Enhancement of acetylcholine release by flumazenil in the hippocampus of rats chronically treated with diazepam but not with imidazenil or abecarnil

Abstract

The effects of long-term treatment (three times a day for 3 weeks) with pharmacologically active doses of the novel anxiolytics and anticovulsants abecarnil (0.5 mg/kg, IP) and imidazenil (0.5 mg/kg, IP) on basal hippocampal acetylcholine release in freely moving rats were compared with those of diazepam (3 mg/kg, IP). Challenge doses of diazepam, abecarnil, and imidazenil decreased the extracellular acetyl-choline concentration in the hippocampus by the same extent in animals chronically treated with the respective drug or vehicle. Moreover, the abrupt discontinuation of long-term treatment with diazepam, abecarnil, or imidazenil failed to affect hippocampal acetylcholine release during the first 5 days of withdrawal. In contrast, the acute administration of the benzodiazepine receptor antagonist flumazenil (1 mg/kg, IP) 2 days after diazepam withdrawal elicited a marked increase (65%) in acetylcholine release in the hippocampus. Flumazenil failed to induce the same effect 5 days after diazepam withdrawal or 2 or 5 days after discontinuation of long-term treatment with abecarnil or imidazenil. These results indicate that (i) the inhibitory effects of full (diazepam), partial (imidazenil), and selective (abecarnil) benzodiazepine receptor agonists on acetylcholine output in rat hippocampus are not affected by repeated drug administration; (ii) discontinuation of long-term treatment with each type of agonist does not affect hippocampal cholinergic mechanisms; and (iii) flumazenil increases acetylcholine release only in the hippocampus of rats chronically treated with diazepam. Together, these data further differentiate the pharmacology of benzodiazepine receptor full agonists from that of partial and selective agonists.

Altered behavioral responses to gamma‐aminobutyric acid pharmacological agents in a mouse model of Huntington's disease

“…Of note, previous studies have reported that high dosages of diazepam (2‐10 mg/kg, i.p.) decrease acetylcholine release in rodent brains . Because the level of acetylcholine is positively correlated with spontaneous locomotor activity, we cannot rule out the possibility that impairment of diazepam‐induced reduction of acetylcholine release might contribute to the inferior response of HD mice to diazepam.…”

“…decrease acetylcholine release in rodent brains. [35][36][37] Because the level of acetylcholine is positively correlated with spontaneous locomotor activity, 38,39 we cannot rule out the possibility that impairment of diazepam-induced reduction of acetylcholine release might contribute to the inferior response of HD mice to diazepam. Importantly, a GABA antagonist elevated the spontaneous locomotor activity and reversed the diazepam-evoked inhibitory effect on locomotor activity in WT mice, but not in HD mice, suggesting that the effect of diazepam on locomotor activity was mediated by GABA A R and that the function of GABA A R was altered in HD mice.…”

Fluoxetine Disrupts the Integration of Anxiety and Aversive Memories

“…Our data raise the possibility that all anxiolytics may ultimately exert their clinical effects through a common mechanism, which is a reduction in anxiety-evoked increases in cholinergic neurotransmission possibly through M1 muscarinic receptors in the hippocampus. Other studies have demonstrated that systemic injections of benzodiazepines reduce hippocampal ACh efflux (Dazzi et al, 1995b). On the other hand, anxiogenic compounds like flumazenil increase hippocampal ACh levels (Imperato et al, 1994).…”

Valium without dependence? Individual GABA_A receptor subtype contribution toward benzodiazepine addiction, tolerance, and therapeutic effects

“…Most interestingly, this acetylcholine release was not seen in the partial agonists imidazenil and abecarnil, which has no efficacy at the α 1 subtype. 79 The fact that benzodiazepine withdrawal is marked by an acetylcholine increase in the nucleus accumbens, which is also seen in other drug withdrawals, further begs clarification of the benzodiazepine–acetylcholine affiliation, and possibly of subunit-specific involvement, which has been overlooked. 78 , 79 …”