GABA-cannabinoid interplays in the dorsal hippocampus and basolateral amygdala mediate morphine-induced amnesia.

The aim of the current study was to investigate the involvement of GABA neurotransmission in the CA1 region and endocannabinoid system in the basolateral amygdala (BLA) on morphine-induced memory impairment. We hypothesized that possible functional interaction between the GABAergic and cannabinoid systems in these brain regions would modulate morphine response in memory processing. Step-through type inhibitory avoidance paradigm was used for evaluating memory consolidation in adult male Wistar rats. Our results indicated that post-training systemic injection of morphine (3 and 5 mg/kg, i.p.) impaired memory retrieval. The microinjection of a GABA-A receptor agonist, muscimol (0.01-0.03 µg/rat) into the CA1 region increased the response of an ineffective dose of morphine (0.5 mg/kg, i.p.) and induced memory impairment, suggesting a synergistic interaction between morphine and muscimol. Interestingly, the activation of the BLA CB1 receptors by the microinjection of WIN55,212-2 (0.05-0.1 µg/rat) increased the effect of ineffective doses of muscimol (0.01 µg/rat; intra-CA1) and morphine (0.5 mg/kg, i.p.), inducing amnesia. The obtained results also showed that microinjection of AM251, a cannabinoid CB1 receptor antagonist, (1-2 µg/rat) into the BLA reversed the synergistic effect of muscimol and morphine, improving memory consolidation. It should be noted that the intra-CA1 microinjection of muscimol, intra-BLA microinjection of WIN55,212-2 or AM251 alone could not affect memory consolidation. Accordingly, it can be concluded that there may be a synergistic interaction between the CA1 GABAergic system and the BLA endocannabinoid neurotransmission with respect to the modulation of morphine-induced memory impairment.

Evaluation of the pharmacological involvement of ATP-sensitive potassium (KATP) channels in the antidepressant-like effects of topiramate on mice.

Acute doses of topiramate (TPM) have been shown to reduce immobility time in the mice forced swimming test (FST) through inhibition of the nitric oxide (NO) pathway. Adenosine triphosphate-sensitive potassium (KATP) channels are known to have an active role in depression. This study investigates the potential participation of KATP channels in the antidepressant-like effect of TPM through the stimulatory effects of NO. FST and tail suspension tests (TST) were applied to adult male mice for assessment of the antidepressant-like activity of TPM. Different doses of glibenclamide and cromakalim were also applied in order to investigate the involvement of KATP channels. Fluoxetine was used as a positive control for evaluation of antidepressant-like effects. In addition, each animal's locomotor activity was evaluated by the open-field test (OFT). TPM (30 mg/kg intraperitoneal (i.p.)) had a significant reductive effect on the immobility behavior similar to fluoxetine (20 mg/kg). Co-administration of sub-effective doses of glibenclamide (1 mg/kg i.p.) and TPM (10 mg/kg i.p.) led to significant synergistic effects in FST and TST. Additionally, the results showed that administration of the sub-effective dose of cromakalim (0.1 and 0.3 mg/kg i.p.) blocked the antidepressant-like effects of TPM (30 mg/kg i.p.) in both tests. These interventions had no impact on the locomotor movement of mice in OFT. This study shows that the antidepressant-like activity of TPM may potentially be mediated by the blocking of the KATP channels.

The dorsal hippocampal group III metabotropic glutamate receptors are involved in morphine effect on memory formation in male mice.

