Lack of tolerance to the anxiolytic effect of diazepam and pentobarbital following chronic administration in perinatally undernourished rats

• Published in: Brain research bulletin 1998-06, Vol.46 (3), p.237-244
• Main Authors: Borghese, Cecilia M, Córdoba, Nancy E, Laino, Carlos H, Orsingher, Otto A, Rubio, Modesto C, Niselman, Viviana
• Format: Article
• Language: English
• Subjects: Animal Nutritional Physiological Phenomena; Animals; Animals, Newborn - physiology; Anti-Anxiety Agents - administration & dosage; Anti-Anxiety Agents - pharmacokinetics; Anti-Anxiety Agents - pharmacology; Biological and medical sciences; Brain - metabolism; Chloride uptake; Chlorides - pharmacokinetics; Diazepam - administration & dosage; Diazepam - pharmacokinetics; Diazepam - pharmacology; Drug Synergism; Drug Tolerance - physiology; Early malnutrition; Elevated plus-maze; Female; GABA A function; gamma-Aminobutyric Acid - pharmacology; Maze Learning - drug effects; Medical sciences; Neuropharmacology; Nutrition Disorders - physiopathology; Pentobarbital - administration & dosage; Pentobarbital - pharmacokinetics; Pentobarbital - pharmacology; Pharmacology. Drug treatments; Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Rats; Rats, Wistar; Time Factors
• ISSN: 0361-9230; 1873-2747
• DOI: 10.1016/S0361-9230(98)00010-0

Adult female rats, undernourished at perinatal age, were evaluated for anxiolytic action in the plus-maze test after acute and chronic administration of diazepam (DZP) and pentobarbital (PTB). Deprived (D) rats chronically treated with vehicle showed an increased anxiety as compared with control (C) animals. A single intraperitoneal (i.p.) administration of DZP (1 mg/kg) or PTB (7.5 mg/kg) produced similar anticonflict effect in both C and D rats. Tolerance to the anxiolytic effect of DZP and PBT developed in C rats after a 15-day administration schedule, whereas no tolerance was observed in D animals. Drug disposition was not altered after chronic treatment either in C or in D rats. γ-aminobutyric acid (GABA)-mediated chloride uptake in microsacs of cerebral cortex of naive D rats was decreased as compared with naive C rats. After chronic DZP administration (1 mg/kg/day i.p. for 15 days), GABA-mediated 36Cl − influx in brain cortex microsacs of C rats did not change; however, GABA efficacy was increased in microsacs of D animals. In addition, chronic DZP treatment induced GABA-benzodiazepine uncoupling in brain cortex of C rats, but not in D animals, as assessed by chloride uptake in microsacs. Chronic PTB treatment (7.5 or 30 mg/kg/day i.p. for 15 days) did not modify GABA stimulation or GABA-PTB interaction in cortical microsacs of C or D rats.