Conditioned Avoidance Response In Rats Research Articles

Activation of dopamine D2 receptors in the shell of nucleus accumbens triggers conditioned avoidance responses in rats

Conditioned avoidance responses (CAR) behavior is a classical instrumental response paradigm, which is widely used to study aversive conditioning and defensive motivation behavior. Previous studies have shown that dopamine D1 and D2 receptors are involved in CAR behavior; however, it is unclear in which brain regions that dopamine evokes CAR behavior. The aim of the study is to investigate whether dopamine triggers CAR behavior via activating dopamine D1 or D2 receptors in the shell of nucleus accumbens or dorsolateral striatum. The present study found that infusion of the dopamine D2 receptor agonist quinpirole, but not D1 receptor agonist SKF38393, into the shell of nucleus accumbens evoked CAR behavior in reserpine-treated rats. Whereas, infusion of neither SKF38393 nor quinpirole into the dorsolateral striatum evoked CAR behavior. In addition, infusion of quinpirole into the shell of nucleus accumbens enhanced CAR behavior in the unsuccessful trained rats without affecting the motor function in the balance beam and locomotor tests. In conclusion, activation of dopamine D2, but not D1 receptors in the shell of nucleus accumbens evokes CAR behavior. However, activation of dopamine D1 and D2 receptors in the dorsolateral striatum does not evoke CAR behavior. It is suggested that the shell of nucleus accumbens is the critical brain region for dopamine to invoke CAR behavior, and activation of dopamine D2 receptors in the shell of nucleus accumbens is sufficient and necessary to evoke CAR behavior.

In vitro and in vivo characterization of Lu AA41178: A novel, brain penetrant, pan-selective Kv7 potassium channel opener with efficacy in preclinical models of epileptic seizures and psychiatric disorders

Activation of the voltage-gated Kv7 channels holds therapeutic promise in several neurological and psychiatric disorders, including epilepsy, schizophrenia, and depression. Here, we present a pharmacological characterization of Lu AA41178, a novel, pan-selective Kv7.2–7.5 opener, using both in vitro assays and a broad range of in vivo assays with relevance to epilepsy, schizophrenia, and depression.Electrophysiological characterization in Xenopus oocytes expressing human Kv7.2-Kv7.5 confirmed Lu AA41178 as a pan-selective opener of Kv7 channels by significantly left-shifting the activation threshold. Additionally, Lu AA41178 was tested in vitro for off-target effects, demonstrating a clean Kv7-selective profile, with no impact on common cardiac ion channels, and no potentiating activity on GABAA channels.Lu AA41178 was evaluated across preclinical in vivo assays with relevance to neurological and psychiatric disorders. In the maximum electroshock seizure threshold test and PTZ seizure threshold test, Lu AA41178 significantly increased the seizure thresholds in mice, demonstrating anticonvulsant efficacy. Lu AA41178 demonstrated antipsychotic-like activity by reducing amphetamine-induced hyperlocomotion in mice as well as lowering conditioned avoidance responses in rats. In the mouse forced swim test, a model with antidepressant predictivity, Lu AA41178 significantly reduced immobility. Additionally, behavioral effects typically observed with Kv7 openers was also characterized. In vivo assays were accompanied by plasma and brain exposures, revealing minimum effective plasma levels <1000 ng/ml.Lu AA41178, a potent opener of neuronal Kv7 channels demonstrate efficacy in assays of epilepsy, schizophrenia and depression and might serve as a valuable tool for exploring the role of Kv7 channels in both neurological and psychiatric disorders.

Discovery of a pyrazolo[1,5-a]pyrimidine derivative (MT-3014) as a highly selective PDE10A inhibitor via core structure transformation from the stilbene moiety

We have developed a new class of PDE10A inhibitor, a pyrazolo[1,5-a]pyrimidine derivative MT-3014 (1). A previous compound introduced was deprioritized due to concerns for E/Z-isomerization and glutathione-adduct formation at the core stilbene structure. We discovered pyrazolo [1,5-a] pyrimidine as a new lead scaffold by structure-based drug design utilizing a co-crystal structure with PDE10A. The lead compound was optimized for in vitro activity, solubility, and selectivity against human ether-á-go-go related gene cardiac channel binding. We observed that MT-3014 shows excellent efficacy in rat conditioned avoidance response test and suitable pharmacokinetic properties in rats, especially high brain penetration.

