Quinpirole and ropinirole, in distinct functional phases of ACD operant-drinking behaviour. D2 receptors have both and post-synaptic localization: quinpirole, at low doses, has been reported to preferentially bind to D2 autoreceptors. Ropinirole, a post-synaptic D2 agonist, is already used to restore dopaminergic tone in Parkinson’s Disease, as well as in the normalisation of the behavioural responses to natural rewards in anhedonic states. The effectiveness of these two different D2 receptors agonists in reducing drug seeking and drug taking, during extinction and relapse in ACD-induced operant behaviour, can imply important translational consequences concerning the pharmacological treatments of alcohol addiction. The aim of the present study was to investigate the neuropharmacological basis underpinning discrete aspects of operant drinking behaviour for ACD in male rats. Previous self-administration studies demonstrated that ACD possesses its own reinforcing and motivational properties since it is able to induce and maintain an operant behaviour in rats and promotes different drug-related behaviours, such as resilience to extinction, induction to relapse and to compulsive-like behaviour. Recent works by Karahanian and colleagues elegantly demonstrated that ACD has a crucial role in mediating ethanol reinforcement in the VTA. Indeed, reducing ACD generation, or increasing its metabolism in the VTA, can lead to a marked reduction of ethanol intake in naive rats, but the increase in ACD metabolism in VTA failed to affect ethanol intake in animals that consumed ethanol chronically for 2-3 months. In this regard, a role for high ACD peripheral levels, able to cross the blood-brain barrier, cannot be ruled out. Since chronic ethanol exposure leads to CYP2E1 induction and decreased activity of aldehyde dehydrogenase, it is worth exploring the pharmacological potential properties of peripheral ACD, which may also account for its positive reinforcing effects. Remarkably, some of the behavioural features of orally self-administered ACD are sensitive to the pharmacological modulation of the cannabinoid CB1 receptor, as well as of the opioid neurotransmission. These systems are largely involved in the induction of alcohol drinking behaviour and relapse and can likely influence ACD drinking behaviour through the modulation of the DAergic reward pathway, thus causing DA release in the nucleus accumbens. In the current experiments, the induction of ACD drinking behaviour was acquired along 30 days. Our data show that in the last period of training, rats’ ACD intake was significantly higher than in the previous weeks suggesting that the incentive motivation for the substance had also been increasing along time. Operant conditioning is a behavioural paradigm specifically tailored to reflect the measure of the reinforcing properties of self-administered drugs.
Chronic exposure to relative high ACD concentrations as those used by investigating the role of two different receptor agonists
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