State-dependent Memory Retrieval Research Articles

State-dependent memory retrieval: insights from neural dynamics and behavioral perspectives.

Memory retrieval is strikingly susceptible to external states (environment) and internal states (mood states and alcohol), yet we know little about the underlying mechanisms. We examined how internally generated states influence successful memory retrieval using the functional magnetic resonance imaging (fMRI) of laboratory mice during memory retrieval. Mice exhibited a strong tendency to perform memory retrieval correctly only in the reinstated mammillary body-inhibited state, in which mice were trained to discriminate auditory stimuli in go/no-go tasks. fMRI revealed that distinct auditory cues engaged differential brain regions, which were primed by internal state. Specifically, a cue associated with a reward activated the lateral amygdala, while a cue signaling no reward predominantly activated the postsubiculum. Modifying these internal states significantly altered the neural activity balance between these regions. Optogenetic inhibition of those regions in the precue period blocked the retrieval of type-specific memories. Our findings suggest that memory retrieval is under the control of two interrelated neural circuits underlying the neural basis of state-dependent memory retrieval.

Cross state-dependent memory retrieval between tramadol and ethanol: involvement of dorsal hippocampal GABAA receptors.

Tramadol and ethanol, as psychoactive agents, are often abused. Discovering the molecular pathways of drug-induced memory creation may contribute to preventing drug addiction and relapse. The tramadol- and ethanol-induced state-dependent memory (SDM) and cross-SDM retrieval between tramadol and ethanol were examined in this study. Moreover, because of the confirmed involvement of GABAA receptors and GABAergic neurotransmission in memory retrieval impairment, we assessed cross-SDM retrieval between tramadol and ethanol with a specific emphasis on the role of the GABAA receptors. The first hypothesis of this study was the presence of cross-SDM between tramadol and ethanol, and the second hypothesis was related to possible role of GABAA receptors in memory retrieval impairment within the dorsal hippocampus. The cannulae were inserted into the hippocampal CA1 area of NMRI mice, and a step-down inhibitory avoidance test was used to evaluate state dependence and memory recovery. The post-training and/or pre-test administration of tramadol (2.5 and 5 mg/kg, i.p.) and/or ethanol (0.5 and 1 g/kg, i.p.) induced amnesia, which was restored after the administration of the drugs 24 h later during the pre-test period, proposing ethanol and tramadol SDM. The pre-test injection of ethanol (0.25 and 0.5 g/kg, i.p.) with tramadol at an ineffective dose (1.25 mg/kg) enhanced tramadol SDM. Moreover, tramadol injection (1.25 and 2.5 mg/kg) with ethanol at the ineffective dose (0.25 g/kg) promoted ethanol SDM. Furthermore, the pre-test intra-CA1 injection of bicuculline (0.0625, 0.125, and 0.25 μg/mouse), a GABAA receptor antagonist, 5 min before the injection of tramadol (5 mg/kg) or ethanol (1 g/kg) inhibited tramadol- and ethanol-induced SDM dose-dependently. The findings strongly confirmed cross-SDM between tramadol and ethanol and the critical role of dorsal hippocampal GABAA receptors in the cross-SDM between tramadol and ethanol.

Cross state-dependent memory retrieval between cannabinoid CB1 and serotonergic 5-HT1A receptor agonists in the mouse dorsal hippocampus

