Pharmacological and mechanistic studies of cholecystokinin-facilitated [3H]dopamine efflux from rat nucleus accumbens

Cholecystokinin (CCK) is co-localized with dopamine (DA) in mesolimbic neurons of the CNS and appears to selectively regulate the output of this system. In an attempt to characterize the nature of CCK interactions with mesolimbic DA-containing nerve terminals, we have investigated CCK regulation of 3H]DA overflow from rat nucleus accumbens slices. CCK-8 produced a saturable and potent (EC50 = 3 nM) facilitation of KCl (35 mM)-evoked 3H]DA efflux from nucleus accumbens, but failed to significantly alter 3H]DA efflux from striatum: The stimulatory action of CCK-8 was unaffected by the muscarinic antagonist atropine, the opiate antagonist naloxone, or the selective ion channel blockers tetrodotoxin and nifedipine. Pharmacological studies revealed that non-sulfated CCK-8 and CCK-4 (up to low micromolar concentrations) did not facilitate 3H]DA efflux from accumbens slices. Furthermore, the effect of CCK-8 was selectively and potently (IC50 = 300 nM) inhibited by the Type A-selective CCK antagonist CR-1409. Taken together, these results indicate that CCK regulates DA efflux from mesolimbic nerve terminals via a direct presynaptic action on receptors which display a pharmacological profile that is similar to Type A CCK receptors in gastrointestinal tissues.