and compared them with haloperidol, chlordiazepoxide (a prototype of sedative–anxiolytic drug) or citalopram (a selective serotonin reuptake inhibitor). We used a composite of two-way avoidance conditioning and acoustic startle reflex model and examined the effects of drug treatments during the acquisition phase (Experiment 1) or extinction phase (Experiments 2 and 3) on multiple measures of conditioned and unconditioned fear/anxiety-like responses. In Experiment 4, we further compared risperidone, olanzapine, haloperidol, citalopram and chlordiazepoxide in a standard elevated plus maze test. Results revealed three distinct anxiolytic-like profiles associated with risperidone, olanzapine and chlordiazepoxide. Risperidone, especially at 1.0mg/kg, significantly decreased the number of avoidance responses, 22kHz ultrasonic vocalization, avoidance conditioning-induced hyperthermia and startle reactivity, but did not affect defecations or time spent on the open arms. Olanzapine (2.0mg/kg, sc) significantly decreased the number of avoidance responses, 22kHz vocalization and amount of defecations, but it did not inhibit startle reactivity and time spent on the open arms. Chlordiazepoxide (10mg/kg, ip) significantly decreased the number of 22kHz vocalization, avoidance conditioning-induced hyperthermia and amount of defecations, and increased time spent on the open arms, but did not decrease avoidance responses or startle reactivity. Haloperidol and citalopram did not display any anxiolytic-like property in these tests. The results highlight the importance of using multiple measures of fear-related responses to delineate behavioral profiles of psychotherapeutic drugs. [Copyright &y& Elsevier]

Abstract: Haloperidol, an antipsychotic agent, stimulates the release of gonadotropin-releasing hormone (GnRH), and this hormone is known to mimic some of the behavioral effects of haloperidol. Hence, the present study was carried out to find out the contribution of GnRH in the behavioral effects of haloperidol. The studies revealed that haloperidol (0.15, 0.25 and 0.5mg/kg, i.p.) and leuprolide (GnRH agonist; 50, 100, 200 and 400μg/kg, s.c.) dose-dependently inhibited conditioned avoidance response (CAR) in male Sprague–Dawley rats. In higher doses, haloperidol (0.5, 1mg/kg, i.p.) and leuprolide (200, 400μg/kg, s.c.) produced catalepsy in rats. Co-administration of sub-effective dose of leuprolide (50 or 100μg/kg, s.c.) and haloperidol (0.15 or 0.5mg/kg, i.p.) similarly inhibited CAR and induced catalepsy. Pre-treatment of rats with antide (GnRH antagonist; 10μg/rat, s.c.), attenuated the inhibitory effect of both the agents on CAR; blocked leuprolide-induced catalepsy; and attenuated the intensity and reduced the duration of haloperidol-induced catalepsy. In conclusion, the studies suggest a possible role of GnRH in the neuroleptic and cataleptic effect of haloperidol. [Copyright &y& Elsevier]

Abstract: Psychotic fear and anxiety disturbances are seen at a relatively high frequency in patients with schizophrenia. Atypical anti-psychotics are believed to show superior efficacy in reducing these symptoms. However, clinical and preclinical evidence regarding their anxiolytic efficacy has been mixed. In this study, we evaluated the possible anxiolytic property of two atypicals clozapine and olanzapine and compared them with typical haloperidol and chlordiazepoxide (a prototype of sedative-anxiolytic drug) in two preclinical models of fear. In Experiment 1, we used a fear-induced passive avoidance and conditioned place aversion paradigm and examined the effects of clozapine (20 mg/kg, sc), haloperidol (0.05 mg/kg, sc) and chlordiazepoxide (10 mg/kg, ip). In Experiments 2 and 3, we used a two-way active avoidance conditioning paradigm and further compared the effects of clozapine (20 mg/kg, sc), haloperidol (0.05 mg/kg, sc), chlordiazepoxide (10 mg/kg, ip) and three doses of olanzapine (0.5, 1.0, and 2.0 mg/kg, sc). Results show that clozapine and chlordiazepoxide, but not haloperidol, significantly attenuated the shock conditioning-induced place aversion, decreased the amount of defecations and the number of the 22-kHz vocalizations. Clozapine also reduced the shock conditioning-induced hyperthermia. Similar to clozapine, olanzapine also significantly decreased the amount of defecations and reduced the shock conditioning-induced hyperthermia, but it did not inhibit the 22-kHz vocalizations. This study demonstrates that clozapine and olanzapine possess an intrinsic anxiolytic property, which is not attributable to its superior anti-“psychotic” effect or its favorable effects on motor functions or learning and memory processes. These findings also suggest that the combined use of passive avoidance and active avoidance conditioning models can be useful in better differentiating typical and atypical anti-psychotics as well as anxiolytics. [Copyright &y& Elsevier]