Understanding the neurobiological mechanisms of drug-related learning and memory formation may help the treatment of cognitive disorders. Dysfunction of the cannabinoid and serotonergic systems has been demonstrated in learning and memory disorders.The present paper investigates the phenomenon called state-dependent memory (SDM) induced by ACPA (a selective cannabinoid CB1 receptor agonist) and 8-OH-DPAT (a nonselective 5-HT1A receptor agonist) with special focus on the role of the 5-HT1A receptor in the effects of both ACPA and 8-OH-DPAT SDM and cross state-dependent memory retrieval between ACPA and 8-OH-DPAT in a step-down inhibitory avoidance task.The dorsal hippocampal CA1 regions of adult male NMRI mice were bilaterally cannulated, and all drugs were microinjected into the intended injection sites. A single-trial step-down inhibitory avoidance task was used to assess memory retrieval and state-dependence.Post-training and/or pre-test microinjections of ACPA (1 and 2 ng/mouse) and 8-OH-DPAT (0.5 and 1 μg/mouse) dose-dependently induced amnesia. Pre-test administration of the same doses of ACPA and 8-OH-DPAT reversed the post-training ACPA- and 8-OH-DPAT-induced amnesia, respectively. This phenomenon has been named SDM. 8-OH-DPAT (1 μg/mouse) reversed the amnesia induced by ACPA (0.5, 1, and 2 ng/mouse) and induced ACPA SDM. ACPA (2 ng/mouse) reversed the amnesia induced by 8-OH-DPAT (0.25, 0.5, and 1 μg/mouse) and induced 8-OH-DPAT SDM. Pre-test administration of a 5-HT1A receptor antagonist, (S)-WAY 100,135 (0.25 and 0.5 μg/mouse), 5 min before ACPA and 8-OH-DPAT dose-dependently inhibited ACPA- and 8-OH-DPAT-induced SDM, respectively.The present study results demonstrated ACPA- and 8-OH-DPAT- induced SDM. Overall, the data revealed that dorsal hippocampal 5-HT1A receptor mechanisms play a pivotal role in modulating cross state-dependent memory retrieval between ACPA and 8-OH-DPAT.

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.

Basolateral amygdala CB1 cannabinoid receptors are involved in cross state-dependent memory retrieval between morphine and ethanol

Ethanol and morphine are largely co-abused and affect memory formation. The present study intended to investigate the involvement of cannabinoid CB1 receptors of the basolateral amygdala (BLA) in cross state-dependent memory retrieval between morphine and ethanol. Adult male Wistar rats received bilateral cannulation of the BLA, and memory retrieval was measured in step-through type passive avoidance apparatus. Our results showed that post-training intraperitoneal (i.p.) administration of morphine (6mg/kg) induced amnesia. Pre-test administration of ethanol (0.5g/kg, i.p.) significantly improved morphine-induced memory impairment, suggesting that there is cross state-dependent memory retrieval between morphine and ethanol. It should be considered that pre-test administration of ethanol (0.1 and 0.5g/kg, i.p.) by itself had no effect on memory retrieval in the passive avoidance task. Interestingly, pre-test intra-BLA microinjection of different doses of WIN55,212-2 (0.1, 0.2 and 0.3μg/rat), a non-selective CB1/CB2 receptor agonist, plus an ineffective dose of ethanol (0.1g/kg, i.p.) improved morphine-induced memory impairment. Intra-BLA microinjection of AM251 (0.4–0.6ng/rat), a selective CB1 receptor antagonist, inhibited the improved effect of ethanol (0.5g/kg, i.p.) on morphine response. Pre-test intra-BLA microinjection of WIN55,212-2 or AM251 had no effect on memory retrieval or morphine-induced amnesia. Taken together, it can be concluded that morphine and ethanol can induce state-dependent memory retrieval. In addition, the BLA endocannabinoid system mediates via CB1 receptors the functional interaction of morphine and ethanol state-dependent memory retrieval which may depend on the rewarding effects of the drugs.

Alterations in the hippocampal phosphorylated CREB expression in drug state-dependent learning

The present study investigated the possible alterations of hippocampal CREB phosphorylation in drug state-dependent memory retrieval. One-trial step-down passive avoidance task was used to assess memory retrieval in adult male NMRI mice. Pre-training administration of ethanol (1g/kg, i.p.) induced amnesia. Pre-test administration of ethanol (1g/kg, i.p) or nicotine (0.7mg/kg, s.c.) reversed ethanol-induced amnesia, indicating ethanol- or ethanol–nicotine induced state-dependent learning (STD). Using Western blot analysis, it was found that the p-CREB/CREB ratio in the hippocampus increased in the mice that showed successful memory retrieval as compared with untrained mice. In contrast, pre-training administration of ethanol (1g/kg, i.p.) decreased the hippocampal p-CREB/CREB ratio in comparison with the control group. The hippocampal p-CREB/CREB ratio enhanced in ethanol- and ethanol–nicotine induced STD. Moreover, memory impairment induced by pre-training administration of WIN (1mg/kg, i.p.) improved in the animals that received pre-test administration of WIN (1mg/kg, i.p.), ethanol (0.5g/kg, i.p.) or nicotine (0.7mg/kg, s.c.), suggesting a cross STD between the drugs. The p-CREB/CREB ratio in the hippocampus decreased in the of WIN-induced amnesia and STD groups in comparison with the control group. In addition, cross state-dependent learning between WIN and ethanol or nicotine was associated with the increase of the hippocampal p-CREB/CREB ratio. It can be concluded that phosphorylation of CREB in the hippocampus is a critical event underlying the interaction of co-administration of drugs on memory retrieval in passive avoidance learning.

