1,721,222 research outputs found
Adenosine A2A antagonists: potential preventive and palliative treatment for Parkinson's disease
No full textDopamine/glutamate interaction as studied by combining turning behaviour and c-Fos expression
No full textDopamine (DA) and glutamate N-methyl-d-aspartate (NMDA) receptors extensively interact in the mediation of motor behaviours originated in basal ganglia. In unilaterally 6-hydroxydopamine (6-OHDA) lesioned rats, this interaction is of a different sign depending on whether D1 or D2 receptors are stimulated. Contralateral turning behaviour induced by D1 agonists is potentiated by the NMDA antagonist MK 801, while turning behaviour induced by D2 agonists is decreased. NMDA receptors not only modulate the acute turning behaviour induced by DA agonists but also the long-term effects induced by stimulation of DA receptors. MK 801, in fact, prevents the sensitization (priming) of D1-mediated turning behaviour induced by a single exposure to a DA agonist. Prevention of priming by MK 801, also appears to be different depending on whether D1 or D2 receptors are stimulated. Studies on c-fos expression induced by DA D1 agonists in the 6-OHDA lesioned striatum show that detection of Fos-like immunoreactivity correlates to the long-term but not the acute effects induced by DA receptor stimulation and NMDA receptor blockade
Differential induction of Fos-like-immunoreactivity in the extended amygdala after haloperidol and clozapine
No full textThe extended amygdala is composed of the central and medial amygdaloid nucleus which through the sublenticular extended amygdala (SLEA) and the interstitial nucleus of the posterior limb of the anterior commissure (IPAC) merge into the bed nucleus of stria terminals (BST). Based on anatomical connections with limbic areas, the extended amygdala has been proposed to play an important role in cognitive and affective processes. This study examines the effect of the atypical antipsychotic clozapine and the classical antipsychotic haloperidol on Fos-like-immunoreactivity (FLI) induction in areas belonging to the extended amygdala. Acute administration of clozapine (10-20 mg/kg) induced FLI in the central amygdaloid nucleus, IPAC, SLEA, and BST lateral division and, as previously described, in areas connected to the extended amygdala, such as the prefrontal cortex and nucleus accumbens shell. In contrast, acute administration of haloperidol (0.1-1 mg/kg) failed to induce FLI in the BST lateral division and SLEA but increased FLI in the IPAC. A small increase in FLI was observed in the central amygdaloid nucleus after 0.1 but not after 1 mg/kg of haloperidol. The present results, showing a preferential influence of clozapine, as compared to haloperidol, in the extended amygdala propose a new brain structure involved in the pharmacological effects of atypical antipsychotics
Role of dopamine receptors in the induction and expression of rotational behavior induced by caffeine in 6-hydroxydopamine-lesioned rats
No full textIn order to define the role of dopamine receptors in the contralateral rotational behavior induced by caffeine in unilaterally 6-hydroxydopamine-lesioned rats, we evaluated the influence of previous exposure (priming) to dopamine receptor agonists and the effect of dopamine receptor blockade on the rotational behavior induced by caffeine. 6-Hydroxydopamine-lesioned rats received single or repeated administrations of the D1/D2 receptor agonist apomorphine (0.3 mg/kg s.c.) (primed) or vehicle (drug-naive). Three days later all rats received caffeine (30 mg/kg s.c.). Drug-naive and single-primed rats did not rotate in response to caffeine, whereas rats repeatedly primed with apomorphine rotate contralaterally. When apomorphine priming was paired to the environment (hemispherical bowls) where rats received caffeine, rotational behavior was significantly higher than that obtained in rats primed in an unpaired environment (cylinders). Repeated priming with the D2/D3 receptor agonist quinpirole (0.2 mg/kg s.c.) Induced a totally context-dependent contralateral rotation in response to caffeine, while caffeine contralateral rotation was not dependent on the context after repeated priming with the D1 agonist SKF 38393 (3 mg/kg s.c.). Caffeine context-dependent rotational behavior was antagonized by either D1 or D2 receptor antagonists SCH 23390 (0.03 mg/kg s.c.) And eticlopride (0.03 mg/kg s.c.), whereas caffeine context-independent rotation was not antagonized by SCH 23390 or eticlopride. The results show that: 1) caffeine does not induce any contralateral rotation in drug-naive 6-hydroxydopamine-lesioned rats; 2) repeated priming with a dopamine agonist enables caffeine to induce contralateral rotation; this rotation is, however, dependent on the context when D2 receptors are stimulated; 3) caffeine context-dependent contralateral rotation is counteracted by dopamine antagonists, whereas context-independent rotation is not antagonized by dopamine receptor blockad
Subchronic caffeine administration sensitizes rats to the motor activating effects of dopamine D1 and D2 receptor agonists
No full textRATIONALE:
Dopamine transmission acting at either the D(1) or D(2) receptor level is known to influence the stimulant properties of caffeine, an antagonist of adenosine A(1) and A(2) receptors. In contrast, how caffeine influences the motor stimulant properties of selective D(1) and D(2) receptor agonists is still undefined.
