European Journal of Pharmacology, 33 (1975) 389--393 © North-Holland Publishing Company, Amsterdam -- Printed in The Netherlands

Short communication INCREASED SUSCEPTIBILITY TO SEIZURES AND DECREASED CATECHOLAMINE TURNOVER IN SPONTANEOUSLY HYPERTENSIVE RATS MORTON E. GOLDBERG, JOHN E. MILMORE, M A R G A R E T K. HAUBRICH and DEAN R. HAUBRICH

Department of Pharmacology, Squibb Institute for Medical Research, Princeton, N.J. 08540, U.S.A. Received 16 June 1975, accepted 8 July 1975

M.E. GOLDBERG, J.E. MILMORE, M.K. HAUBRICH and D.R. HAUBRICH, Increased susceptibility to seizures and decreased catecholamine turnover in spontaneously hypertensive rats, European J. Pharmacol. 33 (1975) 389--393. Spontaneously hypertensive rats (SHR) were compared with normotensive Wistar rats for their sensitivity to tonic extensor seizures. SHR were more sensitive to seizures and did not respond to the anticonvulsant effects of L-DOPA. SHR had a slower turnover rate of norepinephrine in brain stem and cortex and of dopamine in striatum. Steady-state levels of catecholamines were similar in both groups. These findings are consistent with earlier ones that reported an inverse relationship between central catecholamine activity and sensitivity to electroconvulsive seizures. Turnover rate

L-DOPA

Anticonvulsant

1. Introduction The relationship between brain concentration of biogenic amines and sensitivity to electrically or chemically induced seizures has been investigated extensively. Agents that lower the levels of catecholamines in brain also lower the threshold for experimental seizures (Chen et al., 1968; Kilian and Frey, 1973). Conversely, inhibitors of monoamine oxidase elevate the latency to maximal electroshock and, in large doses, afford complete protection from seizures (Prockop et al., 1959). Alterations of adrenergic mechanisms have been observed in spontaneously hypertensive rats (SHR). Louis et al. {1970) reported lower norepinephrine turnover rates in the brain stem and hearts of such subjects than in those of normotensive rats. Several studies have reported that the activity of enzymes associated with the norepinephrine synthesis is lower in the brain and cardiovascular system of the SHR (Yamori et al., 1970; Sjoerdsma, 1972).

Seizures

Catecholamines

Hypertension

The purpose of the present investigation was to study the relationship between seizure susceptibility and brain levels and turnover of norepinephrine and dopamine in normal and SHR.

2. Materials and methods Male Wistar rats (Carworth Farms, Vincentown, N.J.), approximately 10 weeks old, 200--240 g, were used after a 1-week laboratory acclimatization. They were housed two to a cage and were allowed food and water ad libitum until the start of each experiment. Normotensive rats and SHR (derived from Okamoto & Aoki strain (Okamoto and Aoki, 1963)) were tested for threshold to tonic extensor seizures induced by electrical shock after a 60-cycle A.C. current of 0.2 sec applied through pinnal electrodes. Mean arterial blood pressure was determined directly by use of the technique of Laffan et al. (1972). LDOPA (300 mg/kg, i.p., Nutritional Biochem.

390 Corp.) was given 60 min prior to test. This dose has been shown to protect rats from maximal electroshock seizures (Kilian and Frey, 1973). The concentrations of norepinephrine in the cortex, hippocampus, and brain stem and of dopamine in the corpus striatum were determined by the fluorometric procedure of Haubrich and Denzer (1973). Determinations of the turnover rates of norepinephrine and dopamine in these regions were based on nonisotopic, steady-state concepts. Turnover rates were estimated by calculating the rate of decline of these amines after administration of an inhibitor of tyrosine hydroxylase, D,La-methyltyrosine m e t h y l ester (400 mg/kg, i.p. Regis Chem. Co.), as described by Neff and Costa (1967). Statistical differences between treatment group were compared by Student's t-test or by X2 analysis.

3. Results

M.E. GOLDBERG ET AL. sive and normotensive rats, respectively (p

Increased susceptibility to seizures and decreased catecholamine turnover in spontaneously hypertensive rats.

Spontaneously hypertensive rats (SHR) were compared with normotensive Wistar rats for their sensitivity to tonic extensor seizures. SHR were more sens...
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