On the role of adenosine (A)2A receptors in cocaine-induced reward: a pharmacological and neurochemical analysis in rats

Abstract

The findings support a role of A2A receptors in modulating goal-maintained behaviors. They also indicate that increased accumbal GABA release involving an antagonistic A2A-D2 receptor interaction can participate in mediating the inhibitory effects of the A2A agonist on cocaine reward.

Effects of intra-accumbal or intra-prefrontal cortex microinjections of adenosine 2A receptor ligands on responses to cocaine reward and seeking in rats

“…Thus, intra-NAc CGS 21680 (1–2.5 ng/side) had neither effects on the higher dose used for cocaine (0.5 mg/kg/infusion) self-administration nor did it alter the number of inactive lever presses or horizontal locomotor activity. In this paper, local administration of A 2A receptor antagonists did not influence cocaine self-administration which supported previous results obtained with systemic administration of these drugs (Wydra et al 2015a). …”

“…In fact, in rats with intracranially implanted guide cannulae, it is difficult, if ever, to reinstate cocaine seeking evoked by the conditional stimulus under FR 5 schedule of reinforcement (Acosta et al 2008, this paper). Supporting the present findings, our (Wydra et al 2015a) and other authors (Bachtell and Self 2009) studies with systemic CGS 21680 administration demonstrated that this agonist dose dependently reduced cocaine- or cue-induced reinstatement to cocaine seeking. More recently, O'Neill et al (2012) found that pretreatment with the same A 2A agonist administered into the NAc core (with the injection volume 0.5–1 μl/side) dose dependently blunted the cocaine- and cue (under FR1 schedule)-induced reinstatement of cocaine seeking behavior, what together with our present finding (much smaller injection volume of 0.2 μl/side) illustrate that stimulation of A 2A receptors localized to both parts of the NAc may control over cocaine seeking.…”

“…As previously shown, A 2A receptor stimulation after high doses and systemic or intra-NAc agonist administration reduced lever pressing for food or sucrose (Font et al 2008; Wydra et al 2015a, b), while such reduction was not reported for the minimally effective dose of intra-NAc core CGS 21680 (2.5 ng/side) (O'Neill et al 2012). On the other hand, intra-NAc MSX-3 reduced food intake and delayed intake onset in food-deprived rats (Nagel et al 2003) and other studies also strongly indicate brain A 2A receptors as the target to control the exertion of effort in motivational behaviors (Correa et al 2016; Mingote et al 2008; Pardo et al 2012).…”

“…More recently, O'Neill et al (2012) found that pretreatment with the same A 2A agonist administered into the NAc core (with the injection volume 0.5–1 μl/side) dose dependently blunted the cocaine- and cue (under FR1 schedule)-induced reinstatement of cocaine seeking behavior, what together with our present finding (much smaller injection volume of 0.2 μl/side) illustrate that stimulation of A 2A receptors localized to both parts of the NAc may control over cocaine seeking. Interestingly, the previous studies with systemic and intra-NAc drug injections indicate that A 2A receptors alter D 2 receptor signaling as CGS 21680 reduced quinpirole-induced reinstatement (Bachtell and Self 2009; O'Neill et al 2012; Wydra et al 2015a, b), possibly through antagonistic allosteric A 2A -D 2 receptor interactions. The above functional interaction has been raised on tasks involving effort-related processes (Mingote et al 2008; Pardo et al 2012), in motivational disruptions of mother-infant interactions (Pereira et al 2011) or in excessive ethanol drinking (Nam et al 2013).…”

Basimglurant for treatment of major depressive disorder: a novel negative allosteric modulator of metabotropic glutamate receptor 5

“…The D1 receptor expressing accumbens GABA projections mediating reward [79] are likely to develop enhanced activity by the increased D1 receptor activation mediated through the increased DA release induced by basimglurant. These events may also contribute to the antidepressant actions of basimglurant ( Figure 4).…”