Involvement of the Amygdala in the State-Dependent Memory

One of the neural messenger molecules in the CNS is nitric oxide. This molecule produces from L-arginine via the enzyme nitric oxide synthase afterward the stimulation of NMDA receptor. L-arginine-nitric oxide pathway is started through activation of the NMDA receptor in the CNS [159]. Some documents indicated that nitric oxide has modulatory effects on diverse models of learning such as motor learning [160], avoidance learning [161], and spatial learning [162]. Moreover, studies showed that the synthesis of nitric oxide in the dorsal hippocampus is important in the acquisition of inhibitory avoidance learning in the step-down test [163]. There are also report showing that the nitric oxide system of dorsal hippocampal CA1 regions is involved in state-dependent memory [21]. Nitric oxide is well known for its capability to modulate the release of neurotransmitters e.g. glutamate, acetylcholine, dopamine and GABA [164], thus affecting synaptic plasticity and LTP [165]. Thereby, it is likely that the interaction between nitric oxide and various neurotransmitters systems result in state-dependent memory induced by nitric oxide.

A number of studies have also exhibited that the hippocampal nitric oxide system interacted with other mechanisms for modulation of state-dependent memory. Some investigations displayed that nitric oxide and cannabinoid systems may be involved in hippocampal-dependent learning and memory. It has been shown that post-training intra-CA1 administration of CB1 and CB2 receptor agonists, WIN55, 212-2, decreased memory retrieval which restored by pre-test administration of the drug, indicating the WIN55, 212-2 state-dependent memory. In addition, impairment of retrieval-induced by post-training administration of WIN55, 212-2 restored by pre-test intra-CA1 administration of L-arginine whereas pre-test intra-CA1 injection of L-NAME could not affect amnesia produced by WIN55, 212-2. It is likely that WIN55-212-2-state-dependent memory enhances synthesis/release of nitric oxide which can be counteracted via nitric oxide synthase inhibitor substrate [11].

Furthermore, the interaction between the hippocampal nitric oxide and GABAergic systems has been shown in some behavioral studies. Moreover, there is documentation that the release of GABA in the hippocampus, striatum, and basal forebrain is modulated through nitric oxide. As well, there are reports showing that in the hippocampal pyramidal neurons, nitric oxide synthase is linked with the post-synaptic active zone of diverse GABAergic synapses and the release of GABA is biphasically (both excitatory and inhibitory) dependent on the nitric oxide concentration [166]. It has been also reported that the hippocampal nitric oxide mechanism plays a key role in muscimol state-dependent memory. It has been indicated that intra-hippocampal injection of L-arginine prevents memory recall, and intra-hippocampal injection of L-NAME enhance memory recall when co-administered with muscimol, it is possible that muscimol-induced memory recall is related to the activation of the hippocampal nitrergic system. It seems that there is an association between decrease in the nitric oxide release and the physiological state under which muscimol improves memory retrieval [28].

3.1.8. Involvement of the hippocampal GABAergic system in the state-dependent memory

γ-amino butyric acid (GABA) is the important inhibitory neurotransmitter in the CNS  which affect learning and memory processes [152848]. The hippocampus has numerous GABAergic interneurons [96], and these interneurons project from the septum [103]. The ionotropic GABAA and GABAC receptors (both activate Cl currents) and the metabotropic GABAB receptor (G protein-coupled receptor) elicit the effects of GABA [167168]. These receptors are present in the hippocampus and involved in learning and memory processes through involvement in information processing of the hippocampus [103]. It is well documented that intra-hippocampal administrations of GABAA receptor agonists decrease memory whereas their antagonists increase retrieval in different tasks [122169]. Some investigation indicated that the hippocampal GABAA receptors also participate in state-dependent memory [15]. It is thought that GABAA agonists e.g. muscimol produce drug state by acting on chloride ion channels [170]. In the past few years, there has been increasing evidence that muscimol, GABAA agonist, induce state-dependent memory [2848104158].

