An anomaly in the experimental data underlying the theory that neuroleptics act by blockade of dopaminergic neurotransmission is the repeatedly demonstrated failure in several laboratories of parenterally administered neuroleptics to antagonize electrophysiologic actions of locally applied dopamine (DA) in striatum. This failure is enigmatic since many investigators have successfully demonstrated antagonism when both dopamine and neuroleptic are applied directly to striatal neurons by microiontophoresis. We used multibarrel micropipettes to pressure-eject DA agonists onto rat caudate neurons while observing the ability of parenterally administered haloperidol to block the inhibitory actions of dopaminergic agonists on neuronal activity. Experiments performed at times of maximal behavioral effect of haloperidol did not demonstrate agonist-antagonist interaction. This result has been obtained by four other teams of investigators. A variety of pharmacologic manipulations were employed to help solve this enigma. Acute treatment with reserpine and α-methyl-paratyrosine, performed to minimize any possible interference by endogenous DA, did not permit blockade of dopamine by haloperidol. To see if this failure of antagonism could be generalized to other DA agonists, apomorphine, amphetamine, and phencyclidine (PCP) were also investigated. Although the direct dopaminergic agonist apomorphine was not antagonized by haloperidol, the indirect DA agonist PCP was succesfully antagonized. Amphetamine, which has both direct and indirect actions when applied locally, was not antagonized. Antagonism of direct agonists was demonstrated in rats with unilateral 6-hydroxydopamine-induced lesions of the nigrostriatal pathway. In these preparations, parenterally administered haloperidol reversed the receptor-mediated supersensitivity to the inhibitory effects of locally applied DA and apomorphine. These data suggest that in caudate there exist postsynaptic receptors that are more sensitive to haloperidol than those receptors usually activated by DA released into the neuronal milieu from micropipettes. We suggest that PCP's indirect action on endogenous DA in presynaptic terminals results in specific interaction with these receptors. We further suggest that the postsynaptic receptors most sensitive to blockade by haloperidol may also be those receptors that increase in number following denervation. Failure to demonstrate antagonism of direct DA agonists in the absence of supersensitivity suggests that locally applied DA does not normally contact postsynaptic dopaminergic receptors, but rather extrasynaptic receptors with different pharmacologic characteristics.
|Original language||English (US)|
|Number of pages||9|
|Journal||Journal of Neuroscience|
|State||Published - Jan 1 1986|
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