Involvement of NMDA receptor complex in the anxiolytic-like effects of chlordiazepoxide in mice

In the present study, we demonstrated that low, ineffective doses of N-methyl-d-aspartic acid (NMDA) receptor antagonists [competitive NMDA antagonist, CGP 37849, at 0.312 mg/kg intraperitoneally (i.p.), antagonist of the glycineB sites, L-701,324, at 2 mg/kg i.p., partial agonist of glycineB sites, d-cycloserine, at 2.5 mg/kg i.p.] administered jointly with an ineffective dose of the benzodiazepine, chlordiazepoxide (CDP, 2.5 mg/kg i.p.), significantly increased the percentage of time spent in the open arms of the elevated plus-maze (index of anxiolytic effect). Furthermore, CDP-induced anxiolytic-like activity (5 mg/kg i.p.) was antagonized by NMDA (75 mg/kg i.p.) and by an agonist of glycineB sites of the NMDA receptor complex, d-serine [100 nmol/mouse intracerebroventricularly (i.c.v.)]. The present study showed a positive interaction between γ-aminobutyric acid (GABA) and glutamate neurotransmission in the anxiolytic-like activity in the elevated plus-maze test in mice and this activity seems to particularly involve the NMDA receptors

A complex interaction between glycine/NMDA receptors and serotonergic/noradrenergic antidepressants in the forced swim test in mice

Both clinical and preclinical studies demonstrate the antidepressant activity of the functional NMDA receptor antagonists. In this study, we assessed the effects of two glycine/NMDA receptor ligands, namely L-701,324 (antagonist) and d-cycloserine (a partial agonist) on the action of antidepressant drugs with different pharmacological profiles in the forced swim test in mice. Swim sessions were conducted by placing mice individually in glass cylinders filled with warmed water for 6 min. The duration of behavioral immobility during the last 4 min of the test was evaluated. The locomotor activity of mice was measured with photoresistor actimeters. L-701,324 and d-cycloserine given with reboxetine (administered in subeffective doses) did not change the behavior of animals in the forced swim test. A potentiating effect was seen when both tested glycine site ligands were given concomitantly with imipramine or fluoxetine in this test. The lesion of noradrenaline nerve terminals produced by DSP-4 neither altered the baseline activity nor influenced the antidepressant-like action of L-701,324 or d-cycloserine. The depletion of serotonin by p-CPA did not alter baseline activity in the forced swim test. However, it completely antagonized the antidepressant-like action produced by L-701,324 and d-cycloserine. Moreover, the antidepressant-like effects of imipramine, fluoxetine and reboxetine were abolished by d-serine, a full agonist of glycine/NMDA receptors. The present study demonstrates that glycine/NMDA receptor functional antagonists enhance the antidepressant-like action of serotonin, but not noradrenaline-based antidepressants and such their activity seems to depend on serotonin rather than noradrenaline pathway

Adrenal Activity during Repeated Long-Access Cocaine Self-Administration is Required for Later CRF-Induced and CRF-Dependent Stressor-Induced Reinstatement in Rats

Understanding the neurobiological processes that contribute to the establishment and expression of stress-induced regulation of cocaine use in addicted individuals is important for the development of new and better treatment approaches. It has been previously shown that rats self-administering cocaine under long-access conditions (6 h daily) display heightened susceptibility to the reinstatement of extinguished cocaine seeking by a stressor, electric footshock, or i.c.v. administration of the stressor-responsive neuropeptide, corticotropin-releasing factor (CRF). This study tested the hypothesis that adrenal responsiveness during earlier long-access cocaine self-administration (SA) is necessary for the establishment of later CRF-dependent stress-induced reinstatement. Reinstatement by footshock, but not a cocaine challenge (10 mg/kg, i.p.) following long-access SA, was blocked by i.c.v. administration of the CRF receptor antagonist, α-helical CRF9−41 (10 μg). Elimination of SA-induced adrenal responses through surgical adrenalectomy and diurnal corticosterone replacement (ADX/C) before 14 days of SA under long-access conditions had minimal impact on cocaine SA, but blocked later footshock-induced reinstatement. By contrast, ADX/C after SA, but before extinction and reinstatement testing, failed to reduce footshock-induced reinstatement. Likewise, ADX/C before 14 days long-access SA prevented later reinstatement by i.c.v. CRF (0.5 or 1.0 μg). However, significant CRF-induced reinstatement was observed when rats underwent ADX/C following SA, but before extinction and reinstatement testing, although a modest but statistically nonsignificant reduction in sensitivity to CRF's reinstating effects was observed. Taken together, these findings suggest that adrenal-dependent neuroadaptations in CRF responsiveness underlie the increased susceptibility to stress-induced relapse that emerges with repeated cocaine use