Persistent Behavioral Sensitization to Chronic l-DOPA Requires A_2AAdenosine Receptors

Abstract

To investigate the role of A 2A adenosine receptors in adaptive responses to chronic intermittent dopamine receptor stimulation, we compared the behavioral sensitization elicited by repeated L-DOPA treatment in hemiparkinsonian wild-type (WT) and A 2A adenosine receptor knock-out (A 2A KO) mice. Although the unilateral nigrostriatal lesion produced by intrastriatal injection of 6-hydroxydopamine was indistinguishable between WT and A 2A KO mice, they developed strikingly different patterns of behavioral sensitization after daily treatment with low doses of L-DOPA for 3 weeks. WT mice initially displayed modest contralateral rotational responses and then developed progressively greater responses that reached a maximum within 1 week and persisted for the duration of the treatment. In contrast, any rotational behavioral sensitization in A 2A KO mice was transient and completely reversed within 2 weeks. Similarly, the time to reach the peak rotation was progressively shortened in WT mice but remained unchanged in A 2A KO mice. Furthermore, daily L-DOPA treatment produced gradually sensitized grooming in WT mice but failed to induce any sensitized grooming in A 2A KO mice. Finally, repeated L-DOPA treatment reversed the 6-OHDA-induced reduction of striatal dynorphin mRNA in WT but not A 2A KO mice, raising the possibility that the A 2A receptor may contribute to L-DOPA-induced behavioral sensitization by facilitating adaptations within the dynorphinexpressing striatonigral pathway. Together these results demonstrate that the A 2A receptor plays a critical role in the development and particularly the persistence of behavioral sensitization to repeated L-DOPA treatment. Furthermore, they raise the possibility that the maladaptive dyskinetic responses to chronic L-DOPA treatment in Parkinson's disease may be attenuated by A 2A receptor inactivation. Key words: A 2A adenosine receptor; L-DOPA; behavioral sensitization; Parkinson's disease; dyskinesia; dynorphinFor Ͼ30 years the dopamine precursor L-DOPA has been the most effective and commonly prescribed treatment for Parkinson's disease (PD). Despite its considerable symptomatic motor benefit, chronic administration of L-DOPA leads to abnormal motor responses known as dyskinesias, involving involuntary choreic or dystonic movements in Ͼ50% of patients (5 years after the initiation of the treatment) (Chase, 1998;Obeso et al., 2000). Such shortcomings of L-DOPA and other dopaminergic drugs have prompted a search for alternative treatment strategies that provide symptomatic benefits while avoiding the delayed motor complications associated with the long-term use of antiparkinsonian drugs. Several neurotransmitters have been implicated in the motor complications elicited by repeated dopamine receptor stimulation, including glutamate (Marin et al., 1996;Tzschentke and Schmidt, 1998;Calabresi et al., 2000), cannabinoids (Souilhac et al., 1995;Zeng et al., 1999), opioids (Henry and Brotchie, 1996), and adenosine (Richardson et al., 1997;Kanda et al., 2000;Jenner, 2000). Recent...

A Crucial Role for Forebrain Adenosine A2A Receptors in Amphetamine Sensitization

“…Several A 2A antagonists (eg KW-6002) are already in various phases of clinical trials as a novel symptomatic treatment for Parkinson's disease. Our findings support the possibility that brain A 2A blockade may help prevent or delay the development of maladaptive dyskinetic motor responses to chronic dopaminergic stimulation (Pinna et al, 2001;Fredduzzi et al, 2002;Bibbiani et al, 2003). Moreover, our data raise the possibility that A 2A antagonists could provide a rational pharmacological intervention for the treatment of addictive disorders.…”

“…Fredduzzi et al (2002) showed that in unilaterally 6-OHDA-lesioned (global) A 2A KO mice, daily treatment with L-dopa did not produce progressively sensitized behaviors (contralateral rotations and grooming) compared to their WT littermates. In analogous pharmacological studies of A 2A R involvement in neuroplasticity induced by L-dopa in hemiparkinsonian rodents, Bibbiani et al (2003) have recently shown that oral KW-6002 coadministered with L-dopa daily prevented the characteristic shortening of motor response to acute L-dopa challenge.…”

“…In addition, using A 2A R knockout (A 2A KO) mice, our laboratory has shown that behavioral sensitization to repeated treatment either with L-dopa in hemiparkinsonian mice or with amphetamine in unlesioned mice does not develop in the absence of the A 2A R (Fredduzzi et al, 2002;Chen et al, 2003). However, a facilitative role of A 2A Rs in sensitization is controversial and other reports have shown that the A 2A agonist CGS21680 attenuates the development of behavioral sensitization induced by methamphetamine (Shimazoe et al, 2000).…”

Adenosine receptor blockade reverses hypophagia and enhances locomotor activity of dopamine-deficient mice

“…The differences in the effects of adenosine antagonists and dopamine agonists in Th Ϫ/Ϫ ; Dbh Th/ϩ mice suggest that adenosine antagonist treatments for Parkinson's disease patients could be developed that generate less dyskinetic side effects than dopamine replacement therapy, a notion that is supported by results from recent studies using monkeys (36,37). Additionally, other investigators have shown that excessive motor function and increased D 1 receptordependent gene expression induced by repeated injections of L-dopa into 6-hydroxydopamine-lesioned mice are reduced in A 2A receptor-deficient mutants (38). The attenuation by caffeine of L-dopa-elicited hyperlocomotion and striatal c-Fos expression in Th Ϫ/Ϫ ; Dbh Th/ϩ mice is consistent with this finding and also suggests that adenosine antagonists could be used to block L-dopa-induced dyskinesias.…”

A Critical Role of the Adenosine A2AReceptor in Extrastriatal Neurons in Modulating Psychomotor Activity as Revealed by Opposite Phenotypes of Striatum and Forebrain A2AReceptor Knock-Outs

“…This functional antagonism is the basis for the development of A 2A R antagonists as a promising nondopaminergic pharmacological therapy for Parkinson's disease , whereas A 2A R agonists have been proposed as potential therapeutic agents for schizophrenia (Ferre, 1997) and other psychotic disorders (Fredholm et al, 2005). However, contrary to the antagonistic A 2A R-D 2 R interaction model in the striatum and certain pharmacological data (Filip et al, 2006), genetic inactivation of A 2A Rs either globally or specifically in forebrain region attenuates, rather than enhances, the psychostimulant effects of cocaine (Chen et al, 2000), amphetamine (Chen et al, 2003;Bastia et al, 2005), or L-dopa (Fredduzzi et al, 2002;Xiao et al, 2006). These observations suggest that the activation of A 2A Rs in extrastriatal cells may oppose postsynaptic A 2A R function in striatopallidal neurons on the modulation of psychomotor activity.…”