Aversive processing plays a central role in human phobic fears and may also be important in some symptoms of psychosis. We developed a temporal-difference model of the conditioned avoidance response, an important experimental model for aversive learning which is also a central pharmacological model of psychosis. In the model, dopamine neurons reported outcomes that were better than the learner expected, typically coming from reaching safety states, and thus controlled the acquisition of a suitable policy. The model accounts for normal conditioned avoidance learning, the persistence of responding in extinction, and critical effects of dopamine blockade, notably that subjects experiencing shocks under dopamine blockade, and hence failing to avoid them, nevertheless develop avoidance responses when both shocks and dopamine blockade are subsequently removed. These postulated roles of dopamine in aversive learning can thus account for many of the effects of dopaminergic modulation seen in laboratory models of psychopathological processes. [ABSTRACT FROM AUTHOR]

Abstract: In the rat, selective suppression of conditioned avoidance response has been widely reported as a test with high predictive validity for antipsychotic efficacy. Recent studies have shown that the relationship between dopamine D2 receptor occupancy and the suppression of conditioned avoidance response behaviour correlates well with the relationship between human dopamine D2 receptor occupancy and clinical effect. The aim of the present study was to evaluate how pharmacokinetic/pharmacodynamic (PK/PD) predictions of therapeutic effective steady-state plasma levels by means of conditioned avoidance response behaviour in rodents, correlate with clinically relevant plasma exposure for the classical antipsychotic drug haloperidol and four second generation antipsychotics: sertindole, clozapine, risperidone and olanzapine, including selected metabolites. In order to confirm the validity of the present conditioned avoidance response procedure, in vivo striatal dopamine D2 receptor occupancy was determined in parallel using 3H-raclopride as the radioligand. The PK/PD relationship was established by modelling the time–response and time–plasma concentration data. We found the order of dopamine D2 receptor occupancy required to suppress conditioned avoidance response behaviour according to EC50 measurements to be sertindole (+dehydrosertindole)=dehydrosertindole=paliperidone (the metabolite of risperidone)=haloperidol=olanzapine>risperidone≫clozapine. Overall, a good agreement was observed between the rat dopamine D2 receptor occupancy levels providing 50% response in the conditioned avoidance response test and the dopamine D2 receptor occupancy levels reported from responding schizophrenic patients treated with antipsychotics. Predictions of therapeutically effective steady-state levels for sertindole (+dehydrosertindole) and olanzapine were 3–4-fold too high whereas for haloperidol, clozapine and risperidone the predicted steady-state EC50 in conditioned avoidance responding rats correlated well with the therapeutically effective plasma levels observed in patients. Accordingly, the proposed PK/PD model may act as a guide for determining effective plasma concentrations of potential antipsychotics in the clinical setting and thereby accelerating the overall drug development process. [Copyright &y& Elsevier]

Antipsychotic drugs work for patients only when given repeatedly. The overall temporal pattern of symptom improvement is not clear. Some recent data question the traditional ‘delayed-onset’ hypothesis and suggest that the onset of antipsychotic response may be relatively early, and the improvement may grow with repeated treatment. The present study systematically examined the time course of the antipsychotic effect and the underlying behavioral mechanisms using a conditioned avoidance response (CAR) model. Rats repeatedly treated with either typical (haloperidol) or atypical (olanzapine, risperidone) antipsychotics, but not anxiolytics (chlordiazepoxide), show an early-onset, progressive across-session decline in avoidance responding, which re-emerges when the treatment is stopped. This effect is dose-dependent, transferable between antipsychotics, and cannot be attributed to simple sedation or motor side effects. Furthermore, we found that the pattern of this drug-induced decline depends on the number of exposures to the conditioned stimulus in the presence of the drug, and is best understood as the result of drug-induced attenuation of the reinforcing effectiveness of the conditioned stimulus. We also found that repeated drug exposure can create a drug interoceptive state that allows the attenuated reinforcing property of the stimulus to be maintained over time. Together, these data provide preclinical support for the newly postulated ‘early-onset’ hypothesis, and suggest that the repeated antipsychotic CAR model may be useful for understanding the neurochemical and behavioral mechanisms underlying the clinical effects of antipsychotics in patients with schizophrenia.Neuropsychopharmacology (2007) 32, 263–272. doi:10.1038/sj.npp.1301110; published online 31 May 2006 [ABSTRACT FROM AUTHOR]