On the role of A₂A and D₂ receptors in control of cocaine and food-seeking behaviors in rats.

Karolina Wydra,Kjell Fuxe,Agata Suder,Malgorzata Filip,Dasiel O. Borroto-Escuela

doi:10.1007/s00213-014-3818-5

Karolina Wydra, Kjell Fuxe + Show 3 more

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https://doi.org/10.1007/s00213-014-3818-5

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Abstract

Recent studies indicate that adenosine may influence dopamine neurotransmission via A2A receptors which antagonistically interact with D2 receptor-mediated signaling in the brain. We examined the effects of selective A2A receptor ligands such as the agonist CGS 21680 and the antagonists KW 6002 or SCH 58261 as well as of the D2-like receptor antagonist raclopride on reinstatement of cocaine seeking induced by cocaine, the cocaine-conditioned cue, or the D2-like receptor agonist quinpirole in rats. For comparison, effects of the A2A receptor ligands on reinstatement of food seeking were also studied. CGS 21680 significantly attenuated the reinstatement of cocaine (ip) seeking, and even more potently it reduced quinpirole (ip) or the cue-induced relapse of cocaine seeking as well as cue-induced food seeking. A potent reduction toward the cocaine-, quinpirole-, or cue-induced reinstatement of cocaine seeking was seen with raclopride. Pretreatment with KW 6002 or SCH 58261 reinstated cocaine seeking, and such increases were blocked by raclopride. In the higher doses, KW 6002 or SCH 58261 evoked food-seeking. In combination with the subthreshold dose of cocaine (2.5 mg/kg) or with the cue, low doses of KW 6002 but not SCH 58261 reinstated cocaine-seeking behavior, while none of the A2A receptor antagonists affected the cue-induced food-seeking behavior. The results indicate that A2A activation and D2-like receptor blockade counteract cocaine and food relapse. It is proposed that A2A receptor- and D2 receptor-mediated adenosine and dopamine signaling antagonistically interact in the striato-pallidal GABA neurons to regulate cocaine and food-seeking behavior.

Highlights

Cocaine addiction is characterized by an inability of addicts to inhibit drug use relapse triggered by drugs, environmental cues, or stressful life events (Belin et al 2013; Everitt and Heberlein 2013)
As shown for adenosine and DA signaling in striato-pallidal γ-aminobutyric acid (GABA) neurons, D2 receptor-mediated DA transmission can be reduced by A2A receptor agonists, while A2A receptor antagonists increase it (Filip et al 2012; Fuxe et al 2007b, 2010)
The aim of this study was to examine the role of A2A receptors, using two selective antagonists (KW 6002 or SCH 58261) in cocaine-seeking behavior evoked by cocaine, the D2-like receptor agonist quinpirole, or the cue

Summary

Introduction

Cocaine addiction is characterized by an inability of addicts to inhibit drug use relapse triggered by drugs, environmental cues, or stressful life events (Belin et al 2013; Everitt and Heberlein 2013). The neuronal basis of cocaine relapse includes activation of the mesocorticolimbic circuitry with changes in glutamate and dopamine (DA) neurotransmissions (Kalivas 2009; Sinha 2013). Recent data indicate that adenosine may influence DA and glutamatergic neurotransmission, especially in the striatal region (Fuxe et al 2007a, 2008). As shown for adenosine and DA signaling in striato-pallidal γ-aminobutyric acid (GABA) neurons, D2 receptor-mediated DA transmission can be reduced by A2A receptor agonists, while A2A receptor antagonists increase it (Filip et al 2012; Fuxe et al 2007b, 2010). Stimulation of D2 receptors in the ventral and dorsal striatum is involved in mediating the locomotor, sensitizing, and rewarding effects of cocaine or other drugs of abuse, and these

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