clozapine and Ataxia

Recent studies using phencyclidine (PCP) as a model for psychosis have implicated metabotropic glutamate (mGlu) receptors in schizophrenia. We have shown, using an automated motor activity monitoring system, that selective group II mGlu receptor agonists attenuate PCP (5 mg/kg)-evoked increases in ambulations and fine motor movements with similar profiles to the atypical antipsychotic, clozapine.. Because the automated system does not discriminate between specific PCP-evoked behaviors, in this paper we examined the effects of the potent mGlu2/3 receptor agonist LY379268 on PCP-evoked behaviors as assessed by observational methods. Furthermore, we have compared the actions of LY379268 to the atypical antipsychotic clozapine.. LY379268 and clozapine reduced the expression of PCP-induced falling, turning and back pedaling in a dose-dependent manner. Thirty minutes post-PCP administration, 1 mg/kg LY379269 reduced falls and turns by 89% and 53%, respectively, and 1 mg/kg clozapine attenuated turning by 70%. Interestingly, low doses of clozapine increased PCP-elicited falls. Back-pedaling was particularly sensitive to LY379268 and clozapine, with 1 mg/kg of either agent completely abolishing back-pedaling 30 min after PCP administration. However, in contrast to LY379268, attenuation of these behaviors by clozapine only occurred at doses that augmented PCP-evoked ataxia. Furthermore, LY379268 did not affect PCP-evoked forepaw treading.. These results indicate that mGlu2/3 receptors do not mediate a generalized reduction in motor activity, but instead selectively modulate specific PCP behaviors, further implicating group II mGlu receptors as viable drug targets in the treatment of schizophrenia.

Topics: Amino Acids; Animals; Antipsychotic Agents; Ataxia; Behavior, Animal; Bridged Bicyclo Compounds, Heterocyclic; Clozapine; Excitatory Amino Acid Agonists; Hallucinogens; Male; Motor Activity; Phencyclidine; Postural Balance; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate

Alpha2 adrenoceptor antagonists have been shown to reverse D2-antagonist-induced catalepsy leading to the hypothesis that the alpha2 antagonistic properties of clozapine underlie the compound's lack of extrapyramidal symptoms in the clinic. The potential for alpha2 antagonists to reverse the motor deficits produced by D2 antagonists (loxapine and haloperidol) was further investigated using a rotating rod (3.5 rpm) test in male Sprague-Dawley rats that requires coordinated movement to perform the task. The effects of loxapine (0.3 mg/kg, s.c.) were dose-dependently and statistically significantly reversed by the administration of clozapine (1,3, 10 mg/kg, i.p., n=10). Isoloxapine (1 mg/kg, i.p.), RX 821002 (2-methoxy-idazoxan; 5.6 mg/kg, i.p.) and yohimbine (5.6 mg/kg, i.p.) did not reverse the effects of loxapine. Furthermore, the motor deficits produced by haloperidol could not be reversed by RX 821002 (5.6 mg/kg, i.p.) or yohimbine (5.6 mg/kg, i.p.). On the other hand, scopolamine (0.03-0.3 mg/kg, i.p.) dose-dependently and statistically significantly antagonised the effects of both loxapine and haloperidol. These results indicate that the anticholinergic rather than the alpha2 antagonistic properties of clozapine may mediate the reversal of the motor deficit induced by D2 antagonism in a rotating rod test.

Topics: Adrenergic alpha-2 Receptor Antagonists; Adrenergic alpha-Antagonists; Animals; Ataxia; Clozapine; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Haloperidol; Idazoxan; Loxapine; Male; Muscarinic Antagonists; Psychomotor Performance; Rats; Rats, Sprague-Dawley; Scopolamine; Yohimbine

(5-Amino-1,3-dimethyl-1H-pyrazol-4-yl)(2-fluorophenyl)methanone (1) was found to have an antipsychotic-like profile in behavioral tests predictive of antipsychotic efficacy but, unlike available antipsychotic agents, did not bind in vitro to dopamine receptors. Upon further evaluation, 1 was found to cause clonic seizures in aged rodents. An examination of related structures revealed that 5-(substituted aminoacetamide) analogues of 1 shared this novel pharmacology and did not cause seizures. The synthesis and pharmacological evaluation of this series of compounds are described. Two compounds, 2-(diethylamino)acetamide (25) and 2-[[3-(2-methyl-1-piperidinyl)propyl]-amino]acetamide (38), were selected for examination in secondary tests. Like known antipsychotics both compounds reduced spontaneous locomotion in mice at doses that did not cause ataxia and inhibited conditioned avoidance selectively in both rats and monkeys. Unlike known antipsychotics neither 25 nor 38 elicited dystonic movements in haloperidol-sensitized cebus monkeys, a primate model of antipsychotic-induced extrapyramidal side effects. Biochemical studies indicated that these compounds act via a nondopaminergic mechanism. Neither 25 nor 38 bound to dopamine receptors in vitro or caused changes in striatal dopamine metabolism in vivo. In addition, they did not raise serum prolactin levels as do known antipsychotics. Although adverse animal toxicological findings have precluded clinical evaluation of these agents, the present results indicate that it is possible to identify at the preclinical level nondopaminergic compounds with antipsychotic-like properties.

Topics: Animals; Antipsychotic Agents; Apomorphine; Ataxia; Avoidance Learning; Brain; Cebus; Chemical Phenomena; Chemistry; Dopamine; Male; Mice; Motor Activity; Movement Disorders; Pyrazoles; Rats; Rats, Inbred Strains; Receptors, Dopamine; Saimiri