The dopamine reuptake inhibitor MRZ-9547 increases progressive ratio responding in rats.

Drugs that are able to shift effort-related decision making in intact rats towards high-effort response options are largely unknown. Here, we examined the effects of two candidate drugs, MRZ-9547 and its l-enantiomer MRZ-9546 on progressive ratio (PR) responding using two different tasks, a standard PR task that involves increasing ratio requirements and a PR/chow feeding choice task in which animals can lever press for preferred food pellets under a PR schedule or approach freely available less preferred lab chow. Furthermore, we assessed the mechanisms of action of both drugs using in vitro-assay methods and in vivo-microdialysis. Results reveal that MRZ-9547 is a selective dopamine transporter (DAT) inhibitor that moderately stimulated striatal dopamine release. MRZ-9546 was a much less potent DAT inhibitor. Furthermore, MRZ-9547 dose dependently increased the tendency to work for food reinforcement both in the standard PR task and the PR/chow feeding choice task, MRZ-9546 was considerably less active. Relative to MRZ-9547, other DAT-interfering drugs had only moderate (methylphenidate) or marginal (modafinil, d-amphetamine) stimulant effects on PR responding in either task. Collectively, our data demonstrate that the DAT inhibitor MRZ-9547 can markedly stimulate PR responding and shift effort-related decision making in intact rats towards high-effort response options. An analysis of effort-related decision making in rodents could provide an animal model for motivational dysfunctions related to effort expenditure such as fatigue, e.g. in Parkinson's disease or major depression. Our findings suggest that DAT inhibitors such as MRZ-9547 could be potentially useful for treating energy-related symptoms in neurological or neuropsychiatric disorders.

The role of dopamine in the dorsomedial striatum in place and response learning.

The posterior subregion of the dorsomedial striatum (pDMS) has been implicated in spatial learning. Here we investigated the role of dopamine (DA) signals in the pDMS in place and response learning using a T-maze task. Rats subjected to a DA depletion of the pDMS and sham controls were trained for 7 days to retrieve food from the west arm of the maze starting from the south, that is to make a left turn at the choice point. On day 8, a probe test was given in which the starting arm was inserted as the north arm. On days 9-16 animals received further training, and on day 17, a second probe test was performed. We examined whether animals responded on probe tests according to a response strategy (left turn at choice point) or to a place strategy (right turn at choice point). Our results revealed that, unlike sham controls, rats with a pDMS DA depletion preferentially used a response rather than a place strategy already on the first probe test. These findings provide further support for a role of the pDMS in spatially guided behavior and indicate that DA signals in the pDMS are critical for the use of a place strategy.

Dopamine release in the prefrontal cortex and striatum: temporal and behavioural aspects.

Dopamine (DA) neurons originating in the substantia nigra and ventral tegmental area project to a variety of forebrain structures thereby forming a complex neuromodulatory system that is essential for numerous motor, cognitive and motivational processes. DA neurons can operate in distinct temporal modes, i. e. they display responses across varying timescales including fast phasic changes of DA release on a seconds time scale and slower phasic changes in a minutes to hour range. Furthermore, tonic levels of DA provide a DA receptor 'tone'. Here we briefly highlight findings indicating that temporally distinct responses of DA neurons in the prefrontal cortex and striatum are related to different kinds of information and may serve dissociable behavioural functions. Furthermore we consider how DA neuronal activity and temporarily distinct patterns of DA release are regulated and summarize some relevant findings on the basic neuroanatomy of ascending DA systems. A better understanding of the specific functions of phasic and tonic DA signals will be critical for determining the role of DA in behaviour in detail.

Guidance of instrumental behavior under reversal conditions requires dopamine D1 and D2 receptor activation in the orbitofrontal cortex.

