Role of the central amygdala GABA-A receptors in morphine state-dependent memory.

AIMS: In the present experiments, the effects of bilateral microinjections of the GABA-A receptor agonist and/or antagonist into the central amygdala (CeA) on morphine state-dependent memory were examined. MAIN METHODS: In order to assess memory retrieval, a step-through passive avoidance task was used in adult male Wistar rats. KEY FINDINGS: Subcutaneous (s.c.) administration of morphine (5 and 7.5mg/kg) immediately after training (post-training) decreased the memory retrieval. Pre-test administration of the opioid (7.5mg/kg) also induced amnesia. The response induced by post-training morphine (7.5mg/kg) was significantly reversed by pre-test administration of the drug (5 and 7.5mg/kg), indicating morphine state-dependent memory. Pre-test intra-CeA microinjection of muscimol, a GABA-A receptor agonist (0.01, 0.02 and 0.03microg/rat) reduced morphine state-dependent memory. However, the same doses of muscimol by itself had no effect on memory retrieval. Furthermore, pre-test intra-CeA microinjection of bicuculline, a GABA-A receptor antagonist by itself did not alter memory retrieval. The antagonist also did not change post-training morphine (7.5mg/kg)-induced amnesia, but in combination with a lower dose of morphine (0.5mg/kg), improved memory performance. Moreover, muscimol's ability to interfere with morphine state-dependent memory was reversed by co-injection of bicuculline. SIGNIFICANCE: The results suggest that GABA-A receptor mechanism of the CeA may influence morphine state-dependent memory.

Inhibition of dorsal hippocampal nitric oxide synthesis potentiates ethanol-induced state-dependent memory in mice.

In an effort to understand the involvement of dorsal hippocampal nitric oxide system in ethanol (ETOH)-induced state-dependent memory, the effects of microinjection of l-arginine (a precursor of nitric oxide) and/or l-NAME (a nitric oxide synthase inhibitor) into the CA1 regions of dorsal hippocampus on this kind of memory were examined. In order to assess memory retrieval, a single trial step-down inhibitory avoidance task was used in mice. Pre-training intraperitoneal administration of ETOH (0.5 and 1g/kg) dose dependently caused amnesia, while pre-test administration of the same doses of ETOH restored the retrieval and induced state-dependent memory. Pre-test microinjection of l-arginine (0.5, 0.75 and 1 microg/mouse), into the CA1 region of dorsal hippocampus (intra-CA1) had no effect on memory retrieval. However, pre-test intra-CA1 microinjection of the same doses of l-arginine interestingly inhibited ETOH-induced state-dependent memory. The maximum response was obtained with 1 microg/mouse of l-arginine. Furthermore, memory impairment was produced following pre-test intra-CA1 microinjection of l-NAME (0.5, 0.75 and 1 microg/mouse). Pre-test co-administration of a higher dose of l-NAME (1 microg/mouse, intra-CA1) with an ineffective dose of ETOH (0.25 g/kg), improved the memory retrieval. Pre-test intra-CA1 microinjection of l-arginine or l-NAME could not affect ETOH-induced amnesia. In addition, l-arginine-induced inhibition of the pre-test ETOH response was decreased by pre-test microinjection of l-NAME. The ensemble of these observations suggests that ETOH-induced state-dependent memory can be modulated through the dorsal hippocampal nitric oxide system.

Modulation of ethanol state-dependent learning by dorsal hippocampal NMDA receptors in mice.

The possible role of N-methyl-D-aspartate (NMDA) receptors of dorsal hippocampus on ethanol state-dependent learning was studied in adult male mice (Pasteur Institute, Iran). As a model of memory, a single-trial step-down passive avoidance task was used. All animals were bilaterally implanted with cannulae into the CA1 regions of dorsal hippocampi. Results show that intraperitoneal (i.p.) administration of ethanol (0.5 and 1 g/kg) 30 min before training impaired memory performance in animals when tested 24h later. Pretest administration of the same doses of ethanol-induced state-dependent retrieval of the memory acquired under pretraining ethanol (1 g/kg, i.p.) influence. Pretest intra-CA1 microinjection of NMDA (0.001, 0.01, and 0.1 microg/mouse) by itself had no effect on memory retrieval and ethanol-induced amnesia. However, pretest intra-CA1 administration of the same doses of NMDA with an ineffective dose of ethanol (0.25 g/kg, i.p.) significantly restored the retrieval and potentiated ethanol state-dependent learning. On the other hand, pretest administration of a competitive NMDA receptor antagonist D-AP5 (D-(-)-2-Amino-5-phosphonopentanoic acid) (0.01, 0.1, and 1 microg/mouse, intra-CA1) or a noncompetitive NMDA receptor antagonist MK-801 maleate [(5S, 10R)-(+)-5-Methyl-10, 11-dihydro-5H-dibenzo [a, d] cyclohepten-5, 10-imine maleate] (0.25, 0.5, and 1 g/mouse, intra-CA1) 5 min before the administration of ethanol (1 g/kg, i.p.) significantly inhibited ethanol state-dependent learning. Intra-CA1 pretest administration of D-AP5 (0.01, 0.1, and 1 microg/mouse) or MK-801 maleate [5S, 10R)-(+)-5-Methyl-10, 11-dihydro-5H-dibenzo [a, d] cyclohepten-5, 10-imine maleate] (0.25, 0.5, and 1 microg/mouse) alone did not affect memory retention. It may be concluded that dorsal hippocampal NMDA receptors are involved in mediating ethanol state-dependent learning.

