Research report
Chronic WIN55,212-2 elicits sustained and conditioned increases in intracranial self-stimulation thresholds in the rat

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Abstract

The present study sought to examine whether repeated administration of the CB1 receptor agonist WIN55,212-2 affected intracranial self-stimulation (ICSS) behavior and induced phenomena of tolerance or sensitization, similar to typical addictive drugs. Rats received intraperitoneal injections of vehicle for 5 days, vehicle or WIN55,212-2 (0.1, 0.3 or 1 mg/kg) for 20 subsequent days, and vehicle for 5 additional days. Thresholds for ICSS were measured before and after each injection. The initial five injections of vehicle did not affect ICSS thresholds. WIN55,212-2 (1 mg/kg) significantly increased ICSS thresholds from the first day of administration, an effect that remained stable across the subsequent days of administration. During the 5 additional days, where WIN55,212-2 was substituted with vehicle, rats demonstrated a conditioned increase in postinjection thresholds that was significant the first 3 days of this period. These findings indicate that repeated WIN55,212-2 administration elicited a sustained increase in ICSS, i.e., phenomena of tolerance or sensitization were not observed. The present data demonstrate cannabinoid-predictive stimuli that may gain affective salience and play an important role in maintaining cannabinoid administration.

Introduction

Dependence-producing substances with a high abuse potential that produce euphoric states in humans are believed to affect reinforcement and reward mechanisms by actions on certain areas and pathways of the brain, which are collectively known as brain reward systems. In most cases, these drugs also yield reinforcing and rewarding effects in experimental animals, as assessed by relevant animal models, such as self-administration, conditioned place preference and intracranial self-stimulation (ICSS) [29].

Although marijuana is considered to be one of the oldest and most widely used and abused drugs, our knowledge and understanding of the manner it acts in the brain to exert its reinforcing/rewarding effects are far from complete. Animal studies using several behavioral paradigms and under various experimental conditions have shown that Δ9-tetrahydrocannabinol (Δ9-THC) and other synthetic cannabinoid agonists can induce both appetitive and aversive effects (for reviews, see [7], [9], [10], [14], [15], [21], [31], [33]).

Intracranial self-stimulation (ICSS) has been suggested to be a valid approach for studying the rewarding/reinforcing properties of various drugs of abuse [38]. Indeed, drugs with reinforcing properties in animals and addictive potential in humans tend to facilitate the reinforcing effects of brain stimulation in rats, i.e., to lower thresholds for rewarding brain stimulation (ICSS thresholds), shifting to the left the function that relates response strength to stimulation strength. On the other hand, drugs that have a negative impact on reward and reinforcement of behavior typically increase ICSS thresholds shifting the function to the right [4], [38].

Interestingly, there are contradictory reports on the effects of cannabinoids on ICSS. Gardner and colleagues found that Δ9-THC decreases thresholds for ICSS primarily in Lewis rats [8], [13], whereas other studies have found no effect or increased thresholds for ICSS following acute administration of Δ9-THC or synthetic cannabinoid agonists in other rat strains [1], [2], [12], [32], [34], [35], [36]. These discrepancies, which are likely due to methodological differences, remain to be resolved.

A possible explanation for the failure to find a clear reward enhancing effect of cannabinoids in the ICSS model is that the first exposure(s) to the cannabinoid may produce severe dysphoric actions, which may mask the rewarding effects of the drug.

Interestingly, the effects of chronic cannabinoid administration on ICSS have not been examined. Such a study would allow us to track the cannabinoid effects over time, and this information might provide insight into the mechanisms that contribute to the abuse potential of cannabis preparations.

Hence, the purpose of the present study was to investigate whether repeated administration of the CB1 receptor agonist WIN55,212-2 affected ICSS behavior in the rat. Since acute administration of WIN55,212-2 has been shown to increase ICSS thresholds, our study was designed to assess not only the effects of daily WIN55,212-2 injections on brain stimulation reward, but also whether a conditioned stimulus associated with chronic WIN55,212-2 would affect brain reward function. To this end, we used a protocol invented by Markou and co-workers that assessed the effects of repeated cocaine administration on ICSS and potential, associated, conditioned phenomena [11].

Section snippets

Animals and surgery

Male Sprague-Dawley rats (n = 21) weighting 300–350 g at the time of surgery were used. Before surgery they were housed in groups of three and maintained on a 12 h light–12 h dark cycle with free access to food and water. The animals were anaesthetized with intramuscular (i.m.) injection of ketamine hydrochloride (100 mg/kg) and xylazine (10 mg/kg). Atropine sulphate (0.6 mg/kg, i.m.) was injected to reduce bronchial secretion. The animals were implanted with a monopolar stimulation electrode aimed at

Results

In the testing phase (Fig. 2), two-way ANOVA with repeated measures performed on the changes in self-stimulation thresholds showed a statistical significant drug effect [F(3,17) = 14.848, p < 0.001], but neither significant interaction of time and drug nor time effect, indicating neither tolerance nor sensitization. Furthermore, paired-samples t-test indicated statistical significant difference between the groups receiving 1 mg/kg and vehicle (p < 0.001) across all 20 days of administration. In

Discussion

ICSS thresholds remained stable and unaltered when measured before each daily injection of vehicle or WIN55,212-2 over the 30 consecutive days of testing. Furthermore, there was no difference between pre- and post-injection ICSS thresholds during the first 5 consecutive days of the baseline phase. However, postinjection ICSS thresholds were increased after each WIN55,212-2 injection during the testing phase. This effect was significant for the highest dose of WIN55,212-2 (1 mg/kg), and the

Acknowledgements

This study was supported by a grant from the Research Committee (KA 2303) and the Department of Psychology of the University of Crete. Maria Mavrikaki was supported by a scholarship from Alexander S. Onassis Public Benefit Foundation.

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