Morphine State-dependent Memory Research Articles

MiR-33-5p Regulates CREB to Induce Morphine State-dependent Memory in Rats: Interaction with the µ Opioid Receptor.

The aim of the present study was to examine the hypothesis that miR-33-5p attenuates morphine state-dependent (StD) memory via the µ opioid receptor by regulating cyclic AMP response element-binding protein (CREB). The effects of post-training morphine and morphine StD memory and their interaction with pre-test naloxone were evaluated using a single-trial inhibitory avoidance paradigm. Then, the hippocampal miR-33-5p gene and pCREB/CREB protein expression profiles were evaluated using quantitative real-time PCR and western blotting, respectively. We found that while post-training morphine and morphine StD memory respectively up- and down-regulate the miR-33-5p expression profile in the hippocampus, the reverse results are true for the expression of pCREB/CREB. Pre-test naloxone antagonized the response. Overall, our findings suggest that the expression levels of miR-33-5p in the hippocampus set the basis for morphine StD memory with low miR-33-5p enabling state dependency. The mechanism is mediated via miR33-5p and CREB signaling with the interaction of the µ opioid receptor. This finding may be used as a potential strategy for ameliorating morphine-induced memory-related disorders.

Cross state-dependent memory retrieval between morphine and norharmane in the mouse dorsal hippocampus

State-dependent memory (SDM) describes a phenomenon that memory is efficiently restored only when the brain state during restoration matches the state during encoding. Some psychoactive drugs such as morphine, ethanol, and cocaine evoke SDM. The scope of this study was to investigate the cross SDM between morphine and norharmane injected into the dorsal hippocampus of male NMRI mice, and the involvement of μ-opioid receptors (MORs) in the SDM of the drugs. Bilateral cannulae were implanted into the CA1 regions (intra-CA1), and memory retrieval was measured by the step-down apparatus. Results showed that pre-test microinjection of morphine (1 μg/mouse, intra-CA1) reversed amnesia induced by pre-training administration of the same dose of morphine, indicating morphine SDM. Moreover, norharmane (10 μg/mouse) also exerted a SDM. Pre-test microinjection of naloxone (0.5 μg/mouse) abolished amnesia induced by morphine or norharmane, and impaired SDM produced by each drug. The results demonstrated the contribution of MORs in the SDM induced by morphine as well as norharmane. Pre-test administration of morphine (1 μg/mouse, intra-CA1) also inhibited amnesia induced by pre-training intra-CA1 microinjection of norharmane (10 μg/mouse) and vice versa, suggesting a cross SDM between the drugs. In conclusion, it seems that there may be a cross SDM between morphine and norharmane, and MORs have a critical role in this phenomenon.

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.

Blockade of dorsal hippocampal orexin-1 receptors impaired morphine-induced state-dependent learning

Behavioral abnormalities associated with opiate addiction include memory and learning deficits, which are the result of some alterations in the neuromodulatory systems. Recently, orexin has shown to influence drug addiction neural circuitry, specifically in mediating reward-related perception and memory. To explore the possible interaction of orexinergic and opioidergic system on modulation of learning and memory, we have investigated the effects of intra-dorsal hippocampal (intra-CA1) administration of orexin-1 receptor agonist and the competitive orexin-1 antagonist, SB-334867, on morphine-induced memory impairment by using step-down passive avoidance task in mice. Pre-training injection of morphine (5mg/kg, i.p.) impaired memory, which was restored when 24h later the same dose of the drug was administered. Pre-test administration of orexin-1 (0.5, 5 and 50pmol, intra-CA1) had not a significant effect on the retention latency compared to the saline-treated animals, but it restored the memory impairment induced by pre-training morphine (5mg/kg, i.p.). Pre-test administration of SB-334867 (10, 20 and 40nmol, intra-CA1) by itself decreased the retention latencies of passive avoidance task. Co-administration of orexin-1 (0.5, 5 and 50pmol, intra-CA1) and morphine (1mg/kg, i.p.) on the test day induced morphine state-dependent memory. Conversely, pre-test injection of SB-334867 (10, 20 and 40nmol, intra-CA1) inhibited the orexin-1-induced potentiation of morphine state-dependent learning on the test day. It is concluded that dorsal hippocampal orexin-1 receptors may be involved, at least in part, in morphine state-dependent learning in mice.