Discovery of 2-[(E)-2-(7-Fluoro-3-methylquinoxalin-2-yl)vinyl]-6-pyrrolidin-1-yl-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine Hydrochloride as a Highly Selective PDE10A Inhibitor.

Phosphodiesterase (PDE) 10A is a dual hydrolase of cAMP and cGMP and highly expressed in striatal medium spiny neurons. Inhibition of PDE10A modulates the activity of medium spiny neurons (MSN) via the regulation of cAMP and cGMP. Signal control of MSN is considered associated with psychotic symptoms. Therefore PDE10A inhibitor is expected as a therapeutic method for psychosis disease such as schizophrenia. Avanafil (1) is a PDE5 inhibitor (treatment for erectile dysfunction) discovered by our company. We paid attention to the homology of PDE10A and PDE5 and took advantage of PDE5 inhibitor library to discover PDE10A inhibitors, and found a series of compounds that exhibit higher potency for PDE10A than PDE5. We transformed the afforded derivatives, which had weak inhibitory activity against PDE10A, and discovered stilbene as a PDE10A inhibitor. Brain penetration of this compound was improved by further conversion of N-containing heterocycles and their substituents. The afforded dimethylaminopyrimidine was effective for rat conditioned avoidance response (CAR) test; however, it did not exhibit good brain penetration. We performed in-depth optimization focusing on substituents of the quinoxaline ring, and produced 3-methyl-7-fluoro quinoxaline. This compound was the most effective in rat CAR test due to its strong PDE10A inhibitory activity and good pharmacokinetics.

Semax prevents learning and memory inhibition by heavy metals.

Separate and joint effect of Semax, ascorbic acid, lead diacetate, and ammonium molybdate on avoidance conditioning in rats was studied. It was established that the heavy metal salts inhibited the avoidance response, and the peptide counteracted this inhibition as strongly as ascorbic acid or to a comparable degree. These findings confirm the antioxidant properties of Semax.

The flavonoid apigenin delays forgetting of passive avoidance conditioning in rats

The present experiments were performed to study the effect of the flavonoid apigenin (20 mg/kg intraperitoneally (i.p.), 1 h before acquisition), on 24 h retention performance and forgetting of a step-through passive avoidance task, in young male Wistar rats. There were no differences between saline- and apigenin-treated groups in the 24 h retention trial. Furthermore, apigenin did not prevent the amnesia induced by scopolamine (1mg/kg, i.p., 30 min before the acquisition). The saline- and apigenin-treated rats that did not step through into the dark compartment during the cut-off time (540 s) were retested weekly for up to eight weeks. In the saline treated group, the first significant decline in passive avoidance response was observed at four weeks, and complete memory loss was found five weeks after the acquisition of the passive avoidance task. At the end of the experimental period, 60% of the animals treated with apigenin still did not step through. These data suggest that 1) apigenin delays the long-term forgetting but did not modulate the 24 h retention of fear memory and 2) the obtained beneficial effect of apigenin on the passive avoidance conditioning is mediated by mechanisms that do not implicate its action on the muscarinic cholinergic system.

Long-term impacts of adolescent risperidone treatment on behavioral responsiveness to olanzapine and clozapine in adulthood

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.

