Cannabidiol tempers alcohol intake and neuroendocrine and behavioural correlates in alcohol binge drinking  adolescent rats. Focus on calcitonin gene‐related peptide's brain levels

Abstract

Alcohol binge drinking is common among adolescents and may challenge the signalling systems that process affective stimuli, including calcitonin gene‐related peptide (CGRP) signalling. Here, we employed a rat model of adolescent binge drinking to evaluate reward‐, social‐ and aversion‐related behaviour, glucocorticoid output and CGRP levels in affect‐related brain regions. As a potential rescue, the effect of the phytocannabinoid cannabidiol was explored. Adolescent male rats underwent the intermittent 20% alcohol two‐bottle choice paradigm; at the binge day (BD) and the 24 h withdrawal day (WD), we assessed CGRP expression in medial prefrontal cortex (mPFC), nucleus accumbens (NAc), amygdala, hypothalamus and brainstem; in addition, we evaluated sucrose preference, social motivation and drive, nociceptive response, and serum corticosterone levels. Cannabidiol (40 mg/kg, i.p.) was administered before each drinking session, and its effect was measured on the above‐mentioned readouts. At BD and WD, rats displayed decreased CGRP expression in mPFC, NAc and amygdala; increased CGRP levels in the brainstem; increased response to rewarding‐ and nociceptive stimuli and decreased social drive; reduced serum corticosterone levels. Cannabidiol reduced alcohol consumption and preference; normalised the abnormal corticolimbic CGRP expression, and the reward and aversion‐related hyper‐responsivity, as well as glucocorticoid levels in alcohol binge‐like drinking rats. Overall, CGRP can represent both a mediator and a target of alcohol binge‐like drinking and provides a further piece in the intricate puzzle of alcohol‐induced behavioural and neuroendocrine sequelae. CBD shows promising effects in limiting adolescent alcohol binge drinking and rebalancing the bio‐behavioural abnormalities.

Cannabidiol or ketamine for preventing the impact of adolescent early drug initiation on voluntary ethanol consumption in adulthood

“…In accordance with this, for example, both male and female rats pretreated with cannabidiol showed decreased ethanol intake in adulthood as observed by a drop in preference (although only signi cant in male rats), a lower volume of ethanol consumed, and a lower overall dose than rats pretreated with vehicle. These results aligned with previous preclinical data suggesting an improvement of ethanolmotivated behaviors by cannabidiol (reviewed by [28]; see also [26][27][29][30][31]), including the cognitive de cits and neuroin ammation induced by early ethanol exposure [70]. Particularly, prior studies have proven cannabidiol e cacy in pups from pregnant rodents exposed to drugs during gestation, directly in adolescence (immediate effects), and/or in rodents that received drugs in adulthood.…”

“…For example, cannabidiol (30 mg/kg/day, i.p., for up to 4-6 weeks) repaired the behavioral and brain disturbances in offspring exposed to an animal model of fetal alcohol spectrum disorder [31]. When administered during adolescence, cannabidiol (40 mg/kg) before each drinking session reduced ethanol consumption and preference in male rats that underwent the intermittent 20% ethanol two-bottle choice paradigm [30]. Moreover, during adulthood, the administration of cannabidiol in male mice reduced the reinforcing properties, motivation and relapse for ethanol [26].…”

“…Interestingly, adolescence is a period of critical brain development that appears to be highly conserved across species in terms of its neurobehavioral and physiological features. Similar to the stages observed in humans, early (10 to 13 years), middle (14 to 17 years), and late adolescence/young adulthood (18 to 21 years; [3][4]), in rodents, adolescence could be divided into early (postnatal day, PND [21][22][23][24][25][26][27][28][29][30][31][32][33][34], mid (PND [34][35][36][37][38][39][40][41][42][43][44][45][46] and late adolescence (PND 46-59; [7]). Therefore, the use of rodents provides a great preclinical model [5][6] with face and construct validity [7] in which to study particular windows of adolescent vulnerability to psychopathology and therapeutic strategies [8].…”

“…Then, we selected the worst outcome induced by prior adolescent drug exposure, to test whether two therapeutical interventions (cannabidiol or ketamine) would prevent the increased ethanol consumption emerging in adulthood [25]. These options were chosen based on previous preclinical and/or clinical data suggesting an amelioration of ethanol-motivated behaviors both by cannabidiol [26][27][28][29][30][31] or ketamine (reviews by [32][33][34][35]), although most of these studies were tested in either pups from pregnant rodents exposed to drugs during gestation, and/or in rodents that received drugs in adolescence and/or adulthood, but were tested at the same age-window of study, and therefore, data evaluating the possible preventive effects of these options following an early adolescent drug experience are missing.…”

Oxycodone Self-Administration in Female Rats is Enhanced by Δ9-tetrahydrocannabinol, but not by Cannabidiol, in a Progressive Ratio Procedure

“…Although Δ 9 -tetrahydrocannabinol is undoubtedly the cons tuent of cannabis that drives most use, for both recrea onal and therapeu c purposes, addi onal cons tuents may also produce significant effects. Cannabidiol (CBD) reduces alcohol or cocaine seeking behavior in rats when applied via a dermal gel (Gonzalez-Cuevas et al, 2018), as well as cocaine (Galaj et al, 2020) or methamphetamine (Hay et al, 2018) seeking in rats and alcohol seeking in rats (Tringali et al, 2023) (Mirmohammadi et al, 2022). There does not appear to be any evidence whether CBD can alter the rewarding value of opioids.…”