5-HT1A receptor blockade targeting the basolateral amygdala improved stress-induced impairment of memory consolidation and retrieval in rats

The aim of the present study was to investigate the possible role of basolateral amygdala (BLA) 5-HT1A receptors in memory formation under stress. We also examined whether the blockade of these receptors is involved in stress-induced state-dependent memory. Adult male Wistar rats received cannula implants that bilaterally targeted the BLA. Long-term memory was examined using the step-through type of passive avoidance task. Behavioral stress was evoked by exposure to an elevated platform (EP) for 10, 20 and 30min. Post-training exposure to acute stress (30min) impaired the memory consolidation. In addition, pre-test exposure to acute stress-(20 and 30min) induced the impairment of memory retrieval. Interestingly, the memory impairment induced by post-training exposure to stress was restored in the animals that received 20- or 30-min pre-test stress exposure, suggesting stress-induced state-dependent memory retrieval. Post-training BLA-targeted injection of a selective 5-HT1A receptor antagonist, (S)-WAY-100135 (2μg/rat), prevented the impairing effect of stress on memory consolidation. Pre-test injection of the same doses of (S)-WAY-100135 that was targeted to the BLA also reversed stress-induced memory retrieval impairment. It should be considered that post-training or pre-test BLA-targeted injection of (S)-WAY-100135 (0.5–2μg/rat) by itself had no effect on the memory formation. Moreover, pre-test injection of (S)-WAY-100135 (2μg/rat) that targeted the BLA inhibited the stress-induced state-dependent memory retrieval. Taken together, our findings suggest that post-training or pre-test exposure to acute stress induced the impairment of memory consolidation, retrieval and state-dependent learning. The BLA 5-HT1A receptors have a critical role in learning and memory under stress.

Central amygdala nicotinic and 5-HT1A receptors mediate the reversal effect of nicotine and MDMA on morphine-induced amnesia

The present study was designed to investigate possible involvement of the central amygdala (CeA) nicotinic acetylcholine (nACh) and 5-hydroxytryptamine 1A (5-HT1A) receptors in the reversal effect of nicotine and 3,4-methylenedioxy-N-methylamphetamine (MDMA or ecstasy) on morphine-induced amnesia. Two guide cannulas were stereotaxically implanted in the CeA regions and a step-through passive avoidance task was used for the assessment of memory retrieval in adult male Wistar rats. Our results indicated that post-training s.c. administration of morphine (3–7-mg/kg) impaired memory retrieval. Pre-test administration of nicotine (0.3- and 0.5-mg/kg, s.c.) reversed morphine-induced amnesia. In addition, pre-test intra-CeA injection of MDMA (1–2-μg/rat) with an ineffective dose of nicotine (0.1-mg/kg, s.c.) improved memory retrieval, suggesting the interactive effect of the drugs on memory formation. It should be noted that that pre-test intra-CeA injection of 2-μg/rat of MDMA by itself produced amnesia. Interestingly, pre-test intra-CeA injection of mecamylamine, a nACh receptor antagonist (1–2-μg/rat) or (S)-WAY 100135 (0.25–1-μg/rat), a selective 5-HT1A receptor antagonist inhibited the improvement of morphine-induced amnesia which was produced by pre-test co-injection of nicotine and MDMA. Pre-test intra-CeA injection of the same doses of MDMA, mecamylamine or (S)-WAY 100135 by itself had no effect on morphine-induced amnesia. Moreover, pre-test injection of the same doses of mecamylamine or (S)-WAY 100135 into the CeA alone could not change memory retrieval. Taken together, it can be concluded that there is a functional interaction between morphine, nicotine and MDMA via the CeA nicotinic and serotonergic receptor mechanisms in passive avoidance memory retrieval. Moreover, cross state-dependent memory retrieval may have been induced between the drugs and this probably depends on the rewarding effects of the drugs.