Semax prevents functional impairments of avoidance response in rats

ACTH/MSHrelated peptides, known as melanocortins, play an important role in regulation of manyfunctions in the body, including CNS. Among melanocortins, Semax is very prominent because it is anootropic analogue of ACTH (4–10) with prolongedaction [1]. In experiments with animals, the beneficialeffects of Semax on learning with positive reinforcement have been repeatedly reported [2]. Data on theSemax effects on animal learning with negative reinforcement are very few and contradictory. Data onboth learning improvement [3] and no effect [4] havebeen published.Mixed effects of nootropic drugs on learning arewell known [5, 6]; therefore, different approachesimpairing learning and memory, such as maximalelectroshock, ischemia or frontal lobectomy [7] areused for study of nootropic properties of substances.We suppose that use of models without any excessivemethodical complications and extreme physical treatment is very promising. For this purpose, functionalimpairments of the conditioned response of activeavoidance of pain stimulation in rats were suggested[8]. They are based on modification of definite cause–effect, i.e., “avoidance response failure,” and spatialrelationships in experimental environment.Here, we studied the effects of Semax on the development of avoidance conditioning in rats and its functional impairments modeled using failure and spatialmodification approaches.MATERIALS AND METHODSTwentysix male outbred albino rats weighing 250–370 g were used for the experiment. The animals weredaily trained for active avoidance conditioning in ashuttlebox for 7 days. Each daily session consisted of25 stimulus presentations. A shuttlebox was equippedwith a partition with two doors. During training, thedistal door in the partition was opened. The followingprotocol was used for training: a rat was placed into acompartment of the shuttlebox, the conditionedstimulus (tone) was presented, and, 10 s later, theunconditioned stimulus (electroshock) was presented.Crossing to the opposite compartment in response tothe conditioned stimulus was regarded as a conditioned avoidance response. Daily, we recorded thenumber of avoidances and expressed them as percentof the total number of stimulus presentations. On thelast day of training, we used the protocol of avoidancefailure after 20 stimulus presentations. For this purpose, during 5 last stimulus presentations, we did notturn off stimuli when the rat crossed to another compartment in response to conditioned or unconditionedstimuli, and it was subjected to electroshocks. After thefifth presentation, electroshock was stopped immediately, whereas the tone was turned off 2 s later. Then,20 presentations were used for testing of avoidanceresponse under the initial conditions. Since behavioralchanges appeared immediately after functionalimpairment, we analyzed the time course of changesin the indices of avoidance conditioning in blocks of 5presentations.Failure is reversible functional impairment thatallows using the same animals to study consequentlythe effects of nootropics under the conditions of oneand the other model and to obtain a reproducible nootropic effect [9]. Based on this assumption, we reproduced avoidance response one day after its failure.Then we closed the distal door, opened the proximaldoor, and tested avoidance response recall under newconditions during 20 stimuli presentations.Thirty minutes prior to each experiment, we intraperitoneally injected a Semax solution at a dose of0.05 mg/kg in a volume of 1 mL/kg. Control animalswere injected with an equal volume of distilled water.Data in figures are presented as the means andstandard errors.

ADX71743, a Potent and Selective Negative Allosteric Modulator of Metabotropic Glutamate Receptor 7: In Vitro and In Vivo Characterization

Metabotropic glutamate receptor 7 (mGlu(7)) has been suggested to be a promising novel target for treatment of a range of disorders, including anxiety, post-traumatic stress disorder, depression, drug abuse, and schizophrenia. Here we characterized a potent and selective mGlu(7) negative allosteric modulator (NAM) (+)-6-(2,4-dimethylphenyl)-2-ethyl-6,7-dihydrobenzo[d]oxazol-4(5H)-one (ADX71743). In vitro, Schild plot analysis and reversibility tests at the target confirmed the NAM properties of the compound and attenuation of L-(+)-2-amino-4-phosphonobutyric acid-induced synaptic depression confirmed activity at the native receptor. The pharmacokinetic analysis of ADX71743 in mice and rats revealed that it is bioavailable after s.c. administration and is brain penetrant (cerebrospinal fluid concentration/total plasma concentration ratio at C(max) = 5.3%). In vivo, ADX71743 (50, 100, 150 mg/kg, s.c.) caused no impairment of locomotor activity in rats and mice or activity on rotarod in mice. ADX71743 had an anxiolytic-like profile in the marble burying and elevated plus maze tests, dose-dependently reducing the number of buried marbles and increasing open arm exploration, respectively. Whereas ADX71743 caused a small reduction in amphetamine-induced hyperactivity in mice, it was inactive in the mouse 2,5-dimethoxy-4-iodoamphetamine-induced head twitch and the rat conditioned avoidance response tests. In addition, the compound was inactive in the mouse forced swim test. These data suggest that ADX71743 is a suitable compound to help unravel the physiologic role of mGlu(7) and to better understand its implication in central nervous system diseases. Our in vivo tests using ADX71743, reported here, suggest that pharmacological inhibition of mGlu(7) is a valid approach for developing novel pharmacotherapies to treat anxiety disorders, but may not be suitable for treatment of depression or psychosis.

