Measurement of an explosive behaviour induced by MK-801, a PCP analogue, in the mouse

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Expectations for new neuroleptics with improved antipsychotic action has been high since the demonstration of differential antipsychotic efficacy with clozapine (Kane, 1988). The exact mechanism of clozapine’s unique antipsychotic action is unknown, so directions for new drug development have been speculative. Remoxipride is a substituted benzamide of the sulpiride family, it has highly selective D? antagonist activity and an in viva selectivity for limbic D2 receptors. Remoxipride has already been shown to produce significantly fewer motor side effects than the standard neuroleptic haloperidol (Lewander, 1990). Now, we report preliminary data suggesting that remoxipride, like clozapine, has unique antipsychotic activity in neuroleptic-resistant schizophrenic individuals. Sixteen DSM-III-R schizophrenic subjects were characterized as neuroleptic-resistant according to the criteria of Kane, et al. They were tested in a h-week, double-blind, drug-drug, parallel group study, comparing the antipsychotic Three of eight action of remoxipride with haloperidol. remoxipride-treated subjects were “improvers” (38%). whereas 0% of the haloperidol group responded. This response is comparable to that of clozapine (30%) in the U.S. multicenter Clozapine treatment trial. Remoxipride may have differential efficacy in previously poorly responsive neuroleptic treated schizophrenic patients.

injections. Frequent sustained myoclonic jerks occurred in all 6 animals starting lo-16 minutes after clozapine injections (4, IO and 20 mg/kg) and were maximum in number at 10 m&g. A few myoclonic jerks occurred in two of the chlorpromazine treated animals immediately after IP injections of 8 mg/kg and 16 mg/ kg respectively. These two animals exhibited a brief clinical seizure immediately after injection. No abnormal motor behaviour or EEG activity occurred with vehicle or saline injections. Detailed analysis of the motor behaviour and electrical recordings from deep and cortical electrodes will be presented.

MEASUREMENT OF AN EXPLOSIVE BEHAVIOUR INDUCED BY MK-801, A PCP ANALOGUE, IN THE MOUSE S.I. Deutsch*, Psychiatry 50 Irving

IS THE THERAPEUTIC EFFECT OF CLOZAPINE ASSOCIATED WITH EPILEF’TOGENIC ACTIVITY IN DEEP BRAIN NUCLEI? D.D. Denney, J.R. Stevens* Department Portland,

of Psychiatry,

Oregon

Health

Sciences University,

OR, USA

Although dopamine and other receptor blockade is complete within a few hours after starting antipsychotic neuroleptic treatment, therapeutic effects continue to evolve over two to four weeks. This is particularly true of clozapine, which has been more “epileptogenic” than the phenothiazines and butyrophenones. The hypothesis tested in these experiments is that the beneficial effects of antipsychotic neuroleptics and particularly of clozapine, may be related to the production of alterations in neuronal excitability and subcortical “microseizures” in critical brain areas, Such effects could alter the sensitivity of receptors in projection sites and enhance focal excitability perhaps by the process of “kindling”. The amygdala and hippocampus have the lowest threshold for epileptic discharge of any brain region and project to marry areas including nucleus accumbens, thalamus, hypothalamus and frontal cortex. To examine the effect of clozapine and chlorpromazine on electrical activity in amygdala and hippocampus, chronic bipolar electrodes were implanted stereotactically in these areas under ketamine-acepromazine anesthesia in Sprague Dawley rats. Beginning one week after surgery electrical activity was recorded from deep and cortical sites before and after intraperitoneal injection of clozapine (4, 10 and 20 mg/kg) and chlorpromazine (8 and 16 mg/kg) at 2-3 day intervals. On different days similar recordings were made after normal saline and vehicle

Ana Hitri

Service (116A);

Dept.

St., NW; Washington,

Veterans Affairs DC 20422,

Med Center;

USA

MK-801, a noncompetitive antagonist of the NMDA receptor complex, stimulated an outbred strain of NIH Swiss mice to display discrete episodes of explosive jumping behaviour, designated as “popping”. The activity of the mouse during the entire episode is explosive. Discrete episodes of this behaviour were counted without regard to their intensity or duration. The least intense example of this behaviour consisted of a spasmodic contraction of the entire mouse. In the most intense examples of this behaviour, these spasmodic contractions would propel the mouse into the air; an episode of repetitive “popping” into the air could continue for several seconds. Discrete episodes of popping were counted in 5 minute intervals for the duration of a 30 minute observation period. The episodes of this behaviour were characterized with respect to their dose-dependency, latency, and duration. Conventional and atypical antipsychotic medications were shown to attenuate MK-801-stimulated popping in a dose-dependent manner. In view of PCP’s ability to precipitate a schizophrenifomt psychosis in humans, the behaviour may serve as a useful preclinical paradigm for the screening of potentially novel amipsychotic medications.

EFFICACY OF L-TYROSINE ADJUVANT THERAPY IN THE TREATMENT OF SCHIZOPHRENIA XI. Deutsch*, Fay-McCarthy, Psychiatry Center,

R.B. Rosse, B.L. Schwartz, M. J.P. Collins

Service (116A),

Washington,

Dept.

DC 20422,

Veterans Affairs USA

Medical