Cortical regulation of the meso-nucleus accumbens dopamine stress response

It is well established that stress will stimulate dopamine (DA) release in the nucleus accumbens (NAcc). That NAcc DA transmission increases in response to stress is of interest given the postulated involvement of this transmitter in the pathophysiology of schizophrenia. It has been speculated that hyperactivity of DA cells that innervate limbic regions, including NAcc, underlie the positive symptoms associated with this disease, including exaggerated responses to stress. Understanding the mechanisms by which stress can stimulate NAcc DA release, mechanisms which are currently unclear, thus has potential clinical implications. One likely source of influence on meso-NAcc DA function is the DA projection to the prefrontal cortex (PFC), acting through descending excitatory amino acid projections to the meso-NAcc DA system. The meso-PFC DA pathway, itself potently activated by stress, has been implicated both in cognitive functions, and the negative symptomatology associated with schizophrenia. The focus of this thesis was to investigate the potential involvement of the meso-PFC DA system in modulating stress-induced DA release in NAcc.The results of these studies have helped to clarify the circuitry by which meso-NAcc DA transmission is influenced. At the cortical level we demonstrated that DA released in PFC during stress can influence the activity of prefrontal cortical output neurons that project to NAcc, or to DA cell bodies in the ventral tegmental area (VTA), either through a direct, inhibitory action, or indirectly by dampening the inhibitory tone provided by GABA interneurons in PFC. Furthermore, PFC GABA may also affect cortical output indirectly, through presynaptic modulation of stress-induced DA release in this region. The present results also indicate that excitatory amino acids (EAAs) acting at NMDA receptors in NAcc exert an inhibitory influence on stress-induced DA release in both NAcc and VTA. These results suggest that EAAs do not exert a direct effect on DA terminals as has been previously suggested, but instead act on NMDA receptors located on NAcc output neurons, likely GABAergic, that project directly or indirectly to the cell bodies of the mesocorticolimbic DA system. This hypothesis is further supported by the results of our final study, in which manipulation of GABA receptors in the VTA was shown to regulate the NAcc DA stress response. The results of these studies provide novel information on how the meso-NAcc DA stress response is regulated, and indicate several possible sources which may contribute to the altered functioning of ascending DA systems that has been suggested to underlie the pathophysiology of several neuro-affective disorders, including schizophrenia