Involvement of dorsal hippocampal and medial septal nicotinic receptors in cross state-dependent memory between WIN55, 212-2 and nicotine or ethanol in mice

The present study examined whether nicotinic acetylcholine receptors (nAChRs) of the CA1 regions of the dorsal hippocampus and medial septum (MS) are involved in cross state-dependent memory retrieval between WIN55, 212-2 (WIN, a non-selective CB1/CB2 receptor agonist) and nicotine or ethanol. Memory retrieval was measured in one-trial step-down type passive avoidance apparatus in male adult mice. Pre-training intraperitoneal administration of WIN (0.1–1mg/kg) dose-dependently impaired memory retrieval when it was tested 24h later. Pre-test systemic administration of nicotine (0.6 and 0.7mg/kg, s.c.) or ethanol (0.5g/kg, i.p.) improved WIN-induced memory impairment, suggesting a cross state-dependent memory retrieval between the drugs. Pre-test intra-CA1 microinjection of nicotine (1 and 2μg/mouse) before systemic administration of an ineffective dose of nicotine (0.5mg/kg, s.c.) or ethanol (0.25g/kg) significantly reversed WIN-induced memory impairment. Pre-test intra-CA1 microinjection of mecamylamine (1 and 3μg/mouse) inhibited cross state-dependent memory between WIN and nicotine or ethanol. Moreover, pre-test intra-MS microinjection of nicotine (1 and 2μg/mouse) in combination with systemic administration of a lower dose of nicotine (0.5mg/kg), but not ethanol (0.25g/kg), improved memory impairment induced by pre-training administration of WIN. On the other hand, in the animals that received pre-training WIN and pre-test systemic administration of nicotine (0.7mg/kg), but not ethanol (0.5g/kg), pre-test intra-MS microinjection of mecamylamine (1–5μg/mouse) inhibited WIN-nicotine state-dependent memory retrieval. It should be noted that pre-test intra-CA1 or intra-MS microinjection of nicotine or mecamylamine by itself had no effect on memory retrieval and also could not reverse memory impairment induced by pre-training administration of WIN. It can be concluded that WIN and nicotine or WIN and ethanol can induce state-dependent memory retrieval. In addition, our results showed that a cross-state dependency between these drugs may be mediated through a cholinergic nicotinic mechanism.

Dopamine D1 receptors are not critical for opiate reward but can mediate opiate memory retrieval in a state-dependent manner

Although D1 receptor knockout mice demonstrate normal morphine place preferences, antagonism of basolateral amygdala (BLA) D1 receptors only during drug-naive rat conditioning has been reported to inhibit the expression of a morphine place preference. One possible explanation for this result is state-dependent learning. That is, the omission of the intra-BLA infusion cue during testing — which acts as a potent discriminative stimulus — may have prevented the recall of a morphine–environment association and therefore, the consequent expression of a morphine place preference. To examine this possibility, we tested whether intra-BLA infusion of the D1-receptor antagonist SCH23390 during both training and testing might reveal a morphine place preference. Our results suggest that in previously drug-naive animals, D1 receptor antagonism during testing restores the opiate conditioned place preference that is normally absent when D1 receptors are blocked only during training, suggesting that BLA D1 receptors can mediate state-dependent memory retrieval.

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.

