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The present study was conducted to evaluate the influence of AMN082, the metabotropic glutamate receptor subtype 7 (mGlu 7 ) allosteric agonist on different stages of memory processes connected with fear conditioning in the passive avoidance (PA) learning task in mice and negative emotional state (anxiety-like) induced by ethanol- and morphine-withdrawal in the elevated plus maze (EPM) test in rats. To perform the PA test, AMN082 (1.25, 2.5 and 5 mg/kg, i. p.) was injected to interfere with (or inhibit) acquisition, consolidation, and retrieval processes. The retention latency in each group was recorded using a step-through passive avoidance task 24 h after training. In turn, in ethanol- and morphine-withdrawal rats, the influence of AMN082 on anxiety-like behavior was estimated in the EPM test 24 h- (ethanol) and 72- h (morphine) after the last dose of repeated drug administrations. In all experimental groups, AMN082 at the dose of 5 mg/kg significantly decreased the step-through latency of long-term memory in the PA task. These AMN082 effects were reversed by MMPIP (10 mg/kg), the antagonist of mGlu 7 receptor. AMN082 (2.5 and 5 mg/kg) also decreased ethanol- and morphine withdrawal-induced anxiety-like behavior in the EPM test, and this AMN082 (5 mg/kg) effect was counteracted by MMPIP pretreatment. Taken together, the results show that mGlu 7 is involved in fear learning to the context and anxiety-like state connected with unpleasant experiences after ethanol- and morphine withdrawal in rodents. However, it appears that functional dissociation exists between these two AMN082 effects., (Copyright © 2019 Elsevier B.V. All rights reserved.)

In the present study, the effects of adenosine agonists on the development of sensitization to withdrawal signs precipitated after sporadic treatment with diazepam, in mice, were investigated. To obtain the sensitization, the animals were divided into groups: continuously and sporadically treated with diazepam (15.0 mg/kg, s.c.). The adenosine receptor agonists (CPA, CGS 21,680 and NECA) were administered in sporadically diazepam treated mice during two diazepam-free periods. Concomitant administration of pentetrazole (55.0 mg/kg, s.c.) with flumazenil (5.0 mg/kg, i.p.) after the last injection of diazepam or vehicle, induced the withdrawal signs, such as clonic seizures, tonic convulsion and death episodes. The major finding of our experiments is attenuation of withdrawal signs in sensitized mice, inducing by all adenosine agonists. Only higher dose of CPA produced significantly decreased the number of withdrawal incidents, while both used doses of CGS 21,680 and NECA produced more clear effects. These results support the hypothesis that adenosinergic system is involved in the mechanisms of sensitization to the benzodiazepine withdrawal signs, and adenosine A(2A) receptors play more important role in that process.

The involvement of adenosine receptor agonists in benzodiazepine withdrawal signs was evaluated as the seizure susceptibility of mice. The concomitant administration of subthreshold dose of pentetrazole (55.0 or 60.0 mg/kg, s.c.) with flumazenil (10.0 mg/kg, i.p.) in mice chronically treated with temazepam or diazepam induced the appearance of withdrawal signs: clonic seizures, tonic convulsions and death episodes. The administration of the selective A1 (CPA-N6-cyclopentyladenosine), A2A (CGS 21680-2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride) and the non-selective A1/A2A (NECA-5'-N-ethylcarboxamidoadenosine) adenosine receptor agonists (i.p.) evoked the significant attenuation of benzodiazepine withdrawal signs, and these effects were more expressed in temazepam- than in diazepam-dependent mice. CPA has shown the most apparent and dose-dependent attenuating effect. The results confirm that adenosine A1 and A2A receptors are involved in benzodiazepine withdrawal signs, and adenosine A1 receptor plays a predominant role in this phenomenon.