Abstract
Binge alcohol consumption among adolescents affects the developing neural networks underpinning reward and stress processing in the nucleus accumbens (NAc). This study explores in rats the long-lasting effects of early intermittent exposure to intoxicating alcohol levels at adolescence, on: (1) the response to natural positive stimuli and inescapable stress; (2) stress-axis functionality; and (3) dopaminergic and glutamatergic neuroadaptation in the NAc. We also assess the potential effects of the non-intoxicating phytocannabinoid cannabidiol, to counteract (or reverse) the development of detrimental consequences of binge-like alcohol exposure. Our results show that adolescent binge-like alcohol exposure alters the sensitivity to positive stimuli, exerts social and novelty-triggered anxiety-like behaviour, and passive stress-coping during early and prolonged withdrawal. In addition, serum corticosterone and hypothalamic and NAc corticotropin-releasing hormone levels progressively increase during withdrawal. Besides, NAc tyrosine hydroxylase levels increase at late withdrawal, while the expression of dopamine transporter, D1 and D2 receptors is dynamically altered during binge and withdrawal. Furthermore, the expression of markers of excitatory postsynaptic signaling—PSD95; Homer-1 and -2 and the activity-regulated spine-morphing proteins Arc, LIM Kinase 1 and FOXP1—increase at late withdrawal. Notably, subchronic cannabidiol, during withdrawal, attenuates social- and novelty-induced aversion and passive stress-coping and rectifies the hyper-responsive stress axis and NAc dopamine and glutamate-related neuroplasticity. Overall, the exposure to binge-like alcohol levels in adolescent rats makes the NAc, during withdrawal, a locus minoris resistentiae as a result of perturbations in neuroplasticity and in stress-axis homeostasis. Cannabidiol holds a promising potential for increasing behavioural, neuroendocrine and molecular resilience against binge-like alcohol harmful effects.
Highlights
Heavy binge drinking is highly prevalent among high-school and college students in western countries [1]
Our data show that binge-like alcohol exposure during adolescence discretely altered social behaviour in the modified social interaction test (Figure 1B–D)
We observed a significant effect on social investigation (F(3,24) = 11.1, p < 0.0001), with a decrease at withdrawal day 10 (WD10) with respect to binge days (BD) (t = 4.8, p = 0.0004) and CTRL (t = 4.81, p = 0.0003); no differences were observed in the durations of allogrooming (F(3,24) = 2.30, p = 0.1032), social play (Kruskal–Wallis test: p = 0.0808) or cage exploration (F(3,24) = 2.13, p = 0.1223)
Summary
Heavy binge drinking is highly prevalent among high-school and college students in western countries [1]. Adolescents are less responsive to many effects of alcohol intoxication and withdrawal (motor impairment, sedation hangover, anxiety), but are more sensitive to positive effects of alcohol like euphoria and the facilitation of social interaction [2,3,4]. This combination of sensitivities to alcohol facilitates alcohol drinking by adolescents at well above binge levels [5], defined by the National Institute on Alcohol. A subtle balance between DA levels and glutamate release critically regulates synaptic plasticity associated with alcohol abuse and withdrawal [18]
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