Effect of naloxone and morphine on arcaine-induced state-dependent memory in rats

Arcaine is a competitive antagonist of the polyamine binding site at the N-methyl-D-aspartic acid receptor which induces state-dependent recall. However, no study has addressed the involvement of other neurotransmitter/neuromodulators in arcaine-induced state dependency. The current study investigates whether the opioid system is involved in arcaine-induced state-dependent memory retrieval of the inhibitory avoidance task (IA) in rats. The systemic administration of arcaine (30 mg/kg, intraperitoneally (i.p.)) or morphine (5 mg/kg, i.p.) 0, 3, 6, or 9 h post-training, reduced step-down latencies at testing. Arcaine (30 mg/kg, i.p.) or morphine (5 mg/kg, i.p.) injection 30 min before testing reversed the performance deficit induced by administration of arcaine or morphine 0, 3 or 6, but not 9 h post-training. The reversal of arcaine-induced impairment of IA performance was completely transferred to morphine and vice versa. The association of low and ineffective doses of morphine and arcaine (10 and 1.5 mg/kg, respectively) were additive and caused state dependency. Naloxone (2 mg/kg, 3 min post-training, or 1 mg/kg, 1 h pre-test, i.p.) reversed the amnesia and the state dependency induced by morphine and arcaine. These results suggest that state dependency induced by arcaine involves the opioid system.

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.

L-histidine provokes a state-dependent memory retrieval deficit in mice re-exposed to the elevated plus-maze

The effects of L-histidine (LH) on anxiety and memory retrieval were investigated in adult male Swiss Albino mice (weight 30-35 g) using the elevated plus-maze. The test was performed on two consecutive days: trial 1 (T1) and trial 2 (T2). In T1, mice received an intraperitoneal injection of saline (SAL) or LH before the test and were then injected again and retested 24 h later. LH had no effect on anxiety at the dose of 200 mg/kg since there was no difference between the SAL-SAL and LH-LH groups at T1 regarding open-arm entries (OAE) and open-arm time (OAT) (mean ± SEM; OAE: 4.0 ± 0.71, 4.80 ± 1.05; OAT: 40.55 ± 9.90, 51.55 ± 12.10, respectively; P > 0.05, Kruskal-Wallis test), or at the dose of 500 mg/kg (OAE: 5.27 ± 0.73, 4.87 ± 0.66; OAT: 63.93 ± 11.72, 63.58 ± 10.22; P > 0.05, Fisher LSD test). At T2, LH-LH animals did not reduce open-arm activity (OAE and OAT) at the dose of 200 mg/kg (T1: 4.87 ± 0.66, T2: 5.47 ± 1.05; T1: 63.58 ± 10.22; T2: 49.01 ± 8.43 for OAE and OAT, respectively; P > 0.05, Wilcoxon test) or at the dose of 500 mg/kg (T1: 4.80 ± 1.60, T2: 4.70 ± 1.04; T1: 51.55 ± 12.10, T2: 43.88 ± 10.64 for OAE and OAT, respectively; P > 0.05, Fisher LSD test), showing an inability to evoke memory 24 h later. These data suggest that LH does not act on anxiety but does induce a state-dependent memory retrieval deficit in mice.

L-histidine provokes a state-dependent memory retrieval deficit in mice re-exposed to the elevated plus-maze

The effects of L-histidine (LH) on anxiety and memory retrieval were investigated in adult male Swiss Albino mice (weight 30-35 g) using the elevated plus-maze. The test was performed on two consecutive days: trial 1 (T1) and trial 2 (T2). In T1, mice received an intraperitoneal injection of saline (SAL) or LH before the test and were then injected again and retested 24 h later. LH had no effect on anxiety at the dose of 200 mg/kg since there was no difference between the SAL-SAL and LH-LH groups at T1 regarding open-arm entries (OAE) and open-arm time (OAT) (mean +/- SEM; OAE: 4.0 +/- 0.71, 4.80 +/- 1.05; OAT: 40.55 +/- 9.90, 51.55 +/- 12.10, respectively; P > 0.05, Kruskal-Wallis test), or at the dose of 500 mg/kg (OAE: 5.27 +/- 0.73, 4.87 +/- 0.66; OAT: 63.93 +/- 11.72, 63.58 +/- 10.22; P > 0.05, Fisher LSD test). At T2, LH-LH animals did not reduce open-arm activity (OAE and OAT) at the dose of 200 mg/kg (T1: 4.87 +/- 0.66, T2: 5.47 +/- 1.05; T1: 63.58 +/- 10.22; T2: 49.01 +/- 8.43 for OAE and OAT, respectively; P > 0.05, Wilcoxon test) or at the dose of 500 mg/kg (T1: 4.80 +/- 1.60, T2: 4.70 +/- 1.04; T1: 51.55 +/- 12.10, T2: 43.88 +/- 10.64 for OAE and OAT, respectively; P > 0.05, Fisher LSD test), showing an inability to evoke memory 24 h later. These data suggest that LH does not act on anxiety but does induce a state-dependent memory retrieval deficit in mice.

