Selective Effects of Low-Dose D2 Dopamine Receptor Antagonism in a Reaction-Time Task in Rats

Abstract

Operant responses involving a cued discrimination are StnSitively disrupted by neuroleptic drugs that block dopamine (DA) receptors in the brain; however, it is not dtar which DA receptor subtypes may be involved in these effects. The role of Dl or D2 DA receptorI1Itagonists on the execution of a conditioned reaction time (RT) motor task was investigated in the present study. Rats were trained to release a lever after the presentation of a visual cue within a RT limit to be rrinforced by a food pellet. The Dl receptor antagonist In contrast, a selective D2 receptor antagonist raclopride (50, 100, or 200 J1.glkg) induced a dose-dependent increase in the number of incorrect responses (release of the lever over the RT limit) associated with an increase in the RT. The results suggest that the dopaminergic nigrostriatal system, which has previously been shown to be specifically involved in this RT task (Amalric and Koob 1987), appears to be a sensitive site for sensorimotor integration, and that the execution of the conditioned RT motor task may depend preferentially on the activation of the dopaminergic D2 receptors in this system. Most of the neuroleptic drugs are antagonists at both receptor subtypes. However, the recently devel oped OA antagonist, raclopride, has a high affinity for the 02 OA receptor and crosses the blood-brain barrier fairly easily, reaching its peak concentration at about 15 minutes after intravenous injection (Kohler et al. 1985). Raclopride has no effect on the activity of ade nylate cyclase, indicating the absence of action on the 01 receptors (Ogren et al. 1986). On the other hand, the drug SCH-23390 has a very high affinity for the OA 01 receptor, as compared to its affinity for the 02 receptor (Billard et al. 1984;Hyttel 1983;Hjorth and Carlsson 1988); SCH-23390 has been shown to suppress numerous OA-stimulated behaviors such as stereotypy or locomotor activity, demonstrating its dopaminergic action (for review, see Clark and White 1987). Using

Effect of Bilateral 6-Hydroxydopamine Lesions of the Medial Forebrain Bundle on Reaction Time

“…However, unilateral lesions of this magnitude have been examined and were found to produce impairments on the contralateral side of the lesion similar to those observed in the present study (Carli et al 1985(Carli et al , 1989Robbins 1989, 1991;Phillips and Brown 1999). Comparable results were also obtained with antagonists of D 2 DA receptors, further establishing the role of this receptor in motor function (Amalric et al 1993;Smith et al 2000).…”

“…In this task, animals are typically required to respond in a particular way and within a limited period in order to receive a reward, such as a food pellet. This behavioral paradigm is responsive to pharmacological manipulation of dopaminergic neurotransmission mediated by the D 2 subtype of DA receptors Koob 1987, 1989;Amalric et al 1993Amalric et al , 1995Smith et al 2000). For example, we have shown that low dose blockade of D 2 receptors, but not D 1 or D 3 receptors, decreased correct responses in the conditioned reaction time task, increased delayed responses, and lengthened reaction time in a manner suggestive of dysfunctions in movement initiation (Amalric et al 1993;Smith et al 2000).…”

“…This behavioral paradigm is responsive to pharmacological manipulation of dopaminergic neurotransmission mediated by the D 2 subtype of DA receptors Koob 1987, 1989;Amalric et al 1993Amalric et al , 1995Smith et al 2000). For example, we have shown that low dose blockade of D 2 receptors, but not D 1 or D 3 receptors, decreased correct responses in the conditioned reaction time task, increased delayed responses, and lengthened reaction time in a manner suggestive of dysfunctions in movement initiation (Amalric et al 1993;Smith et al 2000). Moreover, deficits in reaction time have also been reported in Parkinson's disease (Evarts et al 1981;Gauntlett-Gilbert and Brown 1998;Berry et al 1999).…”

6-Hydroxydopamine lesion of the rat prefrontal cortex impairs motor initiation but not motor execution

“…The present results have several implications: the increased RT induced by systemic administration of various DA antagonists in this (Hauber and Schmidt 1990) or other simple RT tasks for rodents (Amalric et al 1993;Marrow et al 1993) may not be due exclusively to an impaired DAergic transmission in the CP but also to a DA receptor blockade in the PFC. An involvement of prefrontal DA may be also relevant for increased RT measured in patients with Parkinson's disease (Evarts et al 1981).…”

Enduring Resistance to Extinction of Cocaine-Seeking Behavior Induced by Drug-Related Cues

“…It is unlikely that the suppression of cue-induced responding by SCH 23390 was merely the result of general disruptive effects or impairments in motor performance. Lowdose D 1 antagonist treatments alter the direct reinforcing actions of cocaine without interfering with motor performance (Amalric et al 1993) or food-maintained behavior (Caine and Koob 1994). Consistent with these observations, a selective D 1 antagonist (SCH 39166) was recently shown to attenuate the euphoric effects of cocaine in humans without inducing sedation or nonspecific anhedonic effects (Romach et al 1999).…”