Behaviours alterations of central serotonin deficient mice and inhibitory long-term depression adapted to opioid addiction with a combinatorial plasticity mechanism
Central serotonin (5-HT) is an important neuromodulator for regulating numerous physiological and behavioural activities. Deficiency of serotonin has been implicated in mood disorders, such as depression and posttraumatic stress disorder and panic disorder. The hippocampus receives projection from serotonergic neurons that modulates fear, anxiety, and learning through postsynaptic serotonin receptors. Hippocampal synaptic plasticity is the molecular and cellular mechanism underlying learning and memory. Genetic deletion of serotonin in the brain was achieved by inactivating Lmx1b selectively in the raphe nuclei of the brain stem, resulting in a near complete loss of 5-HT throughout the brain. These 5-HT-deficient mice exhibited no gross abnormality in brain structures and had normal locomotor activity. Spatial learning in the Morris water maze was unaffected, but the retrieval of spatial memory was impaired. The animals showed decreased anxiety-like behaviours. However, contextual fear learning and memory induced by foot-shock conditioning was markedly enhanced, but this enhancement could be prevented by intracerebroventricular administration of 5-HT. Foot shock had no effect on hippocampal synaptic plasticity in 5-HT-deficient mice. Thus, central 5-HT regulates hippocampus-dependent contextual fear memory, and 5-HT modulation of hippocampal synaptic plasticity may be the underlying mechanism. The enhanced fear memory in 5-HT deficient mice supports the notion that 5-HT deficiency confers susceptibility to PTSD in humans. The cardinal features of drug addiction are the compulsive seeking and taking of drugs. The persistence of opioid addiction is a major clinical problem. Addiction and learning may share common pathways. Addiction is some kind of memory, but it is more powerful in utilizing the neural circuit. It likely engages memory mechanisms that may in part attribute to adaptations of excitatory synaptic plasticity in the hippocampus. Addiction is so complicated that not only excitatory synaptic plasticity is involved. We investigate the contribution of 5-HT and inhibitiory synaptic plasticity in addiction. We found that morphine-induced addiction-like behaviors revealed by locomotor sensitization and conditioned place preference tests became markedly enhanced. In addition, addiction-like behaviors in sustained in 5-HT-deficient mice after extinguishment. However, the sustained addiction-like behaviors were prevented by intracerebroventricular administration of 5-HT and 5-HT1A receptor agonist in 5-HT-deficient mice. Hippocampal long-term potentiation (LTP) was further enhanced compared with WT mice. Thus, our data indicate that central 5-HT deficiency leads to high susceptibility to morphine-induced addiction-like behaviors, the cellular mechanisms of which may be attributed to the enhanced hippocampal synaptic plasticity. And we found that neither single in vivo morphine exposure nor subsequent acute withdrawal affects inhibitory long-term depression (I-LTD) in CA1 pyramidal neuron of the rat hippocampal slice, which is usually dependent on cannabinoid receptor 1 (CB1R). In marked contrast, repeated in vivo morphine exposure blocks I-LTD induction, and subsequent acute withdrawal enhances I-LTD dramatically. This phenomenon is attributed to a combinatorial plasticity containing both CB1R- and L-type calcium channel-mediated components. Thus, the adaptations of hippocampal I-LTD by a novel combinatorial plasticity with repeated in vivo opioid exposure and acute withdrawal may contribute, at least partially, to the persistence of opioid addiction.
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