Also, some documentation shows the involvement of GABAergic system of the hippocampus in the modulation of drug state-dependent memory. Parsaei and coworkers (2011) indicated that pre-test injection of bicuculline into the hippocampus increase the effect of pre-test lithium on the reversal of memory, which support the involvement of hippocampal GABA receptors in the effects of lithium on state-dependent learning [15]. Additionally, researchers also suggest that there is an interaction between the GABAergic and opioidergic systems of the hippocampus in learning and memory [48]. It has been reported that GABAergic and opioidergic mechanisms are interconnected via µ-opioid receptors. µ-opioid receptors are present almost exclusively on inhibitory interneurons (principally GABAergic) in the hippocampus. Stimulation of µ-opioid receptors has been displayed to hyperpolarize interneurons and presynaptically inhibit the release of GABA in the hippocampus [171]. So, µ-opioid receptors stimulation can facilitate excitatory inputs in the CA1 dendritic layers through inhibiting synaptic activation of GABA receptors. It seems that the dorsal hippocampal µ-opioid receptors involved in muscimol state-dependent memory by inhibition of GABA release [48].

There are reports indicating that opioidergic [48], muscarinic cholinergic [104], α2-adrenergic [158], and nitric oxide [28] systems in the CA1 area of the dorsal hippocampus are important for inducing muscimol-related state-dependent memory (fig. 5). Some evidence showed that α2-adrenoceptors stimulation enhances the basal release of GABA in the hippocampus, cerebral cortex, and striatum [172]. Jafari-Sabet and coworkers (2013) revealed that α2-adrenoceptor agonists and antagonists may modulate memory retrieval by increasing or reducing basal GABA release respectively. Also, they reported that the α2-adrenoceptors of dorsal hippocampal area play an important role in muscimol state-dependent memory [158]. Studies revealed that there is an interaction between GABAergic and nitric oxide systems in the experimental animals, regarding memory consolidation [44]. Jafari-Sabet et al. (2014) indicated that there is an association between decrease in nitric oxide release in the CA1 and the physiological state under which muscimol facilitates memory retrieval. Thus nitric oxide system in the dorsal hippocampus is involved in the muscimol state-dependent retrieval [28]. On the other hand, Zarrindast et al. (2011) reported that the GABAA receptors in the dorsal hippocampus are involved in state-dependent learning induced by lithium in mice. They indicated that state-dependent learning induced by lithium potentiate and disrupt due to pre-test injection of bicuculline and muscimol into the CA1, respectively [15].

3.2. Involvement of the amygdala in the state-dependent memory

The amygdaloid complex is a prominent limbic formation which generally comprises of four nuclear groups [173]. The central nucleus of the amygdala (CeA) is the key output of this complex which is exceedingly involved in emotional learning, reward-related learning and memory retrieval [17174-176]. In addition, the CeA involve in state-dependent memory, as it plays a key role in state-dependent memory induced by opioid [19], cannabinoid [153], GABAA [18], glutamate [17], acetylcholine [19], and β1-noradrenergic mechanisms [153].

3.2.1. Involvement of the amygdala opioidergic system in the state-dependent memory

Based on membrane properties, the CeA neurons can be mostly classified into three types which have differential physiological and pharmacological effects. Type A neurons showed no spike accommodation but type B neurons exhibited characteristic accommodating response. Type A neurons were classified as either A1 or A2, based on alterations in resting membrane potential and the amplitude of after-hyperpolarizing potential. Zhu and Pan (2004) reported that µ-opioid receptor agonists hyperpolarized a subpopulation of CeA cells, of which the great majority was type A1. This µ-opioid receptor agonist-induced hyperpolarization was mediated through the opening of inwardly rectifying potassium channels. In addition, immunocytochemical studies have indicated that opioid receptors particularly µ-opioid receptors are present in the dendrites of CeA. It has been reported that the opioidergic system of CeA involves in neural signaling, memory, reward behaviors and plasticity related to addictive behaviors [177]. There are also evidences that the CeA opioidergic mechanism plays a role in state-dependent learning [17-19]. Zarrindast and Rezayof  (2004) revealed that morphine state-dependent learning is associated with the reward effects of morphine [9], and the CeA play a key role in the acquisition and expression of morphine reward [174178].