Вeta1-Adrenoreceptors of the CA1 Area Mediate Morphine-Modified State-Dependent Memory in Rats

In our study, we investigated the effects of intra-CA1 microinjections of a selective β1-adrenoreceptor antagonist, betaxolol, on state-dependent memory induced by morphine. A step-through passive avoidance task was used to assess memory retrieval. Male Wistar rats were bilaterally implanted with chronic cannulas in the CA1 regions of the dorsal hippocampus by stereotaxic surgery seven days before training. Each animal was tested 24 h after training to measure the step-through latency and the time spent in a dark chamber of the apparatus. Post-training intra-CA1 administrations of different doses of morphine (5 and 7.5 mg/kg, s.c.) decreased memory retrieval in the retention test (morphine-induced amnesia). The effect of post-training injections of 7.5 mg/kg morphine on retrieval was reversed by pre-test injection of the same dose of morphine. This phenomenon is named morphine state-dependent memory. The results also showed that pre-test intra-CA1 microinjection of ineffective low doses of betaxolol (0.125 and 0.25 mg/rat) inhibited morphine-induced state-dependent memory retrieval. Taken together, our results suggest that the CA1 may be potentially critical for morphine state-dependent memory, and the β1-adrenergic receptor mechanism(s) interact with the opioidergic system in the modulation of this type of memory in the CA1.

Nitric oxide in the nucleus accumbens is involved in retrieval of inhibitory avoidance memory by nicotine

In the present study, the possible effect of nitric oxide agents injected into the nucleus accumbens (NAc) in the presence or absence of nicotine on morphine state-dependent memory in adult male Wistar rats was investigated. As a model of memory, a step-through type inhibitory avoidance task was used. Post-training injection of morphine (4 and 6mg/kg) dose dependently induced the impairment of memory retention. Administration of morphine (4 and 6mg/kg) before retention induced state-dependent retrieval of the memory acquired under post-training morphine (6mg/kg) influence. Injection of nicotine before retention (0.25 and 0.5mg/kg) alone and nicotine (0.1, 0.25 and 0.5mg/kg) plus an ineffective dose of morphine (2mg/kg) reversed the post-training morphine-induced memory impairment. The amnesia elicited by morphine (6mg/kg) was also prevented by pre-retention intra-NAc administration of a nitric oxide synthase (NOS) inhibitor, l-NAME (0.24μg/rat, intra-NAc). Interestingly, an ineffective dose of nicotine (0.1mg/kg) in combination with low doses of l-NAME (0.06 and 0.12μg/rat, intra-NAc) synergistically improved memory performance impaired by morphine given after training. It is important to note that intra-NAc administration of l-NAME before retention impaired memory retrieval by itself. In contrast, pre-retention administration of l-arginine, a nitric oxide (NO) precursor (0.25 and 0.5μg/rat, intra-NAc), which had no effect alone, prevented the nicotine reversal of morphine effect on memory. The results suggest a possible role for nitric oxide of nucleus accumbens in the improving effect of nicotine on the morphine-induced amnesia and morphine state-dependent memory.

Nitric oxide in the ventral tegmental area is involved in retrieval of inhibitory avoidance memory by nicotine

In the present study, the possible involvement of nitric oxide systems in the ventral tegmental area (VTA) in nicotine's effect on morphine-induced amnesia and morphine state-dependent memory in adult male Wistar rats was investigated. Step-through type inhibitory avoidance task was used to test memory retrieval. Post-training administration of morphine (5 and 7.5 mg/kg) induced amnesia. The response induced by post-training morphine was significantly reversed by pre-test administration of the drug. Pre-test injection of nicotine (0.4 and 0.8 mg/kg s.c.) alone and nicotine (0.1, 0.4 and 0.8 mg/kg s.c.) plus an ineffective dose of morphine also significantly reversed the amnesia induced by morphine. Morphine amnesia was also prevented by pre-test administration of l-arginine (1 and 3 μg/rat, intra-VTA), a nitric oxide (NO) precursor. Interestingly, an ineffective dose of nicotine (0.1 mg/kg s.c.) in combination with low dose of l-arginine (0.3 μg/rat, intra-VTA) synergistically improved memory performance impaired by morphine given after training. In contrast, pre-test administration of NG nitro-l-arginine methyl ester hydrochloride (l-NAME), a nitric oxide synthase (NOS) inhibitor (2 μg/rat, intra-VTA) prevented the nicotine reversal of morphine effect on memory. The results suggest a possible role for nitric oxide of ventral tegmental area in the improving effect of nicotine on the morphine-induced amnesia.

