Involvement of Dopamine D2 Receptors in Addictive-Like Behaviour for Acetaldehyde

Abstract

Acetaldehyde, the first metabolite of ethanol, is active in the central nervous system, where it exerts motivational properties. Acetaldehyde is able to induce drinking behaviour in operant-conflict paradigms that resemble the core features of the addictive phenotype: drug-intake acquisition and maintenance, drug-seeking, relapse and drug use despite negative consequences. Since acetaldehyde directly stimulates dopamine neuronal firing in the mesolimbic system, the aim of this study was the investigation of dopamine D2-receptors' role in the onset of the operant drinking behaviour for acetaldehyde in different functional stages, by the administration of two different D2-receptor agonists, quinpirole and ropinirole. Our results show that acetaldehyde was able to induce and maintain a drug-taking behaviour, displaying an escalation during training, and a reinstatement behaviour after 1-week forced abstinence. Acetaldehyde operant drinking behaviour involved D2-receptor signalling: in particular, quinpirole administration at 0.03 mg/kg, induced a significant decrease in the number of lever presses both in extinction and in relapse. Ropinirole, administered at 0.03 mg/kg during extinction, did not produce any modification but, when administered during abstinence, induced a strong decrease in acetaldehyde intake in the following relapse session. Taken together, our data suggest that acetaldehyde exerts its own motivational properties, involving the dopaminergic transmission: indeed, activation of pre-synaptic D2-receptors by quinpirole, during extinction and relapse, negatively affects operant behaviour for acetaldehyde, likely decreasing acetaldehyde-induced dopamine release. The activation of post-synaptic D2-receptors by ropinirole, during abstinence, decreases the motivation to the consecutive reinstatement of acetaldehyde drinking behaviour, likely counteracting the reduction in the dopaminergic tone typical of withdrawal. These data further strengthen the evidence that acetaldehyde may play a crucial role as mediator of ethanol's central effects.

The endocannabinoid‐alcohol crosstalk: Recent advances on a bi‐faceted target

“…Some evidence of a direct effect on the dopaminergic system came from findings on the role played by acetaldehyde (ACD), its first oxidative metabolite. Indeed, ACD directly affects dopaminergic neurotransmission, increasing neuronal firing in the VTA, and stimulating DA release in the NAc shell . Moreover, ACD is able to induce and maintain an addictive behaviour in which seeking and relapse are modulated by the eCB so that ACD is believed to play a primary role in the “first‐hit” of alcohol reinforcement and in the induction of relapse .…”

“…Indeed, ACD directly affects dopaminergic neurotransmission, increasing neuronal firing in the VTA, and stimulating DA release in the NAc shell. 21,[39][40][41] Moreover, ACD is able to induce and maintain an addictive behaviour in which seeking and relapse are modulated by the eCB 12,42 so that ACD is believed to play a primary role in the "first-hit" of alcohol reinforcement and in the induction of relapse. 21,22,39,[43][44][45][46] Indeed, the ECS 21 contributes to alcohol's rewarding effect, and to the occurrence of an addictive phenotype by fine tuning synaptic transmission: the eCB in fact, are key activitydependent messengers that, by short and long-term decreases in synaptic transmission, regulate glutamatergic and GABAergic synapses.…”

Targeting the Stress System During Gestation: Is Early Handling a Protective Strategy for the Offspring?

“…Locomotor activity and explorative behavior were assessed in the open-field arena with a contrast-sensitive, video tracking system, ANY MAZE (Ugo Basile, Gemonio, Italy), in a mean light intensity (100 lx) illuminated room (Brancato et al, 2014). The apparatus consisted in a square box (44 × 44 × 20 cm) and produced a quality-quantitative mapping of the ambulatory patterns, measuring simultaneously: total distance traveled (TDT) in centimeters, number of transition from peripheral to central squares of the arena (NCT) and amount of time spent on the central areas (ATC) in second.…”

Mothering under the influence: how perinatal drugs of abuse alter the mother-infant interaction

“…Specific animal models, in which dams are provided with limited nesting resources in an unfamiliar environment, could be employed. In addition, active metabolites, such as acetaldehyde, by the formation of condensation products with dopamine and serotonin, such as salsolinol and other alkaloids, may act in the brain as main players of alcohol-and tobacco-reinforcing properties (Cannizzaro et al, 2010;Cacace et al, 2012b;Plescia et al, 2013Plescia et al, , 2014bPlescia et al, , 2015aBrancato et al, 2014Brancato et al, , 2017. In this regard, the elucidation of their effects on mother-infant interaction and the developing brain are still lacking.…”