Ethanol state-dependent memory: involvement of dorsal hippocampal muscarinic and nicotinic receptors.

In the present study, the effects of bilateral injections of cholinergic agents into the hippocampal CA1 regions (intra-CA1) on ethanol state-dependent memory were examined in mice. A single-trial step-down passive avoidance task was used for the assessment of memory retention in adult male NMRI mice. Pre-training intraperitoneal injection (i.p.) of ethanol (0.25, 0.5 and 1g/kg) dose dependently induced impairment of memory retention. Pre-test administration of ethanol (0.5 and 1 g/kg, i.p.) induced state-dependent retrieval of the memory acquired under pre-training ethanol (1 g/kg, i.p.) influence. Pre-test intra-CA1 injection of physostigmine (2.5 and 5 microg/mouse, intra-CA1) or nicotine (0.3 and 0.5 microg/mouse, intra-CA1) improved pre-training ethanol (1g/kg)-induced retrieval impairment. Moreover, pre-test administration of physostigmine (2.5 and 5 microg/mouse, intra-CA1) or nicotine (0.3 and 0.5 microg/mouse, intra-CA1) with an ineffective dose of ethanol (0.25 g/kg) significantly restored the retrieval and induced ethanol state-dependent memory. Pre-test intra-CA1 injection of the muscarinic receptor antagonist, atropine (4 and 8 microg/mouse, intra-CA1) or the nicotinic receptor antagonist, mecamylamine (2 and 4 microg/mouse, intra-CA1) 5 min before the administration of ethanol (1g/kg, i.p.) dose dependently inhibited ethanol state-dependent memory. Pre-test intra-CA1 administration of physostigmine (0.5, 2.5 and 5 microg/mouse), atropine (2, 4 and 8 microg/mouse), nicotine (0.1, 0.3 and 0.5 microg/mouse) or mecamylamine (1, 2 and 4 microg/mouse) alone cannot affect memory retention. These findings implicate the involvement of a dorsal hippocampal cholinergic mechanism in ethanol state-dependent memory and also it can be concluded that there may be a cross-state dependency between ethanol and acetylcholine.

GABA(A) receptors of hippocampal CA1 regions are involved in the acquisition and expression of morphine-induced place preference.

In the present study, the effects of bilateral intra-hippocampal CA1 (intra-CA1) injections of GABA(A) receptor agonist and/or antagonist on the acquisition and expression of morphine-induced place preference in male Wistar rats have been investigated. The conditioning treatments with subcutaneous (s.c.) injections of different doses of morphine (0.5-7.5 mg/kg) induced a conditioned place preference (CPP) for the drug-associated place in a dose-dependent manner. Intra-CA1 administration of the GABA(A) receptor agonist, muscimol (0.25, 0.5 and 1 microg/rat) significantly inhibited the morphine (5 mg/kg, s.c.)-induced CPP. Intra-CA1 injections of different doses of the GABA(A) receptor antagonist, bicuculline (0.25, 0.5 and 1 microg/rat), in combination with an ineffective dose of morphine (0.5 mg/kg, s.c.) elicited a significant CPP. However, muscimol or bicuculline by themselves did not elicit any effect on place conditioning. Furthermore, the muscimol-induced inhibition of morphine response was reversed by bicuculline (1 microg/rat, intra-CA1) administration. On the other hand, the bilateral intra-CA1 injections of muscimol (0.25, 0.5 and 1 microg/rat) or bicuculline (0.5, 1 and 2 microg/rat) significantly decreased the expression of morphine-induced CPP. Intra-CA1 administration of different doses of muscimol or bicuculline had no effect on locomotor activity in the testing phase. Our data indicated that the GABA(A) receptors of the hippocampal CA1 regions may play an important role in the acquisition and expression of morphine-induced place preference.