Egis-11150: A candidate antipsychotic compound with procognitive efficacy in rodents

Classical antipsychotics, e.g. haloperidol, chlorpromazine, are potent at controlling the positive symptoms of schizophrenia but frequently elicit extrapyramidal motor side-effects. The introduction of atypical antipsychotics such as risperidone, olanzapine and clozapine has obviated this problem, but none of the current drugs seem to improve the cognitive deficits accompanying schizophrenia. Thus there is an unmet need for agents that not only suppress the psychotic symptoms but also ameliorate the impairment of cognition. Here, we report the preclinical properties of a candidate antipsychotic, Egis-11150, that shows marked pro-cognitive efficacy. Egis-11150 displayed high affinity for adrenergic α1, α2c, 5-HT2A 5-HT7, moderate affinity for adrenergic α2a and D2 receptors. It was a functional antagonist on all of the above receptors, with the exception of 5-HT7 receptors, where it was an inverse agonist. Phencyclidine-induced hypermotility in mice and inhibition of conditioned avoidance response in rats were assessed to estimate efficacy against the positive and social withdrawal test in rats was used to predict efficacy against the negative symptoms of schizophrenia. Passive-avoidance learning, novel object recognition and radial maze tests in rats were used to assess pro-cognitive activity, while phencyclidine-induced disruption of prepulse inhibition in mice was examined to test for effects on attention. Egis-11150 (0.01–0.3 mg/kg, ip.) was effective in all of the preclinical models of schizophrenia examined. Moreover, a robust pro-cognitive profile was apparent. In summary, work in preclinical models indicates that Egis-11150 is a potential treatment for controlling the psychosis as well as the cognitive dysfunction in schizophrenia.This article is part of a Special Issue entitled ‘Cognitive Enhancers’.

Effect of gabapentin on haloperidol induced inhibition of conditioned avoidance response in rat

Background: Haloperidol, an antipsychotic adversely affects acquisition and retention of a learned task. We decided to test the effect of Gabapentin, a new anti-epileptic drug using conditioned avoidance response model with cook’s pole climbing apparatus and haloperidol. Methods: Four groups of six rats were taken for this purpose. All the rats were first given drugs for five days and then trained for a period of 15 days. Gabapentin was given in a dose of 100mg/kg intra peritoneal, while haloperidol was given 0.5mg/kg intra peritoneal. Results: At the end of the training duration rats in the vehicle and gabapentin treated group achieved ≥85% acquisition responses. While the haloperidol and haloperidol + gabapentin group did not achieve the desired percentage of learning. A learning curve was plotted by using the percentage of conditioned responses in each group versus number of days. The mean ± SD percentage of conditioned responses of day 14 and 15 were for haloperidol group 26.19 ±11.90, for vehicle group 86.90 ± 4.29, for the gabapentin treated group 95.24 ± 2.38 and for the gabapentin + haloperidol group 46.42 ± 12.20. These figures and the learning curve suggest that gabapentin treated rats had a better acquisition response and haloperidol depressed learning. Conclusions: At the end of study duration we found that gabapentin significantly improved the acquisition response than the vehicle control group. Also haloperidol depressed the acquisition response. Gabapentin did not lead to reversal of haloperidol induced depression of acquisition process.

Clozapine, but not olanzapine, disrupts conditioned avoidance response in rats by antagonizing 5-HT2A/2C receptors

The present study was designed to assess the role of 5-HT(2A/2C) 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(2A/2C) 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(2A/2C) 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(2A/2C) receptors.

Preclinical profile of a novel metabotropic glutamate receptor 5 positive allosteric modulator

