CRF regulation of striatal dopamine release and its role in motivated behaviors

Major depressive disorder as well as other neuropsychiatric diseases are characterized by a pathological shift in stress responsivity. For example, depressed individuals are more likely to withdraw from the environment and respond to acute mild stressors with avoidance while, for healthy individuals, acute mild stressors often serve as motivators and drive engagement. Therefore, understanding the mechanisms by which acute stressors motivate or demotivate individuals under different conditions is key to understanding the etiology of depression. The stress-associated neuropeptide corticotropin releasing factor (CRF) as well as its two receptors CRF-type 1 and CRF-type 2 are widely distributed throughout central nervous system. Systemic administration of CRF produces avoidance behaviors as well as cognitive impairment. However, it was recently shown that CRF acting in the nucleus accumbens (NAc) potentiates dopamine release to promote approach behavior such as exploration of a novel object. Interestingly, repeated stress disrupts CRF’s ability to increase dopamine and switches the behavioral response to CRF from approach to avoidance. Since this original finding, I have delved further into the mechanism by which CRF increases dopamine release within the NAc in an effort to uncover how this behavioral switch occurs. I have found that that there are two components driving the CRF mediated potentiation of dopamine transients – muscarinic acetylcholine 5 (M5) receptor dependent and independent components. Moreover, I have found that following repeated stressor exposure the M5 dependent component remains intact, while the M5-independent component is disrupted. These data indicate that the M5 receptor could have potential therapeutic potential in treating aberrant striatum-dependent behaviors that emerge following repeated stressor exposure.