The orbitofrontal cortex (OFC) plays a critical role in learning a reversal of stimulus-reward contingencies. Dopamine (DA) neurons probably support reversal learning by emitting prediction error signals that indicate the discrepancy between the actually received reward and its prediction. However, the role of DA receptor-mediated signaling in the OFC to adapt behavior to changing stimulus-reward contingencies is largely unknown. Here we examined the effects of a selective D1 or D2 receptor blockade in the OFC on learning a reversal of previously acquired stimulus-reward magnitude contingencies. Rats were trained on a reaction time (RT) task demanding conditioned lever release with discriminative visual stimuli signaling in advance the upcoming reward magnitude (one or five food pellets). After acquisition, RTs were guided by stimulus-associated reward magnitudes, i.e. RTs of responses were significantly shorter for expected high versus low reward. Thereafter, stimulus-reward magnitude contingencies were reversed and learning was tested under reversal conditions for three blocks after pre-trial infusions of the selective D1 or D2 receptor antagonists R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinhydrochloride (SCH23390), eticlopride, or vehicle. For comparisons, we included intra-OFC infusions of the selective N-methyl-D-aspartate receptor antagonist AP5. Results revealed that in animals subjected to intra-OFC infusions of SCH23390 or eticlopride learning a reversal of previously acquired stimulus reward-magnitude contingencies was impaired. Thus, in a visual discrimination task as used here, D1 and D2 receptor-mediated signaling in the OFC seems to be necessary to update the reward-predictive significance of stimuli.

Transient inactivation of the rat nucleus accumbens does not impair guidance of instrumental behaviour by stimuli predicting reward magnitude.

The involvement of the nucleus accumbens (NAc) in the determination of reaction times (RTs) of instrumental responses by the expectancy of future reward was investigated. A simple RT task demanding conditioned lever release was used, in which the upcoming reward magnitude (5 versus 1 pellet) was signalled in advance by discriminative cues. In rats which acquired the task, RTs of instrumental responses were significantly shorter to the discriminative cue predictive of high reward magnitude. Inactivation of the NAc by lidocaine had no effect on RTs and their determination by cue-associated reward magnitudes, and did not affect the rate of correct responses. In keeping with an earlier study, intra-NAc infusion of amphetamine decreased RTs, impaired RT determination by cue-associated reward magnitudes and reduced the rate of correct responses. The unexpected finding that lidocaine inactivation of the NAc had no effect parallels previous data showing that lesions of NAc did not impair RT performance, while manipulation of intra-NAc glutamate or dopamine transmission impaired various aspects of RT performance in comparable tasks. It is suggested that experimental manipulations such as transient and permanent inactivation, which almost completely inhibit NAc neuronal output, allow alternative routes to be used to effectively control behaviour in the task employed here.

Reverse microdialysis of a dopamine D2 receptor antagonist alters extracellular adenosine levels in the rat nucleus accumbens.

Recent evidence suggests that modulation of dopaminergic transmission alters striatal levels of extracellular adenosine. The present study used reverse microdialysis of the selective dopamine D(2) receptor antagonist raclopride to investigate whether a blockade of dopamine D(2) receptors modifies extracellular adenosine concentrations in the nucleus accumbens. Results reveal that perfusion of raclopride produced an increase of dialysate adenosine which was significant with a high (10 mM) and intermediate (1 mM) drug concentration, but not with lower drug concentrations (10 and 100 microM). Thus, the present study demonstrates that a selective blockade of dopamine D(2) receptors in the nucleus accumbens produced a pronounced increase of extracellular adenosine. The cellular mechanisms underlying this effect are yet unknown. It is suggested that the increase of extracellular adenosine might be related to a homeostatic modulatory mechanism proposed to be a key function of adenosine in response to neuronal metabolic challenges.

Effects of salient environmental stimuli on extracellular adenosine levels in the rat nucleus accumbens measured by in vivo microdialysis.

In the nucleus accumbens (NAc), the neuromodulator adenosine plays a major role in control of behaviour. The NAc subserves behaviour governed by salient stimuli in the environment, however, it is unknown whether such stimuli and the behavioural effects elicited are associated with changes in NAc extracellular adenosine levels. In order to further characterise the neuromodulatory actions of adenosine, the present study investigated for the first time the effects of four prototypical stimuli known to involve NAc processing on extracellular levels of adenosine in the NAc. Using in vivo microdialysis, the following stimuli were examined: (1) an appetitive, unfamiliar stimulus (palatable food), (2) an appetitive, familiar stimulus (standard laboratory food), (3) an aversive stimulus (handling) and (4) a novelty stimulus (cage change). Results revealed that neither of these stimuli significantly changed extracellular adenosine levels in the NAc. These findings demonstrate that NAc extracellular adenosine is not responsive to a number of prototypical salient stimuli in the environment. Thus the data provide no clues to suggest that transient changes of extracellular adenosine in the NAc modulate behavioural responses governed by these stimuli.

