Neurotransmission in dopamine systems of the brain has a central role in controlling a number of functions, including movement, as well as reward and reinforcement for both natural rewards and those associated with addictive drugs.
There is increasing evidence that neurotransmitters in addition to DA are involved, and that their dysregulation contributes to disorders associated with movement and influences the maintenance of craving and the susceptibility to re-use drugs.
Thus, the cortico-striatal glutamate pathway has been implicated considering its association with DA in the striatum. Cholecystokinin (CCK) may also be involved. CCK is a likely co-transmitter in the cortico-striatal glutamate pathway and is also present in DA neurons that innervate limbic regions of the striatum.
While the focus of CCK studies have been its cortical input onto the dorsal striatum and its association with movement, questions regarding the CCK innervation of the ventral striatum remain to be clarified, as do functional aspect s of CCK receptors in cellular signalling mechanisms in the brain.
This project will provide anatomical and histochemical evidence for CCK cortical projections to the ventral striatum, and with in vivo microdialysis will biochemically examine the role of C CK in the limbic system. Effects of CCK on behaviour, with respect to reward, addiction and motor control, after pharmacological modulation and/or genetic deletion of CCK receptors, will also be examined.
Finally, molecular techniques, including gene gun transfer and calcium imaging in organotypic cultures will be implemented to investigate functional properties of CCK receptors in striatal neurons, and to study their relationship with G-proteins and DA and NMDA receptors.
Characterisation of the influence of CCK in limbic regions of the brain may provide possibilities for new experimental, conceptual and therapeutic approaches to control reward, addiction, panic disorders, anxiety and possibly schizophrenia.
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