Acute Ethanol Withdrawal Impairs Contextual Learning and Enhances Cued Learning

Abstract

Background Alcohol affects many of the brain regions and neural processes that support learning and memory, and these effects are thought to underlie, at least in part, the development of addiction. Although much work has been done regarding the effects of alcohol intoxication on learning and memory, little is known about the effects of acute withdrawal from a single alcohol exposure. Methods We assess the effects of acute ethanol withdrawal (6 h post-injection with 4 g/kg ethanol) on two forms of fear conditioning (delay and trace fear conditioning) in C57BL/6J and DBA/2J mice. The influence of a number of experimental parameters (pre- and post-training withdrawal exposure; foreground/background processing; training strength; non-associative effects) is also investigated. Results Acute ethanol withdrawal during training had a bidirectional effect on fear conditioned responses, decreasing contextual responses and increasing cued responses. These effects were apparent for both trace and delay conditioning in DBA/2J mice and for trace conditioning in C57BL/6J mice; however, C57BL/6J mice were selectively resistant to the effects of acute withdrawal on delay cued responses. Conclusions Our results show that acute withdrawal from a single, initial ethanol exposure is sufficient to alter long-term learning in mice. In addition, the differences between the strains and conditioning paradigms used suggest that specific learning processes can be differentially affected by acute withdrawal in a manner that is distinct from the reported effects of both alcohol intoxication and withdrawal following chronic alcohol exposure. Thus, our results suggest a unique effect of acute alcohol withdrawal on learning and memory processes.

GIRK Channels

“…It will also be important to determine the role of GIRK channels in the drug-induced changes of normal learning and memory processes. Our lab recently demonstrated that acute ethanol withdrawal alters associative learning in a manner that is distinct from both acute intoxication and withdrawal from chronic ethanol exposure (Tipps, Raybuck, Buck, & Lattal, 2015). In a follow-up study, we found that the loss of GIRK3 prevented the acute withdrawal-induced changes without altering baseline learning (Megan E. Tipps and Kari J. Buck, unpublished data).…”

Fear conditioning in mouse lines genetically selected for binge-like ethanol drinking

“…It was recently shown that murine genotypes differed in their response to acute alcohol withdrawal on fear-conditioned responses. Furthermore, context-elicited and cue-elicited responses were differentially affected: the former were blunted, and the latter enhanced (Tipps, Raybuck, Buck, & Lattal, 2015). Because of the high prevalence of both binge-like drinking and PTSD in combat veterans (Cucciare et al, 2011; Davis et al, 2003), we plan to adapt existing PTSD models for use in HDID mice.…”

Rapid reacquisition of contextual fear following extinction in mice: effects of amount of extinction, acute ethanol withdrawal, and ethanol intoxication

“…Acute ethanol withdrawal (AEW) is defined as 6 hr following a 4 g/kg intraperitoneal (IP) injection of 20% v/v ethanol (Tipps et al, 2015). This procedure has previously caused signs of alcohol withdrawal in many inbred strains of mice (increased handling-induced convulsions), especially in withdrawal sensitive lines like DBA/2J (Metten & Crabbe, 1994).…”

“…Acute ethanol withdrawal (AEW), which is the peak of withdrawal following the first ethanol intoxication, results in both physical and psychological alterations (Karadayian & Cutrera, 2013; Karadayian, Busso, Feleder, & Cutrera, 2013), including alterations in brain activity (Kozell, Hitzemann, & Buck, 2005; Vilpoux et al, 2009) and impairments in initial contextual fear conditioning in C57BL/6J mice (Tipps, Raybuck, Buck, & Lattal, 2015). Little is known about effects of AEW on later learning, such as extinction or post-extinction re-emergence of behavior, processes which tend to be altered in patients with PTSD (Rothbaum & Davis, 2003).…”