Catalepsy induced by a blockade of dopamine D1 or D2 receptors was reversed by a concomitant blockade of adenosine A(2A) receptors in the caudate-putamen of rats.

The present study sought to determine, in more detail, the effects of an unselective and a selective adenosine A(2A) receptor blockade on catalepsy induced by a blockade of dopamine D1 or D2 receptors in rats. The results demonstrated that systemic administration of the unselective A1/A2 receptor antagonist, theophylline and the selective A(2A) receptor antagonist, CSC potently reversed catalepsy induced by a systemic D2 receptor blockade with raclopride or by a bilateral blockade of D2 receptors in the caudate-putamen (CPu) with S(-)sulpiride. Likewise, systemic administration of theophylline and CSC reversed catalepsy induced by a systemic D1 receptor blockade with SCH23390; theophylline also counteracted catalepsy after an intra-CPu D1 receptor blockade with SCH23390. Intracerebral co-microinfusions of the selective A(2A) receptor antagonist, MSX-3 together with a D1 (SCH23390) or D2 receptor [S(-) sulpiride] antagonist revealed that catalepsy due to intra-CPu D1 or D2 receptor blockade can be potently reversed by an intra-CPu A2A receptor blockade. In conclusion, our results with systemic and intra-CPu drug administration demonstrate that D1 and D2 receptor-mediated catalepsy can both be reversed by a concomitant blockade of A(2A) receptors. Our results implicate that the CPu is a critical neural substrate for antagonistic interactions of a D1/D2 receptor blockade and an A(2A) receptor blockade in control of motor activity. The present results provide further support for the view that A(2A) receptor antagonists may be potential therapeutics for the treatment of Parkinson's disease.

NMDA and dopamine D2 receptors in the caudate-putamen are not involved in control of motor readiness in rats.

RATIONALE: In reaction time (RT) paradigms, in which a variable preparation interval preceded the imperative stimulus, RT become shorter as a function of increasing time from the start of a trial until presentation of the imperative stimulus. The shortening of RT as the preparatory foreperiod elapses reflects increasing motor readiness; however, the underlying neurochemical mechanisms are still poorly defined. OBJECTIVE: The present study investigated in rats whether signals transmitted via the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors and via dopamine D2 receptors in the caudate-putamen (CPu) are involved in motor readiness. METHODS: A simple RT task demanding conditioned lever release was used, in which the upcoming reward magnitude (5 pellets or 1 pellet) was signalled in advance by discriminative stimuli and the imperative stimulus was subsequently presented after a variable foreperiod (200, 500 or 800 ms). RESULTS: In intact rats, RT of conditioned responses was shortened with foreperiod lengthening and with expectancy of the high reward magnitude, but there was no interaction between both factors. Bilateral infusion of the competitive NMDA antagonist DL-2-amino-5-phosphonovaleric acid (APV) (2, 10 micrograms in 0.5 microliter/side), of the preferential dopamine D2 antagonist haloperidol (5, 12.5 micrograms in 0.5 microliter/side) or infusion of vehicle (0.5 microliter/side) into the central subregion of the CPu had no effect on progressive RT shortening with increasing foreperiod. CONCLUSION: The present data provide no clues to suggest that motor readiness relies on stimulation of dopamine D2 and NMDA receptors in the central CPu.

Facilitative effects of an adenosine A1/A2 receptor blockade on spatial memory performance of rats: selective enhancement of reference memory retention during the light period.

The present experiment was designed to examine the role of adenosine in spatial working and reference memory in rats using an 8-arm radial maze task which requires the integrity of the hippocampal formation. We investigated the effects of the unselective adenosine A1/A2 receptor antagonist theophylline on acquisition and retention of spatial working and reference memory. As there is evidence that brain extracellular adenosine levels vary significantly during the light-dark cycle, we tested the effects of theophylline both during the light and the dark period. Acquisition of the task was investigated for 10 consecutive days after rats received daily injections of vehicle or theophylline (15 mg/kg, intraperitoneally). Retention was tested in two nondrug sessions 7 and 14 days after completion of acquisition. The results demonstrate that in saline-treated control rats acquisition and retention of reference memory and, to a lesser extent, working memory was superior in the dark period. The results further revealed that daily administration of theophylline interacted with days to selectively enhance reference memory acquisition in the light, but not in the dark, period. In addition, reference memory retention was significantly enhanced in those rats who learned the task under theophylline treatment during the light period. Overall, the results show that in saline-treated control rats the effectiveness of acquisition and retention of spatial information in a radial maze strongly depends on the time of day. The higher levels of maze performance in the dark period might be related to a better functioning of involved brain systems in the active period of the rat. Furthermore, theophylline-induced blockade of adenosine A1/A2 receptors in the light, but not in the dark, period selectively enhanced reference memory acquisition and retention. Variations of brain extracellular adenosine levels during the light-dark cycle might account for the restriction of reference memory enhancing effects of theophylline to the light period.