The amygdala modulates morphine-induced state-dependent memory retrieval via muscarinic acetylcholine receptors

The current study was conducted to examine the involvement of muscarinic acetylcholine receptors of the amygdala in morphine-induced state-dependent memory retrieval. Male Wistar rats implanted bilaterally with cannulas in the amygdala were submitted to a step-through type passive avoidance task, and tested 24 h after training to measure step-through latency. Post-training s.c. administration of morphine at the doses of 5 and 7.5 mg/kg impaired the memory on the test day, which was restored when the same doses of morphine were used as a pre-test drug. This phenomenon is well known as morphine-induced state-dependent memory retrieval. Bilateral microinjection of the non-selective muscarinic acetylcholine receptor agonist, pilocarpine (0.25 and 0.5 μg/side), into the amygdala with an ineffective dose of morphine (0.5 mg/kg s.c.) significantly improved the memory retrieval and mimicked the effects of pre-test administration of a higher dose of morphine. It should be noted that in the animals that received saline after training and tested following intra-amygdala administration of pilocarpine (0.125, 0.25 and 0.5 μg/side) and those which received post-training morphine (7.5 mg/kg s.c.) and pre-test intra-amygdala microinjection of the same doses of pilocarpine, no significant change was observed in the step-through latencies. On the other hand, pre-test intra-amygdala microinjection of a selective muscarinic acetylcholine receptor antagonist scopolamine (0.125 and 0.25 μg/side) inhibited morphine-induced state-dependent memory retrieval. In addition, no significant changes were seen in memory retrieval of the animals trained before saline treatment and tested following intra-amygdala microinjection of the same doses of scopolamine (0.0625, 0.125 and 0.25 μg/side). Bilateral microinjection of scopolamine into the amygdala reversed the pilocarpine-induced potentiation of the morphine response. In view of the known actions of the drugs used, the present data point to the involvement of amygdala muscarinic acetylcholine receptors in morphine-induced state-dependent memory retrieval.

State dependent and/or direct memory retrieval by morphine in mice

Mice were trained in step-down and step-through type passive avoidance learning tasks and given retention tests. Pre-training administration of morphine impaired retention, the effect recovering completely after an additional injection of the same dose of morphine given 30 min before the retention test. Amnesia produced by scopolamine, cycloheximide and electroconvulsive shock was also reversed by pre-test morphine. Pre-test saline also reversed the morphine-induced memory impairment to some extent, indicating that the recovery may partially be due to the state dependent effect. Thus, it is demonstrated that pre-test morphine not only state dependently but also directly reversed memory impairment in mice.

Alcohol-induced state-dependent learning: Differentiating stimulus and storage hypotheses

State-dependent effects of alcohol have been demonstrated in animals and man. Most studies have used tasks for which accurate performance typically requires that stimulus input was adequately stored initially and that the items were retrieved at the time of testing. Thus an alcohol-induced decrement in performance could be due to impaired storage, impaired retrieval, or both. The purpose of this experiment was to distinguish between stimulus and storage hypotheses of state-dependent learning (SDL). Sixteen subjects were used in a 2×2 design in which the task involved the learning and recall of a 19-item ‘route’ map. During initial learning, all subjects were sober. Immediately after learning, half the subjects were given a moderate dose of alcohol. Twenty-four hours later, all subjects were tested for recall under the same or different conditions. Greater retention was found for those subjects whose drug states were the same in memory storage/consolidation and retrieval. Thus an alcohol state effective during the memory consolidation interval following acquisition appears to be a sufficient condition for producing SDL. In this context, SDL might be better termed state-dependent memory storage and retrieval. The implications of these results for the aetiology and treatment of alcohol dependence are discussed.