Social Isolation Blunted the Response of Mesocortical Dopaminergic Neurons to Chronic Ethanol Voluntary Intake

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.

Acute social isolation evokes midbrain craving responses similar to hunger

“…By contrast, though, in animal models social isolation does sometimes cause increased food consumption(96, for review) and other general changes in motivational systems (14, for review). In rodents, for example, social isolation increases voluntary alcohol intake (42,97,98) as well as morphine consumption (99,100), and can alter DA release in response to alcohol intake (97). A key predictor may be the duration (and possibly the developmental timing) of the isolation: short term acute isolation in adults may cause selective social motivation, whereas long-term or developmental isolation could lead to more general compensatory changes.…”

Nicotine e‐cigarette vapor inhalation and self‐administration in a rodent model: Sex‐ and nicotine delivery‐specific effects on metabolism and behavior

“…In addiction-related processes, stress is known to be a key factor mediating drug intake and relapse-related behaviors 61 , and among these factors, social isolation represents a well-established model of chronic stress, which has been shown to interfere with the mechanisms underlying dependence for different drugs, such as amphetamine 62 , cocaine 63 , ethanol 64 and nicotine 65 . Here, we found similar levels of blood cotinine with one or two rats present during vapor delivery in the chamber.…”

Social isolation postweaning alters reward-related dopamine dynamics in a region-specific manner in adolescent male rats

“…Therefore, based on the evidence from our studies, social isolation appears to have disproportionately enhanced reward-related dopamine dynamics in the NAc in response to a natural reward, as compared to the group housed condition. Interestingly, this isolation-mediated effect on dopamine signaling likely explains the previously documented increased reinforcing effects of cocaine, amphetamine, and ethanol found with self-administration in isolated rats ( Lallai et al, 2016 ; McCool and Chappell, 2009 ; Yajie et al, 2005 ).…”

“…For Cohorts I-IV, rats were anesthetized by intraperitoneal injection of Equithesin (5 ml/kg), and a concentric dialysis probe was inserted at the level of the mPFC (AP +3.2 mm; ML +0.8 mm; DV -5.3 relative to bregma) or NAc shell (AP +2.2 mm; ML +1.0 mm; DV –7.8 mm relative to bregma) ( Lallai et al, 2016 ; Paxinos and Watson, 2005 ). To allow for recovery from surgical procedures, experiments were performed 24–36 h after probe implantation.…”

“…Social isolation has been correlated with lower life satisfaction, higher levels of substance abuse, depression, anxiety, and increased stress in humans ( Clair et al, 2021 ; Loades et al, 2020 ). Rodent studies have also shown that social interaction can act as a primary motivating reinforcer ( Evans et al, 1994 ; Novick et al, 2018 ), whereas social isolation stress can lead to increased depression- and anxiety-associated behaviors, aggression, increased drug self-administration, and impaired learning and memory function ( Bianchi et al, 2006 ; Brenes et al, 2008 ; Del Arco et al, 2004 ; Heidbreder et al, 2000 ; Lallai et al, 2016 ; McCool and Chappell, 2009 ; Schenk et al, 1987 ; Wongwitdecha and Marsden, 1996 ; Yajie et al, 2005 ). Such behavioral effects have been correlated with neurobiological changes in the developing central nervous system.…”