Digoxin withdrawal in patients with dilated cardiomyopathy following normalization of ejection fraction with beta blockers.

BACKGROUND: The effect of withdrawal of digoxin on left ventricular function in patients with a history of idiopathic dilated cardiomyopathy (IDCM) following normalization of left ventricular ejection fraction (LVEF) with beta blockers remains unknown. HYPOTHESIS: This study was undertaken to determine the effect of digoxin withdrawal on left ventricular function in patients with IDCM. METHODS: In 8 consecutive patients with IDCM (5 men, 3 women) who had normalization of LVEF following beta-blocker treatment, digoxin was withdrawn as part of an office protocol. and LVEF was followed. Baseline EF prior to beta blocker initiation (carvedilol = 6, atenolol = 1, metoprolol 1) was measured with isotope ventriculography (IVG), echocardiography, or left ventriculography. Post beta blocker ejection fraction (post BB EF) was measured in all patients with IVG at a mean of 17.25 +/- 5.38 months. Follow-up EF was measured using IVG after digoxin withdrawal at a mean of 6.99 +/- 4.34 months. RESULTS: An experienced blinded reader interpreted the IVG scans. Baseline EF was 28.5 +/- 8.26; post BB EF and follow-up EF were 56.1 +/- 4.65 and 51.0 +/- 7.35, respectively (p = 0.05). CONCLUSION: These data provide potential evidence that digoxin withdrawal can result in a small but significant reduction in LVEF in patients with IDCM who had normalization of LVEF after treatment with beta blockers. Mean LVEF, however, remained within normal (> 50%) on beta-blocker therapy and without digitalis. Large, randomized controlled trials are needed to confirm these findings.

NMDA, but not dopamine D(2), receptors in the rat nucleus accumbens areinvolved in guidance of instrumental behavior by stimuli predicting reward magnitude.

Expectancy of future reward is an important factor guiding the speed of instrumental behavior. The present study sought to explore whether signals transmitted via the NMDA subtype of glutamate receptors and via dopamine D(2) receptors in the nucleus accumbens (NAc) are critical for the determination of reaction times (RTs) of instrumental responses by the expectancy of future reward. A simple RT task for rats demanding conditioned lever release was used in which the upcoming reward magnitude (5 or 1 pellet) was signaled in advance by discriminative stimuli. In trained rats, RTs of conditioned responses with expectancy of a high reward magnitude were found to be significantly shorter. The shortening of RTs by stimuli predictive of high reward to be obtained was dose-dependently impaired by bilateral intra-NAc infusion of the competitive NMDA antagonist dl-2-amino-5-phosphonovaleric acid (APV) (1, 2, or 10 microg in 0.5 microl/side), but not by infusion of the preferential dopamine D(2) antagonist haloperidol (5 and 12.5 microg in 0.5 microl/side) or by infusion of vehicle (0.5 microl/side). In conclusion, the data reveal that in well trained animals stimulation of intra-NAc NMDA, but not of dopamine D(2), receptors, is critically involved in guiding the speed of instrumental responses according to stimuli predictive of the upcoming reward magnitude.

Dopamine release in the rat globus pallidus characterised by in vivo microdialysis.

Brain microdialysis has been used to examine the in vivo effects of potassium and calcium on dopamine release in the dorsal globus pallidus (GP) of rats. Furthermore, the effects of food presentation and consumption on dopamine release in the GP were investigated. Basal dopamine levels in the GP were below the detection limit, therefore nomifensine (30 microM) was added to the perfused artificial cerebrospinal fluid (aCSF). A prominent increase of dopamine release to 370% was observed after perfusion with elevated potassium (100 mM), while perfusion with calcium-free aCSF produced a significant decrease of dopamine efflux to 36% of control levels. Furthermore, presentation and consumption of food resulted in a rapid increase of extracellular dopamine to 130%. The present experiments demonstrate that in the GP extracellular dopamine can be measured by in vivo brain microdialysis. The data suggest that the dopamine release in the GP can be stimulated by a depolarising agent and involves a partially calcium-dependent release mechanism. The data further suggest that dopamine in basal ganglia structures downstream the striatum as the GP is involved in signalling of important stimuli in the environment, e.g. food.