OBJECTIVES:
In this study the acute motor response to the dopamine D(1) receptor agonist SKF 77434 and the D(2)/D(3) receptor agonist quinpirole was studied in rats treated subchronically with caffeine (15 mg/kg i.p., on alternate days) or vehicle, either in the test cage (paired group) or in the home cage (home group).
METHODS AND RESULTS:
Repeated caffeine administration did not induce any significant increase in motor activity or in stereotyped behavior during the course of treatment, indicating that the response to caffeine itself did not develop sensitization. Three days after the last caffeine or vehicle administration, rats were challenged with caffeine, SKF 77434, or quinpirole. Caffeine (5 mg/kg i.p.) elicited the same motor stimulant effects in both caffeine- and vehicle-pretreated rats, confirming the presence of neither tolerance nor sensitization to caffeine itself. SKF 77434 (3 mg/kg s.c.) elicited a higher locomotor activation in caffeine- than in vehicle-pretreated rats, whereas quinpirole (0.15 mg/kg s.c.) induced a similar locomotor activation and a higher stereotyped behavior in caffeine-pretreated rats as compared to rats pretreated with vehicle. The sensitized response to SKF 77434 and quinpirole was not due to environmental conditioning since the responses were similar in either paired or home group.
CONCLUSIONS:
The results provide support for the presence of long-term functional interactions between drugs acting at the adenosine and dopamine receptor levels. Subchronic caffeine, by sensitizing the motor stimulant effects of dopamine D(1) and D(2) receptor agonists, produces adaptive changes which might result in a potentiation of the dopaminergic component of drugs of abuse
Modulation by adenosine A2A receptors of dopamine-mediated motor behavior as a basis for antiparkinson's disease drugs
No full textSeveral studies have evidenced the opposite role played by dopamine and adenosine receptors in the control of motor behavior. In line with those studies, we have previously shown that the acute administration of the A2A receptor antagonist SCH 58261 potentiated the turning behavior induced by L-DOPA in the unilateral 6-hydroxydopamine (6-OHDA) rat model of Parkinson’s disease (PD), suggesting that selective adenosine A2A receptor antagonists might be useful as adjuncts to L-DOPA therapy. One of the most important problems in the treatment of PD is to find a drug regimen effective after chronic administration and devoid of dyskinesia-like side effects. Previous studies have shown that the sensitized turning response, developed in 6-OHDA-lesioned rats after chronic intermittent L-DOPA, is a useful model of dyskinesia. In the present study, we evaluated the effect of a chronic administration of SCH 58261 alone or in combination with L-DOPA in 6-OHDA lesioned rats in order to verify the effectiveness of SCH 58261 after repeated administration and its dyskinetic potential. Repeated administration of SCH 58261 (5 mg/kg) did not produce tolerance to its ability to potentiate L-DOPA-turning behavior. Moreover, chronic intermittent SCH 58261 (5 mg/kg) plus L-DOPA produced a stable turning behavior response during the course of the treatment, whereas L-DOPA alone produced a progressive increase in turning behavior intensity and duration (sensitization). These results suggest that SCH 58261 is effective in potentiating L-DOPA-induced turning behavior even after a chronic treatment and it does not produce, in combination with L-DOPA, motor response alterations. A2A receptor antagonists could be a new and useful tool for the treatment of P
Caffeine and the dopaminergic system
No full textCaffeine is the most widely consumed psychostimulant substance, being self-administered throughout a wide range of conditions and present in numerous dietary products. Due to its widespread use and low abuse potential, caffeine is considered an atypical drug of abuse. The main mechanism of action of caffeine occurs via the blockade of adenosine A1 and A2A receptors. Adenosine is a modulator of CNS neurotransmission and its modulation of dopamine transmission through A2A receptors has been implicated in the effects of caffeine. This review provides an updated summary of the results reported in the literature concerning the behavioural pharmacology of caffeine and the neurochemical mechanisms underlying the psychostimulant effects elicited by caffeine. The review focuses on the effects of caffeine mediated by adenosine A2A receptors and on the influence that pre-exposure to caffeine may exert on the effects of classical drugs of abuse
