Investigation of the failure of parenterally administered haloperidol to antagonize dopamine released from micropipettes in the caudate

Abstract

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 striaturn. 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 a-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 successfully 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 dopami-

Striatal Neuronal Activity and Responsiveness to Dopamine and Glutamate after Selective Blockade of D1 and D2 Dopamine Receptors in Freely Moving Rats

“…These effects, moreover, were attenuated by SCH but not ETI, strongly suggesting an inhibitory role for D1 receptors. This conclusion also agrees with results obtained from both anesthetized (Johnson et al, 1986;Ohno et al, 1987;Hu and Wang, 1988;White and Hu, 1993) and in vitro preparations (Mercuri et al, 1985;Calabresi et al, 1987;Pennartz et al, 1992;Surmeier et al, 1992;Nicola et al, 1996;O'Donnell and Grace, 1996). Interestingly, however, the SCH plus ETI combination revealed a difference in the DA response between spontaneously active and GLUstimulated units.…”

“…To the extent that a brief DA application mimics phasic DA release, our data also support the idea that phasically released DA shares the same, inhibiting pattern of action on both basal and GLUevoked activity. Such inhibiting effects have been found in most studies using DA applications both in anesthetized and in vitro preparations (Mercuri et al, 1985;Chiodo and Berger, 1986;Johnson et al, 1986;Ohno et al, 1987;Nicola et al, 1996), and these effects were typical of the majority of striatal units in freely moving rats. DA, however, has also been shown to enhance GLU-induced excitations (Chiodo and Berger, 1986;Cepeda et al, 1993;Levine et al, 1996;Hu and White, 1997).…”

“…GLU-stimulated units, on the other hand, showed almost no attenuation of the DA response after the SCH plus ETI combination. This outcome is difficult to explain but it is noteworthy that haloperidol, a D2 antagonist with some D1 affinity, frequently fails to block DAinduced inhibitions of striatal (Ben-Ari and Kelly, 1976;Skirboll and Bunney, 1979;Johnson et al, 1986) and prefrontal cortical neurons (Thierry et al, 1986;Godbout et al, 1991), especially those activated by GLU. We have reported similar failures of haloperidol to reverse amphetamine-induced inhibitions of striatal neurons (Haracz et al, 1993).…”

Efflux of dopamine from the synaptic cleft in the nucleus accumbens of the rat brain

“…On the other hand, neurochemical, physiological, and behavioral experiments have implicated a role for extrasynaptic communication by dopamine (Johnson et al, 1986;Schenk and Bunney, 1987;Fuxe and Agnati, 1991;Gonon et al, 1991). In Parkinson's disease, for example, reduced dopamine uptake, due to the loss of dopamine neurons, is thought to enable released dopamine to diffuse farther from the remaining dopamine synapses and into denervated regions (Zigmond et al, 1990).…”

Regulation of the synthesis and metabolism of striatal dopamine after disruption of nerve conduction in the medial forebrain bundle

“…Taken together, these results siggest that haloperidol can act directly on the dopaminergic nerve terminal. Therefore, the results may be unrelated to a strionigral, long-loop, negative feedback activation of the dopaminergic neurone, as is usually suggested (Carlsson et al, 1972;Iwatsubo & Clouet, 1977;Kilpatrick et al, 1985;Johnson et al, 1986). An alternative explanation is that haloperidol may increase striatal DOPAC and HVA by blocking their transport from the striatum (Westerink & Kikkert, 1986).…”