Chronic Diazepam Administration Failed to Induce Tolerance and Withdrawal Syndrome in Perinatally Undernourished Female Rats as Measured in the Open Field Drink Test

Abstract

Adult female rats, receiving a low protein diet at perinatal age and then recovered with balanced chow (D rats), were evaluated in the Open Field Drink Test (OFDT), after different acute and chronic treatments with benzodiazepines (BZD) ligands, as compared with control (C) female rats. Control and D rats showed similar reactivity to acute administration of diazepam (DZP, 1 mg/kg) and FG 7142 (2.5mg/kg), both BZD ligands with anxiolytic and anxiogenic effects, respectively. After chronic DZP treatment (3mg/kg/day i.p. for 3 weeks), C rats developed tolerance to the anxiolytic effect of DZP as well as withdrawal syndrome upon abrupt interruption of chronic treatment. On the contrary, D animals failed to develop tolerance to the anxiolytic effect of DZP, and did not show an increased anxiety upon withdrawal. The functionality of the GABAA receptor-complex, as measured by 36Cl- uptake in cortical cerebral microsacs, was not altered in the DZP withdrawn rats. The lack of tolerance and withdrawal syndrome may be related to the incapacity of D rats to generate adaptive changes after chronic treatments. For instance, C rats showed a lower anxiety level in the OFDT after chronic vehicle administration, whereas D animals did not evidence such an adaptive response. Furthermore, D rats failed to respond to the anxiolytic effect of DZP after chronic vehicle treatment. These results reassert the deleterious effects of perinatal undernutrition on the capacity to develop adaptive responses to repeated drug administration or adequate stimuli.