Interactions between endogenous dopamine and dopamine agonists at release modulatory receptors: multiple effects of neuronal uptake inhibitors on transmitter release

IS Hoffmann, RK Talmaciu and LX Cubeddu

The authors investigated the mechanisms by which inhibitors of the neuronal uptake (NUI) of dopamine (DA) and prolonged stimulations at high rates antagonize the inhibition of acetylcholine (ACh) release from rabbit striatal slices produced by DA receptor agonists. Nomifensine (1 microM) reduced the potency and efficacy of apomorphine (APO) in inhibiting the evoked release of ACh (0.3 Hz, 39 pulses) (noncompetitive kinetics). Highest inhibitory potency and efficacy of APO were obtained at 0.3 Hz and 39 pulses. Increases in stimulation rates and number of pulses (3 Hz and 120 pulses) reduced APO potency and efficacy for inhibition of ACh release (noncompetitive kinetics). At 10 Hz and 500 pulses APO efficacy was further reduced, and the APO concentration-effect curve was biphasic. Inhibition of DA and ACh release produced by other DA receptors agonists such as bromocriptine, piribedil and LY-171555 was also reduced by prolonged stimulations at high frequencies. Depletion of endogenous DA stores by reserpine pretreatment abolished the antagonism of APO produced by NUI and reduced considerably the antagonism produced by high pulses and high rates of stimulation of APO- and LY-171555-induced inhibition of ACh release. However, even after combined pretreatment with reserpine and alpha-methylparatyrosine, the potency and efficacy of APO in inhibiting ACh release at 10 Hz and 500 pulses were less than the values obtained in 0.3 Hz and 39 pulses and at 3 Hz and 120 pulses. The biphasic nature of the APO concentration-effect curve at 10 Hz and 500 pulses was no longer present after reserpine. Interestingly, reserpine pretreatment failed to modify APO-induced inhibition of ACh release at 0.3 Hz and 39 pulses, suggesting that the sensitivity of the DA release modulatory receptors was not affected by the pretreatment. These results indicate that the high synaptic concentration of DA achieved at low stimulation rates in the presence of NUI and at high stimulation rates reduces the potency and efficacy of DA agonists in inhibiting ACh release. However, for prolonged stimulations at high rates not all of the changes seen with DA agonists are mediated by endogenous DA. At high concentrations (10 microM), cocaine and nomifensine inhibited the evoked release of ACh even after depletion of tissue DA stores by reserpine in the absence or presence of a alpha-methylparatyrosine.(ABSTRACT TRUNCATED AT 400 WORDS)

Volume 238, Issue 2, pp. 437-446, 08/01/1986
Copyright © 1986 by American Society for Pharmacology and Experimental Therapeutics