3.2.2. Involvement of the amygdala cannabinoid system in the state-dependent memory

In the CeA, cannabinoids CB1 receptors located on the GABAergic intercalated cells and glutamatergic neurons which may inhibit both glutamate and GABA release [179]. Behavioral studies showed that post-training intra-CeA injections of WIN55,212-2 induced inhibitory avoidance memory impairment which pre-test intra-CeA injections of the same dose of WIN55,212-2 reversed the impairment of inhibitory avoidance memory retrieval that was indicative of drug-related state-dependent memory [105153]. Consolidation and retrieval of inhibitory avoidance memory have been revealed to need intact glutamate receptors [180]. Probably, a state-dependent memory which produced via intra-CeA injection of WIN55,212-2 may result from inhibition of glutamate release in the CeA [179]. State-dependent memory which produced via WIN55,212-2 also seems to be dependent on rewarding properties of the cannabinoids. In support of the later proposition, it has also been indicated that WIN55,212-2 increases neuronal firing of dopaminergic neurons in the forebrain reward loci [181].

3.2.3. Involvement of the amygdala GABAergic system in the state-dependent memory

Investigations demonstrated that the CeA neurons and their efferent projections are mainly GABAergic. The CeA neurons receive GABA afferents from the intercalated neurons, although contributions from the CeA GABAergic neurons directly stimulated through the high-intensity activation cannot be ruled out. Previously, the influence of CeA GABAergic mechanism on learning and memory retention had been reported. So intra-amygdala injection of GABAergic receptor agonists decreases memory, whereas their antagonists increase memory storage and retrieval in inhibitory avoidance tasks [182]. In addition, Zhu and Pan (2004) indicated that the CeA involved in reward-related learning through the GABAergic system [177]. Some investigation indicated that the GABAA receptors of the CeA also participate in state-dependent memory in passive avoidance task [18]. As the CeA [178], and GABAergic mechanisms [183] are involved in reward-related learning, the importance of amygdala GABAergic mechanism in the state-dependent memory seems likely. In addition, Rassouli et al. (2010) showed that pre-test intra-CeA injection of muscimol impair morphine state-dependent memory suggesting that the GABAA receptors of CeA participate in morphine state-dependent memory [18].


3.2.4. Involvement of the amygdala cholinergic system in the state-dependent memory

The amygdala received cholinergic projections from the nucleus basalis magnocellularis (NBM). Immunocytochemical studies showed that the mAChR are found in the amygdala, hippocampus, and neocortex which are participated in cognitive functions such as learning and memory processes. In the CeA a large individual difference in the mAChR immunoreactivity was detected, both in the number of neurons and their staining intensity. studies exhibited that there is a high level of mAChRs in the CeA which play a critical role in the induction of LTP in the amygdala [184]. Some documentation shows the involvement of amygdala cholinergic mechanism in memory storage. It has been indicated that administration of cholinergic receptor antagonists into the amygdala decline learning and memory in a variety of behavioral tasks [185]. As well, the CeA mAChR play a key role in state-dependent memory. There is a possibility that the mAChR induced state-dependent memory retrieval is mediated through interaction with other mechanisms in the amygdala [19]. Rezayof and coworkers (2009) reported that the mAChRs of amygdala play the main role in morphine-induced state-dependent memory retrieval in a step-through passive avoidance learning task. They also reported that pre-test intra-amygdala injection of scopolamine prevents the expression of morphine-related state-dependent memory [19]. Additionally, the cholinergic and serotonergic receptors of CeA have a functional interaction with morphine-induced state-dependent memory retrieval in a step-through passive avoidance learning test (fig. 5). It is likely that the rewarding effects of the drugs lead to produce cross state-dependent memory retrieval between the drugs  [52].

3.2.5. Involvement of the amygdala adrenergic system in the state-dependent memory

The CeA receives dense noradrenergic projections from the locus coeruleus. According to investigations, the amygdala adrenergic receptors modulated inhibitory avoidance memory. β-adrenoceptors of the amygdala involved in the modulation of retrieval of one-trial step-down inhibitory avoidance task [186]. Growing documents displayed that intra-amygdala injections of β-adrenoreceptor agonists improved retention performance in either spatial or emotionally-motivated memory tasks, but their antagonists impaired learning and memory in behavioral studies [186187]. Some evidence exists regarding the participation of the amygdala noradrenergic receptors in state-dependent memory. It appears that the amygdala β-adrenoceptors participate in drug state-dependent memory [153].


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