Involvement of central amygdala NMDA receptor mechanism in morphine state-dependent memory retrieval

In the current study, the effects of intra-central amygdala (CeA) administration of N-methyl- d-aspartate (NMDA) and its competitive antagonist, d-2-amino-5-phosphonopentanoic acid (D-AP5), on morphine state-dependent memory retrieval were investigated. Post-training subcutaneous (s.c.) administration of different doses of morphine (0.5, 2.5, 5 and 7.5 mg/kg) dose-dependently impaired memory. The response induced by post-training morphine (7.5 mg/kg) was reversed by pre-test administration of this drug (5 and 7.5 mg/kg), indicating morphine state-dependent memory retrieval. Pre-test intra-CeA administration of NMDA (0.01 and 0.05 μg/rat) plus an ineffective dose of morphine (0.5 mg/kg, s.c.) restored memory impairment caused by post-training morphine (7.5 mg/kg). However, pre-test intra-CeA administration of NMDA (0.005–0.05 μg/rat), alone, was ineffective on post-training morphine-induced amnesia. Furthermore, pre-test intra-CeA administration of the same doses of NMDA had no effect on memory retrieval. Pre-test intra-CeA administration of D-AP5 (0.1–1.0 μg/rat) decreased morphine state-dependent memory retrieval. However, pre-test administration of D-AP5 (0.1–1 μg/rat) alone decreased memory retrieval, but restored post-training morphine-induced amnesia. In conclusion, our results suggest which CeA may be potentially critical for morphine state-dependent memory retrieval and that CeA NMDA receptor mechanism(s) interact with the opiodergic system in the modulation of morphine state-dependent memory retrieval.

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 7.5 mg/kg) immediately after training (post-training) decreased the memory retrieval. Pre-test administration of the opioid (7.5 mg/kg) also induced amnesia. The response induced by post-training morphine (7.5 mg/kg) was significantly reversed by pre-test administration of the drug (5 and 7.5 mg/kg), indicating morphine state-dependent memory. Pre-test intra-CeA microinjection of muscimol, a GABA-A receptor agonist (0.01, 0.02 and 0.03 µg/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 (7.5 mg/kg)-induced amnesia, but in combination with a lower dose of morphine (0.5 mg/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.

Modulation of morphine state-dependent learning by muscarinic cholinergic receptors of the ventral tegmental area

In the present study, the effects of bilateral intra-ventral tegmental area (intra-VTA) injections of an anticholinesterase, physostigmine and/or muscarinic acetylcholine receptor antagonist, atropine on memory retention and morphine state-dependent learning were examined in adult male Wistar rats. As a model of learning, a step-through passive avoidance task was used. Post-training subcutaneous administration of morphine (0.5, 2.5 and 5 mg/kg) dose-dependently impaired memory retrieval on the test day. Pre-test administration of morphine (2.5 and 5 mg/kg) induced state-dependent retrieval of the memory acquired under post-training morphine influence. Pre-test intra-VTA microinjection of physostigmine (0.5, 1 and 2 μg/rat) or atropine (1, 2 and 3 μg/rat) alone cannot affect memory retention. Interestingly, pre-test intra-VTA administration of physostigmine (1 and 2 μg/rat) reversed post-training morphine (5 mg/kg, s.c.)-induced retrieval impairment. Furthermore, pre-test intra-VTA microinjection of physostigmine (1 and 2 μg/rat) with an ineffective dose of morphine (0.5 mg/kg), synergistically improved memory performance impaired by post-training morphine. On the other hand, pre-test intra-VTA microinjection of atropine (2 and 3 μg/rat) 5 min before the administration of morphine (5 mg/kg, s.c.) dose-dependently inhibited morphine state-dependent memory. Pre-test atropine microinjection also reversed the influence of physostigmine on morphine response. It may be concluded that the muscarinic acetylcholine receptors of the VTA play an important role in morphine-induced recovery of memory, on the test day.