This study investigated the role of dorsal hippocampal (CA1) group III metabotropic glutamate (mGlu) receptors in impairment of memory formation and state-dependent memory induced by morphine. For this purpose, the CA1 area was cannulated and one-trial passive avoidance task was selected to assess the memory function. Morphine was administrated subcutaneously (s.c.) and mGlu receptors agonist or antagonist were microinjected into CA1 regions. The obtained results indicated that pre-training administration of morphine (5 mg/kg; s.c.) decreased memory retention. Moreover, pre-test administration of morphine (5 mg/kg; s.c.) induced morphine state-dependent memory retention under pre-training morphine effect (5 mg/kg; s.c.). Although, intra-CA1 microinjection of lower doses of group III mGlu receptors agonist, L-AP4, (10 and 20 mmol/mouse) and antagonist, CPPG, (10 and 15 mmol/mouse) did not affect memory retention, but higher dose of the drugs (30 mmol/mouse) decreased memory retention. Pre-test microinjection of L-AP4 (10, 20 and 30 mmol/mouse; intra-CA1) had no effect on morphine-induced amnesia, but same doses of L-AP4 plus an effective dose of morphine (1 mg/kg; s.c.) reversed morphine-induced amnesia. Interestingly, amnesia induced by pre-training morphine (5 mg/kg; s.c.) was significantly reversed by pre-test administration of CPPG (30 mmol/mouse; intra-CA1). On the other hand, pre-test co-administration of CPPG (10 and 15 mmol/mouse; intra-CA1) and morphine (5 mg/kg; s.c.) following pre-training morphine (5 mg/kg; s.c.) decreased memory retention. Taken together, our results suggested that morphine effects on memory formation might be mediated via the activity of dorsal hippocampal metabotropic glutamate receptors.

Hippocampal nicotinic receptors have a modulatory role for ethanol and MDMA interaction in memory retrieval.

The aim of the current study was to examine the effect of dorsal hippocampal nicotinic acetylcholine receptors (nAChRs) activation on the functional interaction between ethanol and 3,4-methylenedioxy-N-methylamphetamine (MDMA or ecstasy) in memory retrieval. The dorsal hippocampal CA1 regions of adult male NMRI mice were bilaterally cannulated and memory retrieval was measured in a step-down type passive avoidance apparatus. Post-training or pre-test systemic administration of ethanol (1g/kg, i.p.) induced amnesia. Pre-test administration of ethanol reversed pre-training ethanol-induced amnesia, suggesting ethanol state-dependent learning. Pre-test intra-CA1 microinjection of different doses of MDMA (0.25-1µg/mouse) with an ineffective dose of ethanol (0.25g/kg, i.p.) also induced amnesia. Interestingly, pre-test intra-CA1 microinjection of MDMA (0.25-1µg/mouse) potentiated ethanol state-dependent learning. On the other hand, the activation of the dorsal hippocampal nAChRs by pre-test microinjection of nicotine (0.1-1µg/mouse, intra-CA1) improved amnesia induced by the co-administration of MDMD and ethanol. It is important to note that intra-CA1 microinjection of the same doses of MDMA or nicotine could not affect memory formation by itself. Pre-test intra-CA1 microinjection of nicotine (0.3-0.9µg/mouse) could not reverse amnesia induced by pre-training administration of ethanol while this treatment enhanced MDMA response on ethanol state-dependent learning. Thus, it can be concluded that there may be functional interactions among ethanol, MDMA and nicotine via the dorsal hippocampal nicotinic acetylcholine receptor mechanism in memory retrieval and drug state-dependent learning.

The major neurotransmitter systems in the basolateral amygdala and the ventral tegmental area mediate morphine-induced memory consolidation impairment.

In the present study, we investigated the possible participation of the endocannabinoid system in the basolateral amygdala and N-methyl-d-aspartate (NMDA) or GABA-A receptor neurotransmission in the ventral tegmental area in the memory consolidation impairment induced by morphine administration. To measure memory formation, step-through type passive avoidance apparatus was used with adult male Wistar rats. The results showed that intraperitoneal (i.p.) administration of morphine (3 and 6mg/kg) after the successful training phase had an amnestic effect and induced memory consolidation impairment. After training, injection of a selective cannabinoid CB1 receptor agonist, arachydonilcyclopropylamide (ACPA; 0.4-0.6ng/rat) plus systemic injection of an ineffective dose of morphine (0.5mg/kg, i.p.) into the basolateral amygdala impaired memory consolidation suggesting the facilitatory effect of ACPA on morphine response. Also, the results showed that the injection of bicuculline, a GABA-A receptor antagonist (0.3-0.5µg/rat) or NMDA (0.005-0.02µg/rat) into the ventral tegmental area reversed ACPA-induced potentiation of morphine response and improved memory consolidation. It should be considered that the injection of ACPA into the basolateral amygdala and the injection of bicuculline or NMDA into the ventral tegmental area alone could not affect memory consolidation. Taken together, it seems that there is a functional interaction between the basolateral amygdala endocannabinoid system and the ventral tegmental area GABAergic- or glutamatergic neurotransmission in the modulation of morphine-induced memory consolidation impairment.