Dopamine/adenosine interactions related to locomotion and tremor in animal models: possible relevance to parkinsonism.

Adenosine A(2A) antagonists can exert antiparkinsonian effects in animal models. Recent experiments studied the ability of MSX-3 (an adenosine A(2A) antagonist) to reverse the locomotor suppression and tremor produced by dopamine antagonists in rats. MSX-3 reversed haloperidol-induced suppression of locomotion, and reduced the tremulous jaw movements induced by haloperidol, pimozide, and reserpine. Infusions of MSX-3 into the nucleus accumbens core increased locomotion in haloperidol-treated rats, but there were no effects of infusions into the accumbens shell or ventrolateral neostriatum. In contrast, MSX-3 injected into the ventrolateral neostriatum reduced pimozide-induced tremulous jaw movements. Dopamine/adenosine interactions in different striatal subregions are involved in distinct aspects of motor function.

Tremorolytic effects of adenosine A2A antagonists: implications for parkinsonism.

Drug-induced tremulous jaw movements in rats have been used as a model of parkinsonian tremor. Because adenosine A2A antagonists have antiparkinsonian effects, the present experiments were conducted to study the ability of adenosine A2A antagonism to reverse the tremulous jaw movements produced by the antipsychotic drugs pimozide, haloperidol and reserpine. In one group of studies, rats received daily injections of the dopamine antagonist pimozide, and on day 8 they received injections of pimozide plus various doses of the A2A antagonists KW 6002 or MSX-3. KW 6002 and MSX-3 suppressed pimozide-induced tremulous jaw movements, reduced catalepsy, and increased locomotion. MSX-3 also suppressed the jaw movements induced by haloperidol and reserpine. In addition, local injections of MSX-3 into the ventrolateral neostriatum suppressed pimozide-induced tremulous jaw movements. Thus, adenosine A2A antagonism can reverse the tremulous movements induced by antipsychotic drugs, which is consistent with the hypothesis that antagonism of adenosine A2A receptors can result in antiparkinsonian effects. Adenosine A2A antagonists may be useful for their tremorolytic effects, and may help in treating both idiopathic and antipsychotic-induced parkinsonian symptoms.

Injections of the selective adenosine A2A antagonist MSX-3 into the nucleus accumbens core attenuate the locomotor suppression induced by haloperidol in rats.

There is considerable evidence of interactions between adenosine A2A receptors and dopamine D2 receptors in striatal areas, and antagonists of the A2A receptor have been shown to reverse the motor effects of DA antagonists in animal models. The D2 antagonist haloperidol produces parkinsonism in humans, and also induces motor effects in rats, such as suppression of locomotion. The present experiments were conducted to study the ability of the adenosine A2A antagonist MSX-3 to reverse the locomotor effects of acute or subchronic administration of haloperidol in rats. Systemic (i.p.) injections of MSX-3 (2.5-10.0 mg/kg) were capable of attenuating the suppression of locomotion induced by either acute or repeated (i.e., 14 day) administration of 0.5 mg/kg haloperidol. Bilateral infusions of MSX-3 directly into the nucleus accumbens core (2.5 microg or 5.0 microg in 0.5 microl per side) produced a dose-related increase in locomotor activity in rats treated with 0.5 mg/kg haloperidol either acutely or repeatedly. There were no overall significant effects of MSX-3 infused directly into the dorsomedial nucleus accumbens shell or the ventrolateral neostriatum. These results indicate that antagonism of adenosine A2A receptors can attenuate the locomotor suppression produced by DA antagonism, and that this effect may be at least partially mediated by A2A receptors in the nucleus accumbens core. These studies suggest that adenosine and dopamine systems interact to modulate the locomotor and behavioral activation functions of nucleus accumbens core.

Suppression of food intake and food-reinforced behavior produced by the novel CB1 receptor antagonist/inverse agonist AM 1387.

Cannabinoid CB1 receptor antagonist/inverse agonists are becoming increasingly recognized for their potential therapeutic utility as appetite suppressants. In the current paper we characterize the biochemical and behavioral effects of AM 1387, which is a novel CB1 antagonist. AM 1387 exhibited binding affinity and selectivity for the CB1 over the CB2 receptor. Moreover, AM 1387 decreased GTPgammaS (EC50: 22.82 nM) and increased forskolin-stimulated cAMP (EC50: 274.6 nM), as did the CB1 inverse agonist AM 251 (GTPgammaS EC50: 25.82 nM; cAMP EC50: 363.8 nM), indicating that AM1387 also has inverse agonist properties in vitro. In the behavioral characterization in rats, AM 1387 suppressed lever pressing for food on two operant schedules (fixed-ratio 1 and 5). Timecourse of the effect on fixed-ratio 5 responding was then determined, and the half-life (t1/2=4.87 h) was found to be threefold shorter than what has been shown for SR 141716A, and fourfold shorter than AM 251. Finally, AM 1387 was found to suppress food intake using three diets of differing macronutrient composition and palatability. It was concluded that AM 1387 may be a useful tool for examining the effects of CB1 receptor antagonism or inverse agonism on food intake.

Ratio and time requirements on operant schedules: effort-related effects of nucleus accumbens dopamine depletions.

Accumbens dopamine (DA) depletions produce deficits that are related to the ratio requirement of the operant schedule; however, it is also possible that time without reinforcement is a factor. The present study examined the effects of accumbens DA depletions in rats using variable interval (VI) schedules with additional fixed ratio (FR) requirements. Four VI schedules were used (VI 60/FR 1, VI 120/FR 1, VI 60/FR 10, VI 120/FR 10). Attachment of the additional work requirement increased response rates under control conditions. After surgery, there was no interaction between interval level (i.e. 60 vs. 120 s) and DA depletion, but there was a significant interaction between ratio requirement (i.e. 1 vs. 10) and DA depletion within the first week after surgery. DA depletions substantially impaired performance on the schedules with added FR 10 requirements, an effect that was largely dependent upon a reduction in fast responses (i.e. inter-response times less than 1.0 s). There was little effect of DA depletion on overall responding on VI 60/FR 1 and VI 120/FR 1 schedules. DA depletions also increased the tendency to take long pauses in responding (i.e. > 20.0 s), and this effect was evident across all schedules tested. Thus, accumbens DA depletions interact with work requirements and blunt the rate-enhancing effects of moderate size ratios, and also enhance the tendency to pause. Attachment of ratio requirements to interval schedules is a work-related response cost that provides a challenge to the organism, and DA in nucleus accumbens appears to be necessary for adapting to this challenge.