Pharmacology Biochemistry & Behavior, Vol. 37, pp. 417--424. © Pergamon Press plc, 1990. Printed in the U.S.A. 0091-3057/90 $3.00 + .00 Inhibition by Antibiotic Tetracyclines of Rat Cortical Noradrenergic Adenylate Cyclase and Amphetamine-Induced Hyperactivity O. KOFMAN, 1 E. KLEIN, M. NEWMAN, R. HAMBURGER, O. KIMCHI, T. NIR, H. SHIMON AND R. H. BELMAKER Beer Sheva Mental Health Centre, Ben Gurion University of the Negev, Beer Sheva and Ezrath Nashim Hospital, P.O.B. 140, Jerusalem, Israel Received 6 February 1990 KOFMAN, O., E. KLEIN, M. NEWMAN, R. HAMBURGER, O. KIMCHI, T. NIR, H. SHIMON AND R. H. BELMAKER. Inhibition by antibiotic tetracyclinesof rat cortical noradrenergicadenylate cyclase and amphetamine-induced hyperactivity. PHAR- MACOL BIOCHEM BEHAV 37(3) 417--424, 1990.--Two antibiotic tetracyclines, demeclocycline (DMC) and minocycline, share several biochemical and behavioral properties with lithium (Li). DMC inhibited both noradrenaline- and chloradenosine-sensitive cyclic AMP accumulation in rat cerebral cortical slices both in vitro and ex vivo following two weeks of chronic dietary treatment. Minocycline, a lipophilic tetracycline, produced similar results in vitro. Both DMC and minocycline reduced open-field activity levels in rats following acute treatment, four hours prior to testing. Moreover, both drugs inhibited amphetamine-induced hyperac- tivity in the open field. Chronic treatment with 0.4% and 0.8% dietary DMC for two weeks attenuated amphetamine hyperactivity without affecting baseline activity levels in the open field. Neither DMC nor minocycline attenuated apomorphine-indueed stereo- typy at doses that attenuated amphetamine hyperactivity, a profile which is similar to that of lithium. Unlike lithium, however, DMC did not reverse reserpine-induced hypoactivity. Lithium Adenylate cyclase Amphetamine Demeclocycline Minocycline Bipolar affective illness AMONG Li's numerous biological effects, its inhibition of ade- nylate cyclase has been extensively studied (3). Li at near therapeutic concentrations inhibits noradrenaline-sensitive adeny- late cyclase in rat cortical slices (15). Li at more clearly therapeu- tic concentrations inhibits noradrenaline-sensitive adenylate cyclase in slices of human cortex from the normal edges of surgically removed brain tumours (32). Li at therapeutic concentrations, in patients under chronic treatment, inhibits the epinephrine-induced rise in plasma cyclic AMP (13). Recently, the G-protein component of the adenylate cyclase complex has been suggested as a molecular site of the Li effect on adenylate cyclase (1). Since these effects on adenylate cyclase are unlike those of other psychoactive drugs, compounds with similar properties should be screened to determine if they have the behavioral and clinical profile of Li. Antibiotic tetracyclines have been shown to inhibit ADH- sensitive adenylate cyclase in the kidney at a site distal to the ADH receptor (12). This inhibition is similar to that involved in the pathogenesis of the Li side effect of nephrogenic diabetes insipi- dus (19, 39, 40). Since adenylate cyclase is similar in many tis- sues, tetracycline effects on rat cortical noradrenergic adenylate cyclase were examined in the present study. Since Li inhibits hy- peractivity induced by low dose amphetamine in rats (7,31), we also tested the effects of tetracyclines on this behavior. Prelimi- nary data in both the biochemical and behavioral tests have been previously published (4,5). Neuroleptics, but not Li, inhibit apomorphine-indnced stereo- typy (14); therefore, the effects of tetracyclines on apomorphine- induced stereotypy were tested to define the specificity of their behavioral effects. Li has been reported to inhibit reserpine-in- duced hypoactivity (30) and so here too tetracyclines were stud- ied. Demeclocycline (DMC) was chosen for most experiments, since it is the tetracycline with most marked effects on polyuria and adenylate cyclase in the kidney (18); minocycline was used in some confirmatory experiments since it is lipophilic and crosses the blood-brain barrier more readily than DMC (38). IRequests for reprints should be addressed to Dr. O. Kofman, P.O.B. 4600, Beer Sheva, Israel. 417