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Cholecystokinin: Effects on motor behaviour and addiction

Final Activity Report Summary - CCKOEXIST (Cholecystokinin: Effects on motor behaviour and addiction)

The original project objectives were to study mechanisms underlying deficits in motor behaviour and mental disorders, and to gain experience and expertise in a variety of research techniques, enabling strategic planning, and the ability to effectively solve scientific questions of interest through a number of different techniques. Experiments aimed to provide conclusive evidence for a projection between the cortex and nucleus accumbens / striatum of the rat brain, and the neurotransmitters and receptors that are present in this pathway. Cholecystokinin (CCK) is a neuropeptide that is abundantly expressed in these regions, and thus has the potential to be involved in movement and mental disorders that occur when neurotransmission is disrupted.

In a new animal model of Parkinson's disease, the expression of CCK appears to be unregulated in cortical regions, as shown by immunohistochemistry and in situ hybridization. L-DOPA is widely used for treating patients suffering Parkinson's disease, however, its initial benefits are inevitably marred by the appearance of involuntary movements, referred to as dyskinesias. The observation of increased CCK levels in cortical regions of the Parkinsonian animal model led to studies, where the effects of blocking CCKA and CCKB receptor with antagonists, to inhibit the increased activity of CCK, were examined in dyskinetic Parkinsonian animal models with L-DOPA induced dyskinesia. Neither the CCKA (devazepide) or CCKB (L-365260) receptor antagonists had any effect on the development, nor reduction, of dyskinesias in the animal model examined. Our next objective was to determine the location of CCK receptors in the rodent brain, however efforts to produce a reliable and specific marker for either the CCKA or CCKB receptors proved unsuccessful, as all antibodies developed and tested were present in animal models in which the CCKA/CCKB receptors were genetically removed.

Subsequently, effects of the CCK system on the development of new neurons in the adult mouse brain were examined. Involvement of the CCK system in neurogenesis was highlighted in mice with genetic deletion of CCKA and CCKB receptors, and both receptors. A dramatic reduction in migrating immature neurons in the rostral migratory stream, together with a reduction of neurons in the olfactory bulb, the final destination of these neurons, was observed. Similar deficiencies were also observed in mice with genetic deletion of the NPY Y1 and Y2 receptors, indicating also a role for the NPY system in this process. In the adult, neurogenesis is also known to occur in the hippocampus, an area of the brain important for learning and memory, as well as mood disorders, and is a requirement for normal functioning. It is likely that one of the functions of CCK and NPY, which are present in the hippocampus, is to control the rate of neurogenesis that occurs.

Gaining a deeper understanding of the mechanisms that contribute to the formation of new cells, and their successful integration, is important for the development of therapies designed to replace neurons such as those lost as a consequence of Parkinson's disease, and for strategies designed to treat mood disorders such as anxiety and depression.