Involvement of dorsal hippocampal nicotinic receptors in the effect of morphine on memory retrieval in passive avoidance task

The present study evaluated the possible role of nicotinic acetylcholine receptors of the dorsal hippocampus on morphine-induced amnesia and morphine state-dependent memory in adult male Wistar rats. The animals were bilaterally implanted with chronic cannulas in the CA1 regions of the dorsal hippocampi, trained in a step-through type passive avoidance task, and tested 24 h after training to measure step-through latency. Results indicate that post-training subcutaneous (s.c.) administration of morphine (2.5–7.5 mg/kg) dose-dependently reduced the step-through latency, showing an amnestic response. Post-training intra-CA1 microinjection of nicotine (0.5–1 μg/rat) decreased significantly the amnesia induced by post-training morphine (7.5 mg/kg). Moreover, co-treatment of mecamylamine (0.5 and 1 μg/rat, intra-CA1) with an ineffective dose of morphine (2.5 mg/kg), immediately after training, caused inhibition of memory retrieval. On the other hand, amnesia produced by post-training morphine (7.5 mg/kg) was reversed by pre-test administration of the opioid that is due to a state-dependent effect. Interestingly, pre-test intra-CA1 microinjection of nicotine (0.25 and 0.5 μg/rat) improved post-training morphine (7.5 mg/kg)-induced retrieval impairment. Moreover, pre-test administration of the same doses of nicotine in combination with a lower dose of morphine (0.5 mg/kg), which had no effects alone, synergistically improved memory performance impaired by post-training morphine. Pre-test injection of mecamylamine (0.5–2 μg/rat) prevented the restoration of memory by pre-test morphine. It is important to note that post-training or pre-test intra-CA1 administration of the same doses of nicotine or mecamylamine, alone did not affect memory retrieval. These results suggest that nicotinic acetylcholine receptors of the hippocampal CA1 regions may play an important role in morphine-induced amnesia and morphine state-dependent memory.

Effects of Clozapine and Sulpiride on Morphine State-Dependent Memory in the Step-Down Passive Avoidance Test

The effects of antipsychotic drugs sulpiride and clozapine on morphine state-dependent memory of passive avoidance task were examined in mice. Post-training administration of morphine (5 mg/kg) led to state-dependent learning with impaired memory retrieval on the test day which was reversed by pre-test administration of the same dose of the opioid (5 mg/kg). In animals where memory was impaired by post-training morphine, the administration of either sulpiride or clozapine before pre-test morphine reduced the improvement of memory produced by the opioid. Co-administration of sulpiride with clozapine did not potentiate their antagonistic response. In conclusion, the inhibition of improvement of memory retrieval by morphine treatment on the test day by the two dopamine receptor antagonists seems to be induced through two different receptor mechanisms.

Influence of intracerebroventricular administration of dopaminergic drugs on morphine state-dependent memory in the step-down passive avoidance test

The effects of dopaminergic drugs on morphine state-dependent memory of passive avoidance task were examined in mice. Pre-training administration of morphine (5 mg/kg) led to state-dependent learning with impaired memory retrieval on the test day which was reversed by pre-test administration of the same dose of the opiate. The pre-test intracerebroventricular (i.c.v.) administration of the dopamine D 1 receptor agonist (SKF38393), dopamine D2 receptor agonist (quinpirole) and dopamine D2 receptor antagonist (sulpiride) not only reversed the effect of pre-training morphine treatment, but also increased this action of the drug. Furthermore, the pre-test i.c.v. administration of dopamine D 1 receptor antagonist (SCH23390) prevented the restoration of memory by morphine. In conclusion, the morphine-induced recovery of memory, on the test day, seems to be induced, at least in part, through dopamine receptors.

