Chronic haloperidol treatment leads to an increase in the intramembrane interaction between adenosine A2 and dopamine D2 receptors in the neostriatum

Abstract

Stimulation of adenosine A2 receptors (with the selective adenosine A2 agonist CGS 21680) in rat striatal membrane preparations, produces a decrease in both the affinity of D2 receptors and the transduction of the signal from the D2 receptor to the G protein. This intramembrane A2-D2 interaction might be responsible for the behavioural depressant effects of adenosine agonists and for the behavioural stimulant effects of adenosine antagonists such as caffeine and theophylline. Dopamine denervation induces an increase in the intramembrane A2-D2 interaction, which may underlie the observed higher sensitivity to the behavioural effects induced by adenosine antagonists found in these animals. The present study was designed to examine if chronic treatment with haloperidol, which also produces dopamine receptor supersensitivity, is also associated with an increase in the intramembrane A2-D2 interaction in the neostriatum and with a higher sensitivity to the behavioural effects induced by adenosine antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine A2A Agonists: A Potential New Type of Atypical Antipsychotic

“…Therefore, it was also proposed that adenosine A 2 , agonists could be used in combination with dopamine D 2 antagonists, to reduce the incidence of extrapyramidal side effects (Ferre et al 1994b). Finally, prolonged treatment with the typical antipsychotic haloperidol, but not with the atypical antipsychotic clozapine, was associated with an increased antagonistic A 2 A-D 2 interaction and with an upregulation of both dopamine D 2 and adenosine A 2 A receptors in the rat striatum (Ferre et al 1994c;Parsons et al 1995). It was suggested that the increased A 2 , receptor function could be an endogenous protective mechanism which could avoid the development of extrapyramidal side effects (Ferre et al 1994c), which have been proposed to correlate with the upregulation of striatal dopamine D 2 receptors (Klawans and Rubovits 1972).…”

“…Finally, prolonged treatment with the typical antipsychotic haloperidol, but not with the atypical antipsychotic clozapine, was associated with an increased antagonistic A 2 A-D 2 interaction and with an upregulation of both dopamine D 2 and adenosine A 2 A receptors in the rat striatum (Ferre et al 1994c;Parsons et al 1995). It was suggested that the increased A 2 , receptor function could be an endogenous protective mechanism which could avoid the development of extrapyramidal side effects (Ferre et al 1994c), which have been proposed to correlate with the upregulation of striatal dopamine D 2 receptors (Klawans and Rubovits 1972). Therefore, it was postulated that A 2 A receptor agonists could also be useful for the treatment of the neuroleptic-induced extrapyramidal side effects (Ferre et al 1994c).…”

Subchronic Caffeine Exposure Induces Sensitization to Caffeine and Cross-Sensitization to Amphetamine Ipsilateral Turning Behavior Independent from Dopamine Release

“…Manipulation of the dopamine system, such as dopamine neuron denervation or chronic haloperidol, have been shown to lead to an increase in intramembrane interaction between adenosine A 2A and dopamine D 2 receptors in the striatum (Ferré and Fuxe, 1992;Ferré et al, 1994). On this basis, we hypothesize that after repeated caffeine administration, long-term modifications at the level of the A 2A receptor or its second messenger might lead to an increase in A 2A receptor sensitivity and as a consequence, in the D 2 receptor leading to the sensitized ipsilateral turning observed after caffeine and amphetamine.…”

“…The basis for this reciprocal influence are attributed to the negative interaction between dopamine D 1 and D 2 receptors and adenosine A 1 and A 2A receptors that are blocked by caffeine (Ferré et al, 1997;Fredholm et al, 1999). Caffeine and theophylline acutely potentiate the motor-activating effects induced by dopamine receptor agonists (Ferré et al, 1991;Fredholm et al, 1983;Garrett and Griffiths, 1997;Kuribara, 1994;Misra et al, 1986) and reverse catalepsy induced by dopamine receptor antagonists (Hauber et al, 2001;Malec, 1997;Mandhane et al, 1997), whereas sensitization or upregulation of dopamine receptors sensitize rats to the motor-activating effect induced by caffeine or theophylline (Fenu et al, 2000;Fenu and Morelli, 1998;Ferré et al, 1994).…”

The 5' Untranslated Regions of the Rat A2A Adenosine Receptor Gene Function as Negative Translational Regulators

“…In the central nervous system, expression of A 2A -R is transiently regulated in various areas in developing rat brain (Weaver, 1993), suggesting that adenosine may play an important role in brain development by interacting, at least partly, with transiently expressed A 2A -R. Soon after neurogenesis, the transcript of the rat A 2A -R gene is heavily expressed by striatal neurons (Weaver, 1993) and colocalizes with the D2 dopamine receptor in the GABAergic striopallidal neurons (Ferre et al, 1993). Various lines of evidence suggest a powerful antagonistic A 2A -D2 interaction in the striatum (Ferre et al, 1994). Antagonists of A 2A -R were therefore proposed to have potential clinical application for treating Parkinson's disease (Richardson et al, 1997).…”