Molecular mechanisms of drug dependency and stimulant psychosis induced by methamphetamine

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We hypothesizes that drug dependency and stimulant psychosis induced by methamphetamine are triggered by gene expression which causes remodeling of the synapses in the nucleus accumbens. We analyzed the functions of Arc and Arcadline which are induced by methamphetamine.1)Arcadlin : Neural activity induces structural changes of synapse in which the cell adhesion molecules participate. We found that synapses were expanded laterally in 30 minutes after depolarization. N-cadherin participated in expansion of synapse adhesion plane. Moreover, both AMPA receptor and polymerization of actin are necessary.On the other hand, Arcadlin is a cadherin family and induced by neural activity. We found that Arcadlin formed a complex with N-cadherin and was internalized, and then the number of synapses decreased. Conversely, the neurons from Arcadlin knockout mice increased the number of synapses.2)Arc : Arc is an immediate early gene induced by methamphetamine and its mRNA is carried to the dendrite to synthesize the protein. It was found that the immunoreactivity of MAP2 was markedly decreased by overexpression of Arc. When the electric shock convulsive seizure was applied to mice, immunostaining of Arc was increased in the granular layer and that of MAP was significantly decreased.From these data, Arcadline and Arc which are induced by methamphetamine associate with other proteins to change the synaptic morphology and functions, which may cause drug dependence and stimulant psychosis.