Influence of cholinergic system modulators on morphine state-dependent memory of passive avoidance in mice

Memories are shown to be impaired in mice during step-down passive avoidance tasks with substantial residual effects lasting as long as 24 h after the pre-training administration of morphine. Administration of the same dose of morphine as a pre-test treatment restored memory. Since the cholinergic system has been reported to be involved in several actions of morphine, e.g.: modulation of memory and analgesia, we have investigated the part played by cholinergic modulator drugs, on the memory recall in mice. The locomotor activity of animals was studied as well. Administration of either atropine, a peripheral-central muscarinic antagonist, or mecamylamine, a peripheral-central nicotinic antagonist, failed to alter memory themselves, but significantly prevented morphine-induced memory recall following co-administration with morphine. Neither hexamethonium, a peripheral nicotinic antagonist, nor neostigmine, a peripheral anticholinesterase, showed intrinsic activity or a significant change in morphine-induced memory recall. Finally, physostigmine, a peripheral-central anticholinesterase, not only induced memory recall itself, but also increased morphine-induced retrieval. Memory recall of the step-down passive avoidance task following drug combinations was not related to locomotor activity changes. Thus, morphine-induced memory recall appears to be influenced by central cholinergic activity.

Influence of intracerebroventricular administration of cannabinergic drugs on morphine state-dependent memory in the step-down passive avoidance test

The effects of cannabinergic drugs on morphine state-dependent memory of passive avoidance task were examined in mice. Pre-training (0.25, 0.5 and 5 mg/kg) and post-training (5 mg/kg) administration of morphine impaired memory retrieval on the test day. Impairment of memory retrieval by morphine (5 mg/kg) on the test day was reversed by pre-test administration of the same dose of the opioid. The pre-test intracerebroventricular administration of the cannabinoid CB1/CB2 receptor agonist (WIN55,212-2) (0.75 and 1 microg/mouse) not only mimicked the effect of pre-test morphine treatment, but also increased this action of the opioid. Furthermore, the pre-test intracerebroventricular administration of CB1 receptor antagonist (AM251) (20 and 100 ng/mouse) prevented the restoration of memory by morphine. Pre-training administration of WIN55,212-2 (1 microg/mouse) led to state-dependent learning with impaired memory retrieval on the test day as well, which was reversed by pre-test administration of the drug (0.5, 0.75 and 1 microg/mouse) or morphine (1 and 5 mg/kg). Restoration of impairment induced by WIN55,212-2 was decreased by both the opioid receptor antagonists, naloxone (0.01 microg/mouse) and AM251 (20 and 100 ng/mouse). In conclusion, the improvement of memory retrieval by morphine treatment on the test day seems to be induced, at least in part, by the cannabinoid CB1 receptors.

Influence of cholinergic system modulators on morphine state-dependent memory of passive avoidance in mice

Memories are shown to be impaired in mice during step-down passive avoidance tasks with substantial residual effects lasting as long as 24 h after the pre-training administration of morphine. Administration of the same dose of morphine as a pre-test treatment restored memory. Since the cholinergic system has been reported to be involved in several actions of morphine, e.g.: modulation of memory and analgesia, we have investigated the part played by cholinergic modulator drugs, on the memory recall in mice. The locomotor activity of animals was studied as well. Administration of either atropine, a peripheral-central muscarinic antagonist, or mecamylamine, a peripheral-central nicotinic antagonist, failed to alter memory themselves, but significantly prevented morphine-induced memory recall following co-administration with morphine. Neither hexamethonium, a peripheral nicotinic antagonist, nor neostigmine, a peripheral anticholinesterase, showed intrinsic activity or a significant change in morphine-induced memory recall. Finally, physostigmine, a peripheral-central anticholinesterase, not only induced memory recall itself, but also increased morphine-induced retrieval. Memory recall of the step-down passive avoidance task following drug combinations was not related to locomotor activity changes. Thus, morphine-induced memory recall appears to be influenced by central cholinergic activity.

