Effects of Environmental Enrichment on the Context Dependency of Cocaine-Cue Extinction Learning for Relapse Prevention

• Cocaine addiction currently has no effective treatment methods.

• Drug cue-extinction (exposure therapy) has been proposed as a potential treatment method, but has shown to be context dependent (Conklin & Tiffany et al 2002).

• To be of use in clinical settings, this treatment method would need to be effective in a novel context.

• Previous studies show that context dependency of extinction learning is overcome with administration of a cognitive enhancing drug (e.g. DCS) (Torregrossa et al 2010).

• EE is equally effective as a cognitive enhancing drug when brief interventions of EE are paired with cocaine-cue extinction training (Gauthier et al 2015).

• EE enhances neurogenesis and cognitive functioning, which in turn facilitates learning (Beauquis et al 2010; Fan et al 2007; Gauthier et al 2015).

• The context dependency of extinction learning may be overcome if it is paired with EE.

• What effects does EE have on extinction learning and relapse when extinction is given in a novel context?

• Beauquis, J., Roig, P., De Nicola, A. F., & Saravia, F. (2010). Short-Term Environmental Enrichment Enhances Adult Neurogenesis, Vascular Network and Dendritic Complexity in the Hippocampus of Type 1 Diabetic Mice. PLoS ONE, 5(11), e13993.

• Conklin CA, Tiffany ST. (2002). Applying extinction research and theory to cue-exposure addiction treatments. Addiction, 97:155–167.

• Fan, Y., Liu, Z., Weinstein, P. R., Fike, J. R. and Liu, J. (2007), Environmental enrichment enhances neurogenesis and improves functional outcome after cranial irradiation. European Journal of Neuroscience, 25: 38–46.

• Gauthier, J. M., Lin, A., Nic Dhonnchadha, B. Á., Spealman, R. D., Man, H.-Y., and Kantak, K. M. (2015) Environmental enrichment facilitates cocaine-cue extinction, deters reacquisition of cocaine self-administration and alters AMPAR GluA1 expression and phosphorylation. Addiction Biology.

• Torregrossa, M. M., Sanchez, H., & Taylor, J. R. (2010). D-cycloserine Reduces the Context- Specificity of Pavlovian Extinction of Cocaine Cues Through Actions in the Nucleus Accumbens. The Journal of Neuroscience, 30(31), 10526–10533.

METHODS• Cocaine self-administration

(0.3mg/kg) under a Second-Order Schedule

• Adult Male Wistar rats, group sizes varied n = 8-12

• Rats were placed into 1 of 3 groups:

• Group 1: Rats received EXT in same drug context (A) with no EE (control group)

• Group 2: Rats received EXT in same drug context (A) with EE

• Group 3: Rats received EXT in novel context (B) with EE

INTRODUCTION

RESEARCH QUESTION

During baseline self-administration (before treatments), there were no preexisting group differences • One way ANOVAs confirmed this for average active (p=0.072) and inactive (p=0.28) lever responses,

and cocaine infusions (p=0.21). • One outlier rat (†) disproportionately represented the ABA + EE group for inactive lever responses;

removing the outlier resulted in a more accurate representation of the group. EE facilitated extinction learning• During extinction (no cocaine delivery), lever pressing

generally decreased across weekly sessions. • A two-way RM ANOVA showed a main effect of group

(F[2,25] = 4.1, p=0.030). Tukey tests show that the rats receiving extinction in context A with EE responded significantly less than the control group

(^ p=0.04). • Dunnett tests showed that rats receiving EE had

significantly less responding than the control group on extinction session 2, regardless if they received extinction in context A or B (* p < 0.01).

RESULTS (CONT.) EE deterred relapse after extinction in context A• Repeated two-way ANOVA showed that there is

a main effect of group (F[2,25] = 7.61, p=0.003).• Tukey tests showed that rats receiving extinction

in context A with EE responded significantly less during reacquisition compared to rats receiving extinction in novel context B with EE (^ p=0.002)

• Dunnett post-hoc tests showed that rats receiving extinction in context A with EE deterred cocaine relapse for up to 12 sessions compared to the control group (* p<0.05).

CITATIONS

CONCLUSIONS

Presented by:Kyle Mabry

• EE facilitated the rate of extinction learning, regardless of the change in context. • Combining EE with extinction learning in context A deterred relapse to baseline

rates of cocaine self-administration. • When EE was paired with extinction learning in context B, however, rats relapsed

immediately, as also observed in the control group.• This suggests that EE is not able to overcome the context dependency of extinction

learning. • Pairing EE with a cognitive enhancing drug may be able to surmount the context

dependency of extinction learning.

ORAspen bedding Aspen beddingAspen bedding Cedar bedding

= Intermittent tone Black wall Cedar bedding

= White noise Clear wall Aspen bedding

ABSTRACTAddiction is marked by repeated cycles of abstinence followed by drug relapse brought on by re-exposure to drug-paired cues. Extinction learning disassociates drug-paired cues from the drug itself, but is context-dependent. We used environmental enrichment (EE) paired with cocaine-cue extinction training to investigate whether EE can overcome the context dependency of extinction learning. Adult male rats were conditioned under a second-order schedule of cocaine delivery and cue presentation. After establishing baseline rates of cocaine self-administration, saline was substituted for cocaine during three weekly extinction sessions. The first group (control group) was conditioned, extinguished and tested for relapse in the same context (AAA design), but did not receive EE. The second group was treated identically (AAA design), but also received EE during extinction. The third group was conditioned and relapse tested in context A, but extinguished with EE in a novel context (ABA design). EE consisted of two 4-hr periods provided 24 hours before and immediately following each weekly extinction session. One week later, cocaine was again available for 15 daily self-administration sessions to study relapse in context A. Results showed that EE facilitated rates of extinction learning, whether conducted in context A or context B. As previously observed, combining EE with extinction in context A inhibited cocaine relapse. However, when EE was combined with extinction in context B, rats relapsed immediately, as observed in the control group. Thus, EE cannot overcome the context dependency of extinction learning. Adjunct drug therapies may be required to surmount this obstacle in clinical settings.

RESULTS

†

PI: Kathleen M. KantakGS: Jamie Gauthier

EE was provided in 4-hr blocks 24 hours before and immediately after each weekly extinction session.

Baseline Cocaine Self-Administration

A BA

B