Recent reports have indicated that patients with schizophrenia have a profound hypo-functionality of glutamatergic signaling pathways. Positive allosteric modulation of mGlu 5 receptor has been postulated to augment NMDA function and thereby alleviate the glutamatergic hypo-function observed in schizophrenic patients. Here we report the in vitro and in vivo characterization of CPPZ (1-(4-(2-chloro-4-fluorophenyl)piperazin-1-yl)-2-(pyridin-4-ylmethoxy)ethanone), a structurally novel positive allosteric modulator selective for mGlu 5 receptor. In HEK293 cells stably over-expressing human mGlu 5 receptor, CPPZ potentiates the intracellular calcium response elicited by a suboptimal concentration of the endogenous agonist glutamate. CPPZ does not have any intrinsic agonist activity and behaves functionally as a positive allosteric modulator. This is further supported by binding data, which demonstrate that CPPZ is able to displace the negative allosteric modulator MPEP but does not compete with the orthosteric ligand quisqualic acid. Instead, CPPZ enhances the binding of the orthosteric ligand. In native preparations, CPPZ potentiates calcium flux in rat cortical neurons stimulated with the group I agonist dihydroxyphenylglycine (DHPG). In addition, CPPZ modulates long-term potentiation in rat hippocampal slices, a process known to be NMDA dependent. In vivo, CPPZ reverses hyper locomotion triggered by the NMDA open channel blocker MK801 in CD1 mice. CPPZ was also able to reduce rat conditioned avoidance responding to electric shock. Both in vitro and in vivo data demonstrate that this novel compound acts as an mGlu 5 receptor positive allosteric modulator, which modulates NMDA dependent responses and suggests that the enhancement of mGlu 5 receptor activity may prove useful in the treatment of schizophrenia.

An investigation of the behavioral mechanisms of antipsychotic action using a drug–drug conditioning paradigm

Antipsychotic drugs at noncataleptic doses selectively suppress conditioned avoidance response in rats. In our previous study, we had used a two-way active avoidance response paradigm to show that the antipsychotic-induced interoceptive state is one of the mechanisms underlying the avoidance-disruptive effect of antipsychotics. In this study, we sought to further examine this mechanism using a novel drug-drug conditioning procedure. We made use of the fact that both the typical neuroleptic haloperidol and the atypical neuroleptic olanzapine disrupt conditioned avoidance responding, whereas chlordiazepoxide (an anxiolytic) does not. We reasoned that if the antipsychotic interoceptive state is important in causing a disruption on avoidance responding (an index of antipsychotic efficacy), pairing chlordiazepoxide (a cueing drug conditional stimulus) with haloperidol or olanzapine (a cued drug unconditional stimulus) should engender chlordiazepoxide to exhibit this property and behave like an antipsychotic drug. Chlordiazepoxide exhibited an acquired antipsychotic-like property in disrupting avoidance responding after being repeatedly paired with haloperidol, but not with olanzapine. In contrast, it significantly attenuated the antiavoidance efficacy of olanzapine but not haloperidol after being repeatedly paired with these drugs. This study suggests that the haloperidol-induced interoceptive drug state is directly involved in its antiavoidance action, and chlordiazepoxide may attenuate the antiavoidance efficacy of antipsychotics (especially olanzapine). To the extent that the antiavoidance effect predicts clinical effects of antipsychotic treatment, this study suggests that the antipsychotic-induced interoceptive drug state may be an important behavioral mechanism mediating the clinical effects of antipsychotic treatments.

The Specific Features of Congenital and Acquired Forms of Behavior in the Postresuscitative Period (Experimental Study)

Academician of the USSR Academy of Medical Sciences V. A. Negovsky stated that there was an association of the pathogenesis of postresuscitative central nervous system (CNS) lesions with the individual typological characteristics. Therefore the objective of the investigation was to study the early brain structural and functional changes in resuscitated rats, which were related to the baseline type of behavior. The investigation was carried out on outbred albino male rats. Circulation was stopped under ether anesthesia for 10 minutes via intrathoracic ligation of the cardiac vascular fascicle. Before clinical death simulation, the animals were divided by the types of behavior according to their behavioral activity in the elevated cross labyrinth or open field test. Postresuscitatively, the rats were found to preserve their individual typological features of behavior. At the same time the animals with baseline various behavioral patterns showed great differences in becoming familiar with a new environment. The study of conditioned reflex activities suggested the predominant impact of postresuscitative cerebral changes on different mechanisms responsible for active avoidance conditioning in rats with baseline different behavioral types. Examination of the CA1 and CA4 pyramidal cell neuronal populations of the hippocampus indicated that in the elevated cross labyrinth test, the resuscitated animals with a high baseline behavioral activity had more pronounced neurodystrophic and degenerative changes in the study brain regions than the rats with a low activity. The findings not only have supported V. A. Negovsky&#8217;s ideas on the association of the pathogenesis of postresuscitative cerebral disorders with the individual typological characteristics of the CNS, but also revealed differences in the neuropathophysiological mechanisms of these disorders, and ascertained the structural features of postresuscitative cerebral lesions in the animals with baseline different type of behavior. Key words: ischemia, behavioral pattern, central nervous system, orientation-investigatory reaction, conditioned reflex, morphometry, neuronal populations.

