Altered extracellular dopamine concentration in the brains of cholecystokinin-A receptor deficient rats

The gut-brain peptide cholecystokinin (CCK) has been implicated in the regulation of dopamine (DA) transmission in the brain. CCK agonists have been shown to modify baseline and stimulant-induced DA release in the brain via CCK-A mediated mechanisms. However, the role of endogenous CCK in regulating brain DA via CCK-A receptors has not been fully elucidated. Recently, a strain of rats (Otsuka Long Evans Tokushima Fatty (OLETF)), lacking the CCK-A receptor due to a genetic mutation, was discovered, providing a potentially useful tool to study the DA regulatory role of CCK-A receptors. In order to further clarify the role of CCK-A receptors in the regulation of central DA transmission, extracellular DA levels in the nucleus accumbens (NAC) and the caudate-putamen (CP) of OLETF rats, and their non-mutant counterparts, Long Evans Tokushimo Otsuka rats, was assessed by microdialysis at baseline and in response to cocaine (15 mg/kg) and amphetamine (0.5 mg/kg) administration. Baseline levels of extracellular DA were significantly elevated in the CP but not in the NAC of OLETF rats. In contrast, the NAC exhibited a greater DA response to cocaine (15 mg/kg) and amphetamine (0.5 mg/kg) in OLETF rats. This is the first direct evidence, of which we are aware, supporting altered DA regulation in OLETF rats. These findings suggest that CCK-A receptors play an important role in the regulation of central DA transmission, and support the notion that the OLETF rat is a useful model to study this regulation. (C) 2003 Published by Elsevier Ireland Ltd.