Molecular Pharmacology, Vol 15, 386-395, Copyright © 1979 by the American Society for Pharmacology and Experimental Therapeutics

Effects of Acute and Chronic Barbiturate Administration on Synaptosomal Calcium Accumulation

¹ Department of Psychology, College of Pharmacy, the University of Texas at Austin, Austin, Texas 78712
² Department of Pharmacology, College of Pharmacy, the University of Texas at Austin, Austin, Texas 78712

Synaptosomes were isolated from four treatment groups of DBA/2J mice: Group I-Control; Group II-7 day tolerant (received dietary phenobarbital, 2.5 mg/g Purina Lab Chow for 7 days); Group III-20 hr withdrawn; and Group IV-7 day recovered (received dietary phenobarbital for 7 days followed by normal diet for 7 days). Pentobarbital (0.45 mM) added in vitro to synaptosomes from control mice significantly depressed (21.4%) potassium depolarized ⁴⁵Ca⁺⁺ accumulation but did not significantly alter nondepolarized ⁴⁵Ca⁺⁺ uptake or subsequent ⁴⁵Ca⁺⁺ efflux. Chronic administration of phenobarbital to mice in the tolerant and withdrawn conditions resulted in behavioral tolerance and subsequent withdrawal symptomatology, but neither KCl-induced ⁴⁵Ca⁺⁺ accumulation nor ⁴⁵Ca⁺⁺ efflux was significantly altered. In vitro addition of pentobarbital (0.45 mM) to synaptosomes from tolerant mice did not significantly depress KCl-induced ⁴⁵Ca⁺⁺ accumulation (8.1%) but did significantly depress KCl-induced ⁴⁵Ca⁺⁺ accumulation by synaptosomes from withdrawn mice (15.2%) and recovered mice (16.8%). These data suggest that barbiturates may depress calcium-mediated stimulus-secretion coupling events contributing to central nervous system depression. Further, functional tolerance after chronic barbiturate treatment may result from a membrane adaptation facilitating calcium-mediated secretory functions.