Olanzapine and risperidone disrupt conditioned avoidance responding in phencyclidine-pretreated or amphetamine-pretreated rats by selectively weakening motivational salience of conditioned stimulus

The rat conditioned avoidance response model is a well-established preclinical behavioral model predictive of antipsychotic efficacy. All clinically approved antipsychotic drugs disrupt conditioned avoidance responding - a feature that distinguishes them from other psychotherapeutics. We previously showed that the typical antipsychotic drug haloperidol disrupts avoidance responding by progressively attenuating the motivational salience of the conditioned stimulus (CS) in normal rats. In this study, using two pharmacological rat models of schizophrenia [e.g. phencyclidine (PCP) or amphetamine sensitization], we examined whether atypicals such as olanzapine or risperidone disrupt avoidance responding through the same behavioral mechanism. Rats were first pretreated with PCP, amphetamine, or saline under one of two different injection schedules for either 1 or 3 weeks. They were then trained to acquire avoidance responding to two types of CS (CS1 and CS2) that differed in their ability to predict the occurrence of the unconditioned stimulus. Finally, rats were tested repeatedly under olanzapine (1.0 mg/kg, subcutaneously) or risperidone (0.33 mg/kg, subcutaneously) daily for 5 or 7 consecutive days. We found that repeated olanzapine or risperidone treatment produced a progressive across-session decline in avoidance responding to both CS1 and CS2. Olanzapine and risperidone disrupted the CS2 (a less salient CS) avoidance to a greater extent than the CS1 avoidance. Pretreatment with PCP and amphetamine did not affect the disruptive effect of olanzapine or risperidone on avoidance responding. On the basis of these findings, we suggest that the atypical drugs olanzapine and risperidone, like the typical drug haloperidol, also disrupt avoidance responding primarily by attenuating the motivational salience of the CS.

WAY-163909, a 5-HT2C agonist, enhances the preclinical potency of current antipsychotics

5-HT(2C) agonists, by decreasing mesolimbic dopamine without affecting nigrostriatal dopamine, are predicted to have antipsychotic efficacy with low extrapyramidal side effects (EPS). Combining 5-HT(2C) agonists with low doses of existing antipsychotics could increase treatment efficacy while reducing treatment liabilities such as EPS (typical antipsychotics), and the propensity for weight gain (atypical antipsychotics). The objectives of these studies were to combine WAY-163909, a selective 5-HT(2C) agonist, with either the typical antipsychotic haloperidol, or the atypical antipsychotic clozapine, at doses that were ineffective on their own, with the expectation that a shift in potency in several rodent behavior models predictive of antipsychotic activity would occur. In mice, co-administration of either haloperidol, or clozapine, produced a significant leftward shift in the ability of WAY-163909 to block apomorphine-induced climbing behavior, without any affect on apomorphine-induced stereotypy or an increased propensity for catalepsy. In the rat-conditioned avoidance model, WAY-163909 was combined with either haloperidol or clozapine at doses that individually produced reductions in avoidance response on the order of 10%, while the combination of WAY-163909 and either of the antipsychotics resulted in a greater than 70% reduction in avoidance, with no evidence of response failures, or pharmacokinetic interaction. Doses of either haloperidol or clozapine, that failed to antagonize an MK-801 induced deficit in prepulse inhibition, significantly attenuated the sensory gating deficit when combined with WAY-163909. Data support the notion that 5-HT(2C) receptor agonists, co-administered with other marketed antipsychotics, allow for dose sparing with a more favorable side-effect profile.

ADX47273 [S-(4-Fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]-oxadiazol-5-yl]-piperidin-1-yl}-methanone]: A Novel Metabotropic Glutamate Receptor 5-Selective Positive Allosteric Modulator with Preclinical Antipsychotic-Like and Procognitive Activities

