Tolerance to the cognitive impairing effects but not the anticonvulsant effects of NO-328, a selective GABA uptake inhibitor

El

P.mo.307

Judge, M.E., Swedberg, M.D.B. and Suzdak, P.D. Depts. of Behavioral Neurology. Behavioral Pharmacology, and Neurochemisrry, Novo Nordisk /Ferrosan DH-2860

CNS Division, Syd&arken

5,

Soeborg Denmark

NO-328 (N(4,4-Di(3-Methyl-2-Thienyl)But-3-En-l-y1)Nipocotic acid) is a potent and selective GABA uptake inhibitor in vitro (IC, = 67 nM) which is currently being evaluated as a potential treatment of epilepsy. NO-3B has been previously shown to be a potent anticonvulsant in both DMCM-induced seizures (ED,) = 0.8 mg/kg i.p.) and PTZ-induced seizures (ED,, = 1.1 mg/kg i.p.) in mice. Anticonvulsant agents such as the benzodiazepines and dilantin have been previously shown to produce memory impairment in both animals and man. The present investigation examines the effect of NO-328 in a one trial approach-avoidance conflict memory task after acute and chronic administration. Mice (female NMRI, 10 weeks old) were trained in a one trial approach-avoidance conflict memory task (water vs shock (0.3 mA x 0.01 sec.)) and tested one day later. NO-328 impaired memory production at higher doses (3-10 mg/kg i.p.). The benzodiaxepine receptor agonist diazepam also impaired memory production at higher doses (3-10 mg/kg i.p.). Upon chronic (4 day) administration of NO-328 tolerance developed to the acute memory impairment effects of the compound without corresponding tolerance to the anticonvulsant effects of the compound. These data suggest that NO-328 possesses a highly desirable pharmacological profile (tolerance to the initial memory impairment without tolerance to the anticonvulsant effectiveness) which distinguishes it from anti-convulsant compounds which readily produce tolerance to their anticonvulsive effects.

ova in0 Wooles, W.R., Zhang, X. and Myers, R.D. Department

of Pharmacology,

School of Medicine, East Carolina

University, Greenville, NC 27858, U.S.A.

It has been established that the RVL is involved in the control of cardiovascular and baroreflex activity (Ross et al., 1984). Although the neurotransmitter(s) involved in this effect have not been delineated, we have recently shown that microinjection of glutamate into an area close to the ventral surface of the rostral ventrolateral medulla (RVLM) produced an increase in mean arterial blood pressure (MAP) secondary to enhanced sympathetic efferent discharge, and a severe bradycardia (Zhang et al., 1989a). The purpose of the present study was to determine changes in catecholamine and neurotransmitter amino acid release caused by microinjection of glutamate into the RVLM. L-glutamate in artificial CSF was perfused through a newly devised, triple bore, micro push-pull cannula (Zhang et al., 1989b) into the RVLM of Sprague Dawley rats anesthetized with alpha chloralose. This procedure allowed us to either perfuse or inject l-glutamate through one barrel, artificial CSF through the second and to withdraw 25 ul samples of CSF at 5 mitt intervals through the third. The concentration of released amino acids and catecholamines was determined by HPLC with electro-chemical detection prior to and during the cardiovascular changes induced by glutamate. Simultaneous recordings were made of MAP, HR and SED which allowed correlation of changes in catecholamine and amino acid release from the RVLM with glutamate-induced changes in the cardiovascular variables. MAP was increased 65 mm Hg by the perfusion of 5 nM of l-glutamate for 10 min and was accompanied by a