Lack of feedback inhibition on rat basolateral amygdala following stress or withdrawal from sedative-hypnotic drugs.

Previous research has demonstrated that suppression of inhibition in projection neurons of the basolateral complex of the amygdala (BLA) represents an essential mechanism underlying the emergence of negative emotional responses, including exaggerated fear and anxiety. The present work evaluates inhibitory postsynaptic potentials (IPSPs) in pyramidal projection neurons of the BLA in rats subjected to either diazepam or ethanol withdrawal or uncontrollable stress. These are experimental paradigms conducive to a negative emotional state. In slices containing the BLA, IPSPs were studied using whole-cell patch clamp. In control animals, a small IPSP was evoked by sub-threshold stimulation of the external capsule. When an action potential (AP) was evoked by supra-threshold stimuli, IPSPs were considerably larger; these IPSPs were sensitive to blockade of GABA(A) receptors by picrotoxin. However, IPSPs were clearly reduced in diazepam- or ethanol-withdrawn and in stressed rats. Firing of an AP by a depolarizing pulse applied through the patch pipette consistently evoked an inhibitory postsynaptic current (IPSC) in the pyramidal neurons of control animals from all three experimental models; these IPSCs were mediated by GABA(A) receptor activation and were blocked after suppression of glutamatergic transmission. In contrast, no IPSCs were observed in slices from diazepam- or ethanol-withdrawn or stressed animals, although the depolarizing pulse regularly evoked an AP in pyramidal neurons. It is concluded that, in withdrawn or stressed rats, GABAergic disinhibition occurs due to attenuation or suppression of feedback inhibition.

Antidepressants attenuate both the enhanced ethanol intake and ethanol-induced anxiolytic effects in diazepam withdrawn rats.

We have recently shown that the abrupt discontinuation of chronic diazepam (DZM) administration facilitated ethanol consumption and enhanced the anxiolytic properties of ethanol. Tricyclic antidepressants such as desipramine and the selective serotonin reuptake inhibitor fluoxetine have been shown to reduce alcohol intake in rodent models of alcoholism and in alcoholics who are depressed. In the present study, we tested whether desipramine (1.25; 2.5 and 5 mg/kg, i.p.) and fluoxetine (5 mg/kg, i.p.) treatment affect both ethanol intake in a free-choice test and the anxiolytic effect induced by ethanol in DZM withdrawn rats. Adult male Wistar rats were submitted to a chronic DZM treatment (2 mg/kg per day) or vehicle (VEH) for 21 days. Twenty-four hours after the last DZM injection, rats were subjected to a free-choice paradigm between water and increasing ethanol concentrations with or without concurrent desipramine or fluoxetine administration (ethanol concentration (v/v) was increased every 4 days as follows: 2, 4, 6, 8 and 10% for the final 8 days). Chronic treatment with desipramine (24 days, twice a day, 2.5 and 5 mg/kg, i.p.) and fluoxetine (24 days, once a day; 5 mg/kg, i.p.) significantly reduced the amount of ethanol intake in DZM withdrawn rats. Furthermore, subchronic treatments with desipramine (4 days, twice a day, 2.5 and 5 mg/kg) and fluoxetine (4 days, once a day, 5 mg/kg, i.p.) blocked the anxiolytic-like behavior in the elevated plus maze induced by ethanol (1 g/kg; i.p.) in DZM withdrawn rats at day 5 of withdrawal. The present findings suggest that desipramine and fluoxetine could be effective pharmacological tools to prevent the subsequent development of ethanol dependence in rats previously exposed to DZM withdrawal.