Positive allosteric modulators (PAMs) of metabotropic glutamate receptor subtype 5 (mGlu5) enhance N-methyl-d-aspartate receptor function and may represent a novel approach for the treatment of schizophrenia. ADX47273 [S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-methanone], a recently identified potent and selective mGlu5 PAM, increased (9-fold) the response to threshold concentration of glutamate (50 nM) in fluorometric Ca(2+) assays (EC(50) = 170 nM) in human embryonic kidney 293 cells expressing rat mGlu5. In the same system, ADX47273 dose-dependently shifted mGlu5 receptor glutamate response curve to the left (9-fold at 1 microM) and competed for binding of [(3)H]2-methyl-6-(phenylethynyl)pyridine (K(i) = 4.3 microM), but not [(3)H]quisqualate. In vivo, ADX47273 increased extracellular signal-regulated kinase and cAMP-responsive element-binding protein phosphorylation in hippocampus and prefrontal cortex, both of which are critical for glutamate-mediated signal transduction mechanisms. In models sensitive to antipsychotic drug treatment, ADX47273 reduced rat-conditioned avoidance responding [minimal effective dose (MED) = 30 mg/kg i.p.] and decreased mouse apomorphine-induced climbing (MED = 100 mg/kg i.p.), with little effect on stereotypy or catalepsy. Furthermore, ADX47273 blocked phencyclidine, apomorphine, and amphetamine-induced locomotor activities (MED = 100 mg/kg i.p.) in mice and decreased extracellular levels of dopamine in the nucleus accumbens, but not in the striatum, in rats. In cognition models, ADX47273 increased novel object recognition (MED = 1 mg/kg i.p.) and reduced impulsivity in the five-choice serial reaction time test (MED = 10 mg/kg i.p.) in rats. Taken together, these effects are consistent with the hypothesis that allosteric potentiation of mGlu5 may provide a novel approach for development of antipsychotic and procognitive agents.

S33138 (N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1] benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenyl-acetamide), a Preferential Dopamine D3 versus D2 Receptor Antagonist and Potential Antipsychotic Agent: III. Actions in Models of Therapeutic Activity and Induction of Side Effects

In contrast to clinically available antipsychotics, the novel benzopyranopyrrolidine derivative, S33138 (N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1]benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenyl-acetamide), behaves as a preferential antagonist of D(3) versus D(2) receptors and does not interact with histamine H(1) and muscarinic receptors. In contrast to haloperidol, clozapine, olanzapine, and risperidone, S33138 (0.16-2.5 mg/kg s.c.) did not disrupt performance in passive-avoidance and five-choice serial reaction time procedures. Furthermore, upon either systemic administration (0.04-2.5 mg/kg s.c.) or introduction into the frontal cortex (0.04-0.63 mug/side), S33138 potently attenuated the perturbation of social recognition by scopolamine or a prolonged intersession delay. Over a comparable and low-dose range, S33138 (0.04-0.63 mg/kg s.c.) elevated dialysis levels of acetylcholine in the frontal cortex of freely moving rats. At higher doses (2.5-10.0 mg/kg s.c.), S33138 also increased frontocortical levels of histamine, whereas monoamines, glutamate, glycine, and GABA were unaffected. By analogy to the other antipsychotics, S33138 (0.63-10.0 mg/kg s.c.) inhibited conditioned avoidance responses in rats, apomorphine-induced climbing in mice, and hyperlocomotion elicited by amphetamine, cocaine, dizocilpine, ketamine, and phencyclidine in rats. S33138 (0.16-2.5 mg/kg s.c.) also blocked the reduction of prepulse inhibition elicited by apomorphine. In comparison with the above actions, only "high" doses of S33138 (10.0-40.0 mg/kg s.c.) elicited catalepsy. To summarize, reflecting preferential blockade of D(3) versus D(2) receptors, S33138 preserves and/or enhances cognitive function, increases frontocortical cholinergic transmission, and is active in models of antipsychotic properties at doses well below those inducing catalepsy. In comparison with clinically available agents, S33138 displays, thus, a distinctive and promising profile of potential antipsychotic properties.

Peculiarities of active avoidance conditioning in rats with various forms of inherited arterial hypertension

Peculiarities of active avoidance conditioning were studied in NISAG rats (hereditary stress-induced arterial hypertension) and spontaneously hypertensive SHR rats. Conditioning was successful in 90% normotensive Wistar rats and in only 9.1% NISAG rats. Hypertensive SHR rats were intermediate between Wistar and NISAG rats by their learning capacity (66.7%). Our results suggest that differences in learning capacity of hypertensive rats are determined by genetic characteristics of animal behavior and emotional state, rather than blood pressure elevation.