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

Abstract

Rationale: Many studies have found that ethanol intoxication and withdrawal impairs initial acquisition or extinction of learned behaviors. Rapid reconditioning following extinction is a form of post-extinction re-emergence of conditioned behavior that has not been studied for its interaction with ethanol intoxication or withdrawal. Objectives: The goals of this paper were to define the parameters that allow rapid post-extinction reacquisition of fear in mice and investigate the effect of acute ethanol withdrawal and intoxication on acquisition, extinction, and post-extinction reconditioning. Methods: We examined acquisition, extinction, and post-extinction reconditioning of contextual fear in male C57BL/6 mice. Acute ethanol withdrawal occurred 6 hr following a 4 g/kg injection of 20% ethanol and acute ethanol intoxication occurred 5 min following a 1.5 g/kg injection of 20% ethanol. Results: A weak context-shock pairing caused rapid reacquisition of conditioned freezing following moderate, but not extensive extinction. Acute ethanol intoxication impaired initial conditioning and acute ethanol withdrawal impaired rapid reacquisition after extinction, but not reconditioning or extinction itself. Conclusions: These findings show that rapid reconditioning occurs following moderate, but not extensive extinction in C57BL/6J mice. Additionally, acute ethanol withdrawal and intoxication may differentially affect different phases of conditioning. Results are discussed in terms of current ideas about post-extinction behavior and ethanol’s effects on memory.

Behavioral and immunohistochemical characterization of rapid reconditioning following extinction of contextual fear

“…This is in contrast to our previous work with mice, which found that extensive extinction eliminated rapid reconditioning (Williams and Lattal 2019). The slow rate of reacquisition that sometimes occurs could be due to a number of factors, including performance variables and differences in exposure to the context causing latent inhibition (Bouton and Swartzentruber 1989;Brooks et al 2003;Williams and Lattal 2019). We found that extensive context preexposure did appear to weaken initial conditioning, but this was not specific to the context of preexposure (Experiment 3).…”

“…This effect was not always robust (e.g., Group REC 3 EXT in Experiment 2), but there was no evidence that postextinction reconditioning was impaired relative to initial conditioning. There are many demonstrations that massive extinction may slow reacquisition (Bouton 1986;Leung et al 2007) and we have previously found that massive extinction impairs rapid reacquisition of contextual fear in mice (Williams and Lattal 2019). It is notable that in Experiments 1-3 freezing extinguished quickly and showed little spontaneous recovery across extinction sessions.…”

“…Rats were run through a modified version of the rapid reacquisition procedure we have previously used in mice (Williams and Lattal 2019). For all experiments, initial conditioning was a 12-min session, in which rats received four unsignaled footshocks (1 sec, 0.75 mA) at 2.5, 5, 9, and 11.5 min into the session.…”

“…Studies of reconditioning after extinction have revealed that the amount of reconditioning can be influenced by the amount of extinction. For example, following relatively brief extinction, reconditioning occurs more quickly compared to initial conditioning, but following extensive extinction, this effect may be eliminated or reconditioning maybe even slower compared to initial conditioning (e.g., Pavlov 1927;Bouton 1986;Bouton and Swartzentruber 1989;Hart et al 1995;Rescorla 2001;Leung et al 2007;Williams and Lattal 2019). Although reconditioning has been used as a tool to assess the strength of extinction learning in the face of neurobiological manipulations (Raybuck et al 2013;Bolkan and Lattal 2014;Hart et al 2014), the neurobiology of reconditioning itself is understudied compared to other postextinction unmasking phenomena.…”

Editorial: the psychopharmacology of extinction—from theory to therapy

“…Considering the comorbidity between anxiety disorders and alcohol addiction, the interaction of pharmacological processes associated with addiction—such as alcohol withdrawal—and prolonged exposure therapy is potentially of great clinical impact. This relationship is addressed by Williams and Lattal (2019), with their data highlighting the complex relationship between fear learning and drug withdrawal. However, there are commonalities between fear and drug memory extinction, particularly with respect to the impact of individual differences on long-term behavioural outcomes.…”