The five choice serial reaction time task: comparison between Sprague-Dawley and Long-Evans rats on acquisition of task, and sensitivity to phencyclidine.

The 5-choice serial reaction time task (5-CSRTT) allows examination of multiple aspects of cognition/executive functions (attention/impulsivity/ perseveration). Most 5-CSRTT studies are performed with pigmented (i.e. Long-Evans: LE) rats; however, albino strains (i.e. Sprague-Dawley: SD) are more commonly used in behavioural pharmacology experiments. Hence, we compared 5-CSRTT performances of SD and LE rats and their sensitivity to acute phencyclidine (PCP, 1-2.5 mg/kg). SD required significantly fewer sessions(35 versus 50) than LE rats for task acquisition, especially at shortest stimulus light duration (1 s). However,once trained, under vehicle conditions, both strains performed similarly. In contrast, PCP treatment differentially affected the two strains. Thus, whilst percentage of accuracy was decreased for both strains, in SD rats number of premature responses was more markedly decreased, whereas omissions and latency time to correct responses were more notably increased. In addition, PCP monotonically diminished in SD, but augmented (1-1.5 mg/kg) in LE rats compulsive responding. To summarize, under our experimental conditions, the SD offer advantages over LE strain for speed of acquisition of 5-CSRTT. Once trained, basal performances of both strains were equivalent and stable enough for challenge with pharmacological compounds. However, PCP differentially affected the strains on several parameters considered.

Induction by antipsychotics of "win-shift" in the drug discrimination paradigm.

In a two-lever, food-rewarded drug discrimination paradigm, behavior seems to be governed by a win-stay/lose-shift rule; rats continue to press the lever that yields food, and, when not rewarded, they shift responding to the alternative lever. Here, we report on the effects that antipsychotics and further neuropharmacological agents exert in those conditions. At higher doses, antipsychotics disrupt most or all behavioral parameters in this paradigm. However, at lower doses, rats may select the appropriate lever with normal latency and accuracy, obtain a first food pellet (i.e., "win"), and then, remarkably, shift responding to the alternative lever ("win-shift"). This suggests that antipsychotics can block the effects of reward selectively, i.e., at doses where the initial, secondarily reinforced behavior including the initiation of lever pressing, remains intact. Indeed, saline-treated rats that are given no reward (i.e., "lose") after having selected a lever, also press the alternative lever ("lose-shift"). The induction of selective win-shift is specific to antipsychotics, but it varies greatly among them. Perhaps relating to its alleged "incisive" action on delirium and hallucinations, and, surprisingly, in view of its extrapyramidal actions, acutely administered haloperidol (0.04-0.08 mg/kg) demonstrates win-shift to an exceptional extent, shared only with the newly proposed agent (3-cyclopent-1-enyl-benzyl)-[2-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-ethyl]-amine fumarate (F 15063; 0.31-0.63 mg/kg); the more sedative antipsychotic chlorpromazine demonstrated little selectivity. The paradigm offers a novel tool to characterize antipsychotics with regard to presumably pathogenic motivational processes; mixed D(2)-antagonist/5-hydroxytryptamine(1A)-agonist agents such as F 15063 may conceivably share the powerful antipsychotic action of haloperidol while avoiding the sensitization that develops to extrapyramidal effects of haloperidol and consequent negative symptoms.

Putative antipsychotics with pronounced agonism at serotonin 5-HT1A and partial agonist activity at dopamine D2 receptors disrupt basal PPI of the startle reflex in rats.

INTRODUCTION: Prepulse inhibition (PPI) of the startle reflex has been extensively studied because it is disrupted in several psychiatric diseases, most notably schizophrenia. In rats, and to a lesser extent, in humans, PPI can be diminished by dopamine (DA) D(2)/D(3) and serotonin 5-HT(1A) receptor agonists. A novel class of potential antipsychotics (SSR181507, bifeprunox, and SLV313) possess partial agonist/antagonist properties at D(2) receptors and various levels of 5-HT(1A) activation. MATERIALS AND METHODS: It thus appeared warranted to assess, in Sprague-Dawley rats, the effects of these antipsychotics on basal PPI. RESULTS: SSR181507, sarizotan, and bifeprunox decreased PPI, with a near-complete abolition at 2.5-10 mg/kg; SLV313 had a significant effect at 0.16 mg/kg only. Co-treatment with the 5-HT(1A) receptor antagonist WAY100,635 (0.63 mg/kg) showed that the 5-HT(1A) agonist activity of SSR181507 was responsible for its effect. By contrast, antipsychotics with low affinity and/or efficacy at 5-HT(1A) receptors, such as aripiprazole (another DA D(2)/D(3) and 5-HT(1A) ligand), and established typical and atypical antipsychotics (haloperidol, clozapine, risperidone, olanzapine, quetiapine, and ziprasidone) had no effect on basal PPI (0.01-2.5 to 2.5-40 mg/kg). DISCUSSION: The present data demonstrate that some putative antipsychotics with pronounced 5-HT(1A) agonist activity, coupled with partial agonist activity at DA D(2) receptors, markedly diminish PPI of the startle reflex in rats. CONCLUSIONS: These data raise the issue of the influence of such compounds on sensorimotor gating in humans.

Actions of novel antipsychotic agents on apomorphine-induced PPI disruption: influence of combined serotonin 5-HT1A receptor activation and dopamine D2 receptor blockade.

The dopamine D1/D2 agonist apomorphine (0.63 mg/kg) disrupted prepulse inhibition (PPI) of acoustic startle in rats, a model of sensorimotor gating deficits observed in schizophrenia. All current antipsychotics, which antagonize D2 receptors, prevent this apomorphine-induced deficit. A novel class of antipsychotics possesses, in addition to D2 antagonist property, various levels of 5-HT1A agonist activity. Considering that the latter itself produces PPI deficits, it appeared necessary to assess the potential of this novel class of antipsychotics to reverse apomorphine-PPI deficits. Potent D2 antagonists, like haloperidol (0.63-2.5 mg/kg), risperidone (0.63-10 mg/kg), and olanzapine (0.63-40 mg/kg) prevented apomorphine PPI disruption. The atypical antipsychotics, clozapine (40 mg/kg), nemonapride (0.01-2.5 mg/kg), ziprasidone (10 mg/kg), and aripiprazole (0.01 and 10 mg/kg), which all exhibit 5-HT1A agonist properties, reversed PPI deficits at some doses only, whereas the anti-dyskinetic agent sarizotan (0.16-10 mg/kg), an efficacious 5-HT1A agonist, did not. New generation antipsychotics with marked 5-HT1A agonist properties, such as SLV313 and SSR181507 (0.0025-10 mg/kg and 0.16-10 mg/kg, respectively) did not reverse these deficits whereas bifeprunox (0.04-2.5 mg/kg) did. To reveal the contribution of 5-HT1A agonist properties in the lack of effects of SLV313 and SSR181507, we pretreated rats with the 5-HT1A antagonist WAY100635 (0.63 mg/kg). Under these conditions, significant reversal of PPI deficit was observed, indicating that D2 antagonist properties of SLV313 and SSR181507 are now sufficient to overcome the disruptive effects of apomorphine. To summarize, antipsychotics possessing agonist efficacy at 5-HT1A receptors exhibit diverse profiles against apomorphine-induced PPI deficits, depending on the balance between D2 and 5-HT1A activities, suggesting that they may display distinct activity on some aspects of gating deficits in schizophrenic patients.