Synaptic Actions of Amphetamine in the Striatum

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Project summary Addictive psychostimulants such as amphetamine act at dopamine synapses in the striatum. Presynaptic amphetamine action drives dopamine release via activity-dependent and activity-independent mechanisms. Dopamine acts on multiple dopamine receptors that are differentially distributed on striatal neurons. Beyond this volume transmission, dopamine neurons engage in synaptic transmission that is operative on a fast time scale, compared to volume transmission, and involves not only dopamine, but also GABA and glutamate. This project focuses on these synaptic connections as a novel substrate for psychostimulant action. The synaptic transmission exerts excitatory effects through dopamine D1 receptors, ionotropic and metabotropic glutamate receptors, and inhibitory effects through dopamine D2 receptors and GABAA receptors. While dopaminergic and GABAergic synaptic connections are widespread, glutamatergic connections are concentrated in the medial nucleus accumbens and the anterior lateral dorsal striatum. Synaptic connections to cholinergic interneurons are the strongest, most complex, involving dopamine, GABA and glutamate. Remarkably glutamate cotransmission is abrogated by amphetamine administration, and abrogation of glutamate cotransmission attenuates psychostimulant responsiveness. The guiding hypothesis is that amphetamine- induced plasticity of a subset of dopamine neuron synapses is critical for driving the striatal circuitry towards the addicted state, particularly dopamine neuron synapses distinguished by glutamate cotransmission. The three specific aims are to: <1> Determine quantitatively amphetamine-induced plasticity of dopamine neuron synaptic connections to cholinergic interneurons in striatal subregions identified by synaptic connectivity-based clustering. <2> Determine direct synaptic effects of amphetamine on dopamine neuron synaptic transmission in striatal subregions distinguished by glutamate cotransmission. <3> Determine amphetamine effects on dopamine neuron terminal activity during amphetamine-induced behaviors. This project will advance understanding of the synaptic substrate of amphetamine action in the striatum, revealing loci of drug-induced plasticity that will inform the pharmacotherapy of addiction.