Intermittent ethanol consumption depresses endocannabinoid-signaling in the dorsolateral striatum of rat
Recent research suggests that adaptations elicited by drugs of abuse share common features with traditional learning models, and that drugs of abuse cause long-term changes in behavior by altering synaptic function and plasticity. In this study, endocannabinoid (eCB) signaling in the dorsolateral striatum, a brain region vital for habit formation, was evaluated in acutely isolated brain slices from ethanol (EtOH)-consuming rats and control rats. EtOH-consuming rats had free access to a 20% EtOH solution for three 24 hour sessions a week during seven weeks and consumed an average of 3.4 g/kg per session. eCB-mediated long-lasting disinhibition (DLL) of population spike (PS) amplitude induced by moderate frequency stimulation was impaired in EtOH-consuming rats, and was not restored by the muscarinic receptor antagonist scopolamine (10 μM). The lack of DLL could be linked to a reduced GABA(A) receptor tone, since bicuculline-mediated disinhibition of striatal output was significantly reduced in slices from EtOH-consuming rats. However, eCB signaling induced by high frequency stimulation (HFS) was also impaired in slices from EtOH-consuming rats and isolated control rats. Activation of presynaptic cannabinoid 1 receptors (CB1R) with WIN55,212-2 (250 nM, 1 μM) significantly modulated PS amplitude in slices from age-matched control rats while slices from EtOH-consuming rats remained unaffected, indicating that eCB signaling is inhibited at a level that is downstream from CB1R activation. Intermittent alcohol intake for seven weeks might thus be sufficient to modulate a presynaptic mechanism that needs to be synergized with CB1R activation for induction of long-term depression (LTD). In conclusion, alcohol consumption inhibits striatal eCB signaling in a way that could be of importance for understanding the neurological underpinnings of addictive behavior.
[Show abstract] [Hide abstract] ABSTRACT: Impaired striatal neuroplasticity may underlie increased alcoholism documented in those with posttraumatic stress disorder (PTSD). Cannabinoid receptor-1 (CB1) is sensitive to the effects of ethanol (EtOH) and traumatic stress, and is a critical regulator of striatal plasticity. To investigate CB1 involvement in the PTSD-alcohol interaction, this study measured the effects of traumatic stress using a model of PTSD, mouse single-prolonged stress (mSPS), on EtOH-induced locomotor sensitization and striatal CB1 levels.0Comments 0Citations
- "Finally, traumatic stress and chronic EtOH differentially impact the endocannabinoid system. In rodent studies, chronic EtOH exposure increases endocannabinoid release  while decreasing endocannabinoid signaling , and clinical studies show a decrease in CB1-binding in many brain regions, including the striatum of alcoholics . Alternatively, stress rodent models suggest an initial increase in endocannabinoids with acute stress followed by decreases in endocannabinoids after chronic stress  . "
[Show abstract] [Hide abstract] ABSTRACT: Habitual actions enable efficient daily living, but they can also contribute to pathological behaviors that are resistant to change, such as alcoholism. Habitual behaviors are learned actions that appear goal-directed but are in fact no longer under the control of the action’s outcome. Instead, these actions are triggered by stimuli, which may be exogenous or interoceptive, discrete or contextual. A major hallmark characteristic of alcoholism is continued alcohol use despite serious negative consequences. In essence, although the outcome of alcohol seeking and drinking is dramatically devalued, these actions persist, often triggered by environmental cues associated with alcohol use. Thus, alcoholism meets the definition of an initially goal-directed behavior that converts to a habit-based process. Habit and alcohol have been well investigated in rodent models, with comparatively less research in non-human primates and people. This review focuses on translational research on habit and alcohol with an emphasis on cross-species methodology and neural circuitry.0Comments 0Citations
- "Moreover, long-term alcohol intake induces neurochemical adaptations in the dorsolateral caudate of primates, including increased sensitivity at kappa opioid receptors and reduced dopamine release and clearance , although the role of this subregion of the dorsal striatum in habit strategies is unclear. In rats, chronic intermittent alcohol exposure attenuates the induction of corticostriatal LTD in dorsolateral striatum by acting on extracellular signal-regulated kinase pathway or decreasing endocannabinoid signaling [118, 119]. Likewise, the effects of ethanol exposure on neuronal activity in the amygdala are well described120121122. "
[Show abstract] [Hide abstract] ABSTRACT: Alcohol use disorder (AUD) is a worldwide public health problem and a polygenetic disorder displaying substantial individual variation. This work aimed to study individual differences in behavior and its association to voluntary alcohol intake and subsequent response to naltrexone in a seamless heterogenic group of animals. Thus, by this approach the aim was to more accurately recapitulate the existing heterogeneity within the human population. Male Wistar rats from three different suppliers (Harlan Laboratories B.V., RccHan™:WI; Taconic Farms A/S, HanTac:WH; and Charles River GmbH, Crl:WI) were used to create a heterogenic group for studies of individual differences in behavior, associations to intermittent voluntary alcohol intake and subsequent response to naltrexone. The rats were tested in the open field prior to the Y-maze and then given voluntary intermittent access to alcohol or water in the home cage for 6 weeks, where after, naltrexone in three different doses or saline was administered in a Latin square design over 4 weeks and alcohol intake and preference was measured. However, supplier-dependent differences and concomitant skew subgroup formations, primarily in open field behavior and intermittent alcohol intake, resulted in a shifted focus to instead study voluntary alcohol intake and preference, and the ensuing response to naltrexone in Wistar rats from three different suppliers. The results showed that outbred Wistar rats are diverse with regard to voluntary alcohol intake and preference in a supplier-dependent manner; higher in RccHan™:WI relative to HanTac:WH and Crl:WI. The results also revealed supplier-dependent differences in the effect of naltrexone that were dose- and time-dependent; evident differences in high-drinking RccHan™:WI rats relative to HanTac:WH and Crl:WI rats. Overall these findings render RccHan™:WI rats more suitable for studies of individual differences in voluntary alcohol intake and response to naltrexone and further highlight the inherent heterogeneity of the Wistar strain. The overall results put focus on the importance of thoroughly considering the animals used to aid in study design and for comparison of reported results.0Comments 2Citations
- "Rcc rats exhibited a stabile intake that peaked more or less upon initial access, which has been shown previously (Palm et al., 2011b; Goepfrich et al., 2013;), while Crl and Tac rats showed an initial increase followed by stabilization (Palm et al., 2011b). The lack of a pronounced escalation in intake was similar to previous reports on intermittent access paradigms (Adermark et al., 2011; Palm et al., 2011b; Suchankova et al., 2013;), but in contrast to others (Carnicella et al., 2014). Comparing intake on the days of alcohol access, i.e., drinking days, the Rcc group displayed increased intake on drinking day 1 relative to day 2 or day 3, which implies an alcohol deprivation effect as previously observed (), while not as distinct in the Tac and Crl groups. "