Dorsal hippocampal dopamine receptors are involved in mediating ethanol state-dependent memory.

In the present study, the effects of bilateral injections of dopaminergic agents into the hippocampal CA1 regions (intra-CA1) on ethanol (EtOH) state-dependent memory were examined in mice. A single-trial step-down passive avoidance task was used for the assessment of memory retention in adult male NMRI mice. Pre-training intra-peritoneal (i.p.) administration of EtOH (0.25, 0.5 and 1 g/kg) dose dependently induced impairment of memory retention. Pre-test administration of EtOH (0.5 g/kg)-induced state-dependent retrieval of the memory acquired under pre-training EtOH (0.5 g/kg) influence. Intra-CA1 administration of the dopamine D(1) receptor agonist, SKF 38393 (0.5, 1 and 2 g/mouse) or the dopamine D(2) receptor agonist, quinpirole (0.25, 0.5 and 1 microg/mouse) alone cannot affect memory retention. While, pre-test intra-CA1 injection of SKF 38393 (2 microg/mouse, intra-CA1) or quinpirole (0.25, 0.5 and 1 microg/mouse, intra-CA1) improved pre-training EtOH (0.5 g/kg)-induced retrieval impairment. Moreover, pre-test administration of SKF 38393 (0.5, 1 and 2 microg/mouse, intra-CA1) or quinpirole (0.5 and 1 microg/mouse, intra-CA1) with an ineffective dose of EtOH (0.25 g/kg) significantly restored the retrieval and induced EtOH state-dependent memory. Furthermore, pre-training injection of the dopamine D(1) receptor antagonist, SCH 23390 (4 microg/mouse), but not the dopamine D(2) receptor antagonist, sulpiride, into the CA1 regions suppressed the learning of a single-trial passive avoidance task. Pre-test intra-CA1 injection of SCH 23390 (2 and 4 microg/mouse, intra-CA1) or sulpiride (2.5 and 5 microg/mouse, intra-CA1) 5 min before the administration of EtOH (0.5 g/kg, i.p.) dose dependently inhibited EtOH state-dependent memory. These findings implicate the involvement of a dorsal hippocampal dopaminergic mechanism in EtOH state-dependent memory and also it can be concluded that there may be a cross-state dependency between EtOH and dopamine.

Influence of nitric oxide on morphine-induced amnesia and interactions with dopaminergic receptor agents.

The interactions of dopaminergic receptors and nitric oxide (NO) with morphine-induced memory of passive avoidance have been investigated in mice. Pre-training administration of morphine (1, 3 and 5 mg/kg, s.c.) dose-dependently decreased the learning of a one-trial passive avoidance task. Pre-training administration of L-arginine, a nitric oxide precursor (50, 100 and 200 mg/kg, i.p.), alone did not affect memory formation. The drug (100 and 200 mg/kg) decreased significantly amnesia induced by pre-training morphine (5 mg/kg). Pre-training administration of L-NAME (N(G)-nitro-L-arginine methyl ester), a nitric oxide synthase (NOS) inhibitor (20 and 30 mg/kg, i.p.), dose-dependently impaired memory formation. In addition, co-pretreatment of different doses of L-NAME (10, 20 and 30 mg/kg) with lower dose of morphine (1 mg/kg), which did not induce amnesia by itself, caused inhibition of memory formation. Pre-training administration of apomorphine, a dopaminergic receptor agonist (0.25, 0.5 and 1 mg/kg, i.p.), alone also did not affect memory formation, but morphine-induced amnesia was significantly inhibited by pretreatment with apomorphine (0.5 and 1 mg/kg, 5 min, i.p.). On the other hand, the inhibition of morphine-induced amnesia by L-arginine (200 mg/kg, i.p.) was significantly decreased by pretreatment with different doses of dopamine D1 receptor antagonist, SCH 23390 (0.001, 0.01 and 0.1 mg/kg, i.p.) or D2 receptor antagonist, sulpiride (12.5, 25, 50 and 100 mg/kg, i.p.). However, the dopamine receptor antagonists could not affect memory formation by themselves. It may be concluded that the morphine-induced impairment of memory formation can be prevented by nitric oxide donor and, in this effect, dopaminergic mechanism is involved.