Neuropathways and synaptic adaptations underlying drug addiction in central dopamine systems

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There is a rising trend in addiction to drugs, such as opioids (heroin) and stimulants (methamphetamine and ecstasy). A key feature of this addiction is intensified craving for the drug with repeated use. A major brain component thought to mediate drug-craving is the dopamine (DA) neurotransmitter system, consisting of cells in the midbrain that project nerve terminals to forebrain structures involved in reward-based learning. DA cells undergo long-term depression (LTD) and potentiation (LTP) of synaptic strength when excitatory inputs to DA cells are stimulated. These findings are important to drug addiction as amphetamine has been shown to block LTD and enhance LTP in brain slices of DA cells. Thus, changes in LTD and LTP by illicit drugs may underlie the conditions necessary for expression of drug-induced behavioural sensitisation, the best-accepted model of drug-craving in human addiction. To date, these studies have all been conducted in brain slices. Therefore, the functional importance of this synaptic plasticity in midbrain DA cells has yet to be shown in terms of changes in DA release in forebrain terminals in the living animal. For the first time we will address this issue by recording DA cell firing activity together with DA release using a newly developed technique that permits DA release to be monitored in the living brain in 'real-time' (100,000 samples-sec). This will allow us to identify the origin (cortical excitatory inputs) and receptor mechanisms that mediate LTP and LTD in DA cells and their effects on DA release. Recording DA cell activity with real-time measurement of DA release will promote a new cutting-edge technology to the Australian Neurosciences. These data will provide 'first of its kind' evidence of the functional anatomy and receptor mechanisms underlying synaptic plasticity in DA neurons associated with repeated drug use and ultimately enhance our basic understanding of the neural mechanisms of human drug addiction.