Abstract
Previous studies have shown that stress can increase the response of mesolimbic dopaminergic neurons to acute administration of drugs of abuse included ethanol. In this study, we investigated the possible involvement of the mesocortical dopaminergic pathway in the development of ethanol abuse under stress conditions. To this aim we trained both socially isolated (SI) and group housed (GH) rats to self administer ethanol which was made available only 2 ha day (from 11:00 to 13:00 h). Rats have been trained for 3 weeks starting at postnatal day 35. After training, rats were surgically implanted with microdialysis probes under deep anesthesia, and 24 hlater extracellular dopamine concentrations were monitored in medial prefrontal cortex (mPFC) for the 2 hpreceding ethanol administration (anticipatory phase), during ethanol exposure (consummatory phase) and for 2 hafter ethanol removal. Results show that, in GH animals, dopamine extracellular concentration in the mPFC increased as early as 80 min before ethanol presentation (+50% over basal values) and remained elevated for 80 min during ethanol exposure. In SI rats, on the contrary, dopamine extracellular concentration did not show any significant change at any time point. Ethanol consumption was significantly higher in SI than in GH rats. Moreover, mesocortical dopaminergic neurons in SI animals also showed a decreased sensitivity to an acute administration of ethanol with respect to GH rats. Our results show that prolonged exposure to stress, as in social isolation, is able to induce significant changes in the response of mesocortical dopaminergic neurons to ethanol exposure and suggest that these changes might play an important role in the compulsivity observed in ethanol addiction.
Highlights
In the research field of drug addiction the mesolimbic dopaminergic system has always received great attention since the evidence that most of the substances of abuse are able to increase dopamine extracellular concentration in the Nucleus Accumbens (Di Chiara and Imperato, 1988)
We have previously shown (Dazzi et al, 2002b), that acute administration of ethanol is able to induce a biphasic effect on dopamine extracellular concentration in the medial prefrontal cortex (mPFC), with lower doses inducing an increase and higher doses a decrease, respectively, in dopamine output
To evaluate whether in socially isolated (SI) rats mesocortical dopaminergic neurons show a different sensitivity to the acute administration of ethanol, we used the same doses we used in our previous article (0.5–2 g/kg, i.p.)
Summary
In the research field of drug addiction the mesolimbic dopaminergic system has always received great attention since the evidence that most of the substances of abuse are able to increase dopamine extracellular concentration in the Nucleus Accumbens (Di Chiara and Imperato, 1988). MPFC is part of the mesocorticolimbic dopaminergic system whose neurons project from the VTA to the Nucleus Accumbens and Amydgala (Björklund and Dunnet, 2007) These areas together form the reward and motivation circuitry which is crucial in the regulation of functions that are altered in drug addiction, such as attribution of incentive salience to a stimulus (Robinson and Berridge, 1993), activation of goal-directed behaviors (Salamone et al, 2007), evaluation of reward (Koob and Volkow, 2010). During abstinence from alcohol, mPFC functionally disconnects from the Amygdala while retaining connection to the Nucleus Accumbens; this functional disconnection has been suggested to be crucial for impaired executive control over motivated behavior suggesting that disregulation of mPFC interneurons may be an early index of neuroadaptation in alcohol dependence (Koob et al, 2014)
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