A critical evaluation of behavioral rodent models of motor impairment used for screening of antiparkinsonian activity: The case of adenosine A2A receptor antagonists
No full textAnimal models of motor dysfunction constitute the basis for the screening of new drugs with potential efficacy in diseases characterized by motor impairment, such as Parkinson’s Disease (PD). Taking adenosine A2A receptor antagonists as an example of a new class of drugs for PD, the review will examine the most utilized rodent models of motor impairment and the results reported in the literature with this class of drugs. The results obtained so far in rodent models of PD suggested that A2A receptor antagonists might have symptomatic therapeutic efficacy in PD. They may ameliorate initiation of movement, gait and muscle rigidity, sensorimotor integration deficits, and tremor. Moreover, A2A receptor antagonists when administered with a low sub-threshold dose of l-DOPA potentiated its efficacy. However, the clinical trials so far performed have evaluated their efficacy in the “ON/OFF” of PD patients with motor complications, showing a limited efficacy of this class of drug. Therefore, on one hand, animal models of PD might have a limited validity; on the other hand, clinical trials should explore the efficacy of A2A receptor antagonists on a broader range of parkinsonian conditions
Interaction between dopamine and adenosine A2A receptors as a basis for the treatment of Parkinson's disease
No full textThe adenosine A2A receptor antagonist SCH 58261 increases the turning behavior induced by L-dopa in unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats. In this study we have evaluated the effect of a chronic intermittent administration of L-dopa or SCH 58261 plus L-dopa on turning behaviour. Chronic intermittent administration of SCH 58261 plus L-dopa produced a stable turning behavior during the course of the treatment, whereas L-dopa alone produced a progressive increase in turning behavior. Moreover, repeated administration of SCH 58261 failed to produce tolerance to its ability to potentiate L-dopa-induced turning behavior. The results indicate that SCH 58261 is effective after chronic administration and suggest that SCH 58261 plus L-dopa, differently from L-dopa alone, does not produce alterations in motor responses during the course of the treatment
Repeated amphetamine administration and long-term effects on 50-kHz ultrasonic vocalizations: possible relevance to the motivational and dopamine-stimulating properties of the drug
No full textUltrasonic vocalizations (USVs) of 50kHz are thought to indicate positive affective states in rats, and are increasingly being used to investigate the motivational properties of drugs of abuse. However, previous studies have observed that only dopaminergic psychostimulants of abuse, but not other addictive drugs, stimulate 50-kHz USVs immediately after their administration. This would suggest that 50-kHz USVs induced by addictive dopaminergic psychostimulants might reflect rewarding dopaminergic effect, rather than motivational effect. To elucidate this issue, our study compared the effects of the psychostimulant of abuse amphetamine and the dopamine receptor agonist apomorphine on 50-kHz USVs. Rats that received five drug administrations on alternate days in a novel test-cage, were first re-exposed to the test-cage 7 days after treatment discontinuation to assess drug-conditioning, and then received a drug challenge. USVs were recorded throughout the experiments together with locomotor activity. To further clarify how amphetamine and apomorphine influenced 50-kHz USVs, rats were subdivided into “low” and “high” vocalizers, and time-dependence of drug effects was assessed. Amphetamine and apomorphine stimulated both 50-kHz USVs and locomotor activity, though they elicited dissimilar changes in these behaviors, depending on drug dose, rats’ individual predisposition to vocalize, and time. Moreover, only amphetamine-treated rats displayed both sensitized 50-kHz USVs emission and conditioned vocalizations on test-cage re-exposure. These results indicate that the effects of amphetamine on 50-kHz USVs are not mimicked by a dopaminergic agonist with a low abuse potential, and may further support the usefulness of 50-kHz USVs in the study of the motivational properties of psychoactive drugs
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