Effect of lithium on morphine state-dependent memory of passive avoidance in mice

In the present study, effects of lithium chloride (LiCl) on morphine induced state-dependent memory of passive avoidance task were examined in mice. One-trial step-down paradigm was used for the assessment of memory retention in adult male NMRI mice. Administration of morphine (5 mg/kg) subcutaneously (s.c.) 30 min before training or testing induced impairment of memory performance. Injection of the same dose of the drug 30 min before testing restored memory retention impaired under pre-training morphine effect. Intraperitoneal (i.p.) injection of lithium, 60 min before training or prior to testing also impaired memory performance. Under the pre-training of morphine, the response of the opioid was restored when animals received LiCl (80 and 160 mg/kg) as pre-test injection. Pre-training administration of lower dose of lithium (20 mg/kg), but not the higher doses of the drug (80 and 160 mg/kg) impaired memory retention in passive avoidance test. LiCl-induced impairment of memory retention was restored by pre-test administration of morphine. In the animals receiving pre-training morphine, combined pre-test morphine and LiCl administration increased the restoration of memory by the opioid. It can be concluded that there may be a cross-state dependency between morphine and lithium.

Effects of intracerebroventricular administration of ultra low doses of histaminergic drugs on morphine state-dependent memory of passive avoidance in mice

The effects of intracerebroventricular (i.c.v.) administration of ultra low doses (ULDs) of histamine, clobenpropit and pyrilamine are studied on morphine state-dependent (STD) memory in mice. Although pre-test administration of different doses of histamine and clobenpropit showed no effect on impairment of memory induced by pre-training morphine, when the above drugs were co-administered with morphine, they inhibited the restoration of memory by morphine. These effects were opposite to microgram doses of the same drugs.

Discrepancy between effects of milligram and nanogram doses of a COX-2 inhibitor (celecoxib) on morphine state-dependent memory of passive avoidance in mice

This experiment examined and compared the effects of pre-test administration of a selective COX-2 inhibitor (celecoxib), at the doses in the range of mg/kg and ng/kg on morphine state-dependent learning in step-down passive avoidance task in mice. Pre-training administration of 5 mg/kg of morphine-impaired memory retrieval tested 24 h later, which was restored by pre-test administration of the same dose of the drug. Pre-test administration of celecoxib (12.5, 25 and 50 mg/kg), alone or in combination with morphine (1 mg/kg) prevents morphine-induced memory impairment. Ultra-low doses (ULDs) of celecoxib (2, 10 and 50 ng/kg) produced no change in morphine-induced memory impairment. However, co-administration of nanogram doses of celecoxib with 5 mg/kg of morphine in the test day prevented morphine-induced memory improvement, an action different from mg/kg doses. These findings implicate the involvement of COX-2 in memory retrieval and demonstrate that the effect of celecoxib ULD is different from that of mg/kg doses.

The influence of NMDA receptor agonist and antagonist on morphine state-dependent memory of passive avoidance in mice

The measurement of step-down latency in passive avoidance has been used to study memory in laboratory animals. The pre-training injection of 5 mg/kg morphine impaired memory, which was restored when 24 h later the same dose of the drug was administered. To explore the possible involvement of NMDA modulators on morphine-induced memory impairment, we have investigated the effects of intracerebroventricular (i.c.v.) administration of NMDA and the competitive NMDA antagonist, dl-AP5, on morphine-induced memory impairment or recall, on the test day. Morphine (5 mg/kg, s.c.) was administered 30 min before training to induce impairment of memory and 24 h later, 30 min before test to improve it. Pre-test administration of NMDA (0.00001, 0.0001 and 0.001 μg/mouse, i.c.v.) did not alter the retention latency compared to the saline-treated animals. But restored the memory impairment induced by pre-training morphine (5 mg/kg, s.c.). Pre-test administration of dl-AP5 (1, 3.2 and 10 μg/mouse, i.c.v.) by itself decreased the retention latencies. The same doses of dl-AP5 increased pre-training morphine-induced memory impairment. Co-administration of NMDA (0.0001 and 0.001 μg/mouse, i.c.v.) and morphine (5 mg/kg, s.c.) on the test day increased morphine memory improvement. Conversely, dl-AP5 (1, 3.2 and 10 μg/mouse, i.c.v.) inhibited morphine-induced memory recall. It is concluded that NMDA receptors may be involved, at least in part, in morphine state-dependent learning in mice.