Dopamine D1 or D2 receptor blockade in the globus pallidus produces akinesia in the rat.

In the present study, the involvement of dopamine D1 and D2 receptors in the dorsal globus pallidus (GP) in motor control was investigated in rats. Results show that bilateral microinfusions of the dopamine D1 receptor antagonist SCH23390 or the dopamine D2 antagonist S( - )-sulpiride into the GP induced akinesia determined by means of the catalepsy test. These findings indicate that pallidal dopamine D1 and D2 receptors are critically involved in the control of motor behaviour. The findings further imply that defective dopaminergic transmission in the GP might contribute to akinesia due to lesion- or drug-induced dopamine hypofunction in experimental animals and in neurodegenerative diseases, e.g. Parkinson's disease, affecting the nigrostriatal dopamine system.

Blockade of dopamine D2, but not of D1 receptors in the rat globus pallidus induced Fos-like immunoreactivity in the caudate-putamen, substantia nigra and entopeduncular nucleus.

In the present study, we investigated Fos-like immunoreactivity (FLI) evoked by pallidal dopamine (DA) D1 and D2 receptor blockade in the caudate-putamen (CPu), substantia nigra (SN) and entopeduncular nucleus (EP), i.e. major target areas of pallidal efferents. Results demonstrate that infusion of the selective D1 antagonist SCH23390 (1 and 4 microg/0.5 microl) into the globus pallidus (GP) did not induce FLI in the CPu, SN and EP. In contrast, intrapallidal infusion of a low dose of the selective D2 antagonist S(-)-sulpiride (15 microg/0.5 microl) induced FLI restricted to the CPu. A higher dose of intrapallidal S(-)-sulpiride (25 microg/0.5 microl) induced FLI in the CPu as well as in the SN and EP. These findings add further evidence to notion that the GP plays a central role in the basal ganglia circuitry and demonstrate an involvement of extrastriatal DA via D2 receptors.

Regulation of sensorimotor gating by interactions of dopamine and adenosine in the rat.

Prepulse inhibition (PPI) of the acoustic startle response is a behavioural tool used to assess sensorimotor gating processes and its disturbances in rats and in humans. PPI in rats is reduced by an overactivity of the dopamine (DA) system. Because there are functional interactions between DA and adenosine receptors, we tested whether PPI can be influenced by the mixed DA receptor agonist apomorphine (APO) and by the unselective adenosine antagonist theophylline (THEO). Combined administration of APO (0.5 mg/kg, i.p.) and THEO (20 mg/kg, i.p.) in doses devoid of significant effects on their own significantly reduced PPI. The PPI-disrupting effect of the combined THEO plus APO treatment was dose-dependently antagonized by co-administration of the selective adenosine A1 agonist CPA (0.15-1.5 mg/kg, i.p.), but not by the A2A agonist CGS21680 (0.1-2 mg/kg, i.p.). These data demonstrate that antagonistic interactions between DA and adenosine, involving adenosine A1 receptors, play an important role in the regulation of PPI. The possible implications of these findings for the use of adenosine agonists in the treatment of schizophrenia are discussed.

Involvement of basal ganglia transmitter systems in movement initiation.

