A Differential Role for the Adenosine A2A Receptor in Opiate Reinforcement vs Opiate-Seeking Behavior

Abstract

The adenosine A 2A receptor is specifically enriched in the medium spiny neurons that make up the 'indirect' output pathway from the ventral striatum, a structure known to have a crucial, integrative role in processes such as reward, motivation, and drug-seeking behavior. In the present study we investigated the impact of adenosine A 2A receptor deletion on behavioral responses to morphine in a number of reward-related paradigms. The acute, rewarding effects of morphine were evaluated using the conditioned place preference paradigm. Operant self-administration of morphine on both fixed and progressive ratio schedules as well as cue-induced drug-seeking was assessed. In addition, the acute locomotor response to morphine as well as sensitization to morphine was evaluated. Decreased morphine selfadministration and breakpoint in A 2A knockout mice was observed. These data support a decrease in motivation to consume the drug, perhaps reflecting diminished rewarding effects of morphine in A 2A knockout mice. In support of this finding, a place preference to morphine was not observed in A 2A knockout mice but was present in wild-type mice. In contrast, robust cue-induced morphine-seeking behavior was exhibited by both A 2A knockout and wild-type mice after a period of withdrawal. The acute locomotor response to morphine in the A 2A knockout was similar to wild-type mice, yet A 2A knockout mice did not display tolerance to chronic morphine under the present paradigm. Both genotypes display locomotor sensitization to morphine, implying a lack of a role for the A 2A receptor in the drug-induced plasticity necessary for the development or expression of sensitization. Collectively, these data suggest a differential role for adenosine A 2A receptors in opiate reinforcement compared to opiate-seeking.

Behavioural and Anatomical Characterization of Mutant Mice With Targeted Deletion of D1 Dopamine Receptor^|^ndash;Expressing Cells: Response to Acute Morphine

“…Morphine also induces a decrease in locomotion and total rearing in mice of both sexes that is not modified in MUT mice. While both stimulant and depressive locomotor effects of morphine have been reported in rodents, depending on the dose and the interval after administration (10, 31, 38 -41), a decrease in locomotor activity and rearing behaviour has been observed in WT mice following the administration of 10 mg/kg morphine by other investigators (8,9). MUT mice given vehicle showed a reduction in chewing relative to WT mice given vehicle; this profile was unaltered in MUT and WT mice given morphine.…”

The Necessity of α4* Nicotinic Receptors in Nicotine-Driven Behaviors: Dissociation Between Reinforcing and Motor Effects of Nicotine

“…Daily 2 h sessions were held in the dark phase. Intravenous self-administration of nicotine (0.05 mg/kg/ infusion) was assessed in WT (n ¼ 10) and a4À/À littermates (n ¼ 11) according to an established protocol previously used for morphine and cocaine (Brown et al, 2009;McPherson et al, 2010). Mice were anaesthetized (isoflurane 1.5-1.8%) and indwelling venous cannulae were implanted into the jugular vein.…”

“…The conditioned place preference apparatus has been previously described (Brown et al, 2009;McPherson et al, 2010). WT (n ¼ 18) and a4À/À mice (n ¼ 16) were habituated to the experimental room for at least 30 min before each session.…”

“…'Breakpoint' was assessed using a progressive ratio schedule, where an increasing number of active lever presses were required to receive each infusion (1,3,9,13,16,18,20,22,24,25,27,28,29,31,32,34,35,37,39,41,44,47,52,64,76,88,100,112,124,136 lever presses for each subsequent infusion) (Brown et al, 2009). The breakpoint was defined as the last completed ratio, after which a period of 60 min ensued where no reinforcer was earned or the final ratio completed within the 2 h session.…”

“…Mice were engaged in natural reward-based instrumental learning task, as previously described (Brown et al, 2009;McPherson et al, 2010). Delivery of 10% sucrose solution to a liquid receptacle in the chamber (5 ml) was contingent upon an active lever press.…”