The basal ganglia have been implicated in a number of important motor functions, in particular in the initiation of motor responses. According to the current model of basal ganglia functions, motor initiation is supposed to be associated with an inhibition of basal ganglia output structures (substantia nigra pars reticulata/entopeduncular nucleus) which, in turn, might be brought about by corresponding striatal activity changes conveyed via direct and indirect intrinsic pathways to the substantia nigra pars reticulata and the entopeduncular nucleus. Rodent studies using neuropharmacological manipulations of basal ganglia transmitter systems by neurotoxins or drugs provide converging evidence that dopamine within the caudate-putamen, but also within extrastriatal basal ganglia nuclei, is involved in motor initiation by modulating the activity of direct and indirect intrinsic pathways. However, the striatal segregation of dopamine D1 and D2 receptors in control of the direct and indirect projection neurons seems not to be maintained throughout the basal ganglia. In dopamine intact animals, striatal glutamate plays a major role in response initiation probably through actions on striatopallidal neurons involving N-methyl-D-aspartate, but not alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors. Striatal adenosine might also contribute to movement initiation by acting on adenosine A2A receptors located on striatopallidal neurons. Analysis of two integral parts of the indirect pathway revealed that inactivation of the subthalamic nucleus was found to facilitate response initiation, while inactivation of the globus pallidus resulted in facilitation as well as inhibition of response initiation indicating a complex contribution of this latter nucleus. Glutamate and gamma-amino-butyric acid (GABA) controlling the activity of the substantia nigra pars reticulata could be involved in control of response initiation in a way predicted by the simplified model of basal ganglia functions. In contrast, the role of the entopeduncular nucleus in response initiation and its control through GABA and glutamate is at variance with this hypothesis, suggesting functional differences of the output structures. Taken together, neurochemical systems of the basal ganglia significantly contribute to intact response initiation by mechanisms which are only partly consistent with predictions of the current functional scheme of the basal ganglia. This suggests that a more complex model is required to account for these disparate findings.

The effects of globus pallidus lesions on dopamine-dependent motor behaviour in rats.

Motor effects of bilateral lesions of the globus pallidus induced by quinolinic acid (30 and 60 nmol in 0.5 microl) were investigated in rats. Globus pallidus lesions with 60 nmol quinolinic acid produced a significant reduction of spontaneous motor activity measured by a reduced locomotor activity in an open field and by a reduced sniffing activity in an experimental chamber. In addition, D-amphetamine (1 mg/kg, i.p.)-induced hyperlocomotion and D-amphetamine (3 mg/kg, i.p.)-induced stereotyped sniffing were significantly reduced in animals with quinolinic acid lesions (60 nmol). Globus pallidus lesions with 60 nmol quinolinic acid potently reversed catalepsy induced by systemic administration of the dopamine D1 receptor antagonist SCH23390 (0.75 and 1 mg/kg, i.p.) or the dopamine D2 receptor antagonist raclopride (1.25 and 5 mg/kg, i.p.), while lesions with 30 nmol quinolinic acid exerted anti-cataleptic effects which were only partly significant. In line with current models of basal ganglia functions, these findings indicate that inactivation of the globus pallidus reduced spontaneous motor activity and motor hyperactivity after dopamine receptor stimulation. However, the present data also demonstrate that inactivation of the globus pallidus reversed motor hypoactivity induced by a blockade of dopamine D1 and D2 receptors. Therefore, a more complex functional model of the globus pallidus is required to account for the opposite effects on motor behaviour observed after lesions of this basal ganglia nucleus.

Motor effects induced by a blockade of adenosine A2A receptors in the caudate-putamen.

Motor effects mediated through adenosine A2A receptors within the caudate-putamen were investigated in rats using bilateral microinfusions of MSX-3 (9 microg in 1 microl per side), a water-soluble phosphate prodrug of the selective A2A receptor antagonist MSX-2. Blockade of striatal A2A receptors produced a significant motor stimulation measured by an enhanced sniffing activity. Furthermore, catalepsy induced by systemic dopamine D1 (0.75 mg/kg SCH23390, i.p.) or dopamine D2 receptor blockade (1.5 mg/kg raclopride, i.p.) was potently reversed. These findings suggest that A2A receptors within the caudate-putamen are tonically activated by endogenous adenosine and that a striatal A2A receptor blockade produces motor stimulant effects, in particular in animals with dopamine hypofunction. The present results support the view that A2A receptor antagonists may be potentially useful therapeutics for the treatment of Parkinson's disease.

Blockade of subthalamic dopamine D1 receptors elicits akinesia in rats.

The role of dopamine in the subthalamic nucleus to control motor behaviour was investigated in rats using bilateral microinfusions of the dopamine D1 receptor antagonist SCH23390 and the dopamine D2 receptor antagonist S(-)-sulpiride. Selective blockade of subthalamic D1 receptors, but not of D2 receptors, produced catalepsy. These findings suggest that dopamine D1 receptors within the subthalamic nucleus play a prominent role in the regulation of motor functions. Furthermore, the data point to the possibility that a reduced dopaminergic tone at subthalamic dopamine D1 receptors might contribute to akinesia in Parkinson's disease.