Adolescent cannabinoid exposure induces irritability-like behavior and cocaine cross-sensitization without affecting the escalation of cocaine self-administration in adulthood

Jenni Kononoff,Marsida Kallupi,Eric R Kandel,Philippe A Melas,Giordano De Guglielmo,Maria Scherma,Denise B Kandel,Olivier George,Adam Kimbrough,Paola Fadda

doi:10.1038/s41598-018-31921-5

Abstract

Cannabis use is typically initiated during adolescence and is a significant risk factor for the development of cocaine use in adulthood. However, no preclinical studies have examined the effects of adolescent cannabinoid exposure on cocaine dependence in adulthood using the escalation model of cocaine self-administration and the assessment of negative emotional states. In the present study, we found that exposure to the cannabinoid receptor agonist WIN55,212-2 (WIN) in adolescence produced irritability-like behavior and psychomotor cross-sensitization to cocaine in adolescence. In adulthood, rats were allowed to self-administer cocaine. The acquisition of cocaine self-administration was lower in rats with adolescent WIN exposure compared with controls. However, both WIN-exposed and control rats escalated their cocaine intake at the same rate, had similar responding under a progressive-ratio schedule of reinforcement, and had similar psychomotor responses to cocaine. Interestingly, the increase in irritability-like behavior that was previously observed in adolescence after WIN exposure persisted into adulthood. Whether the persisting increase in irritability-like behavior after WIN exposure has translational relevance remains to be studied. In summary, these results suggest that psychoactive cannabinoid exposure during adolescence is unlikely to have a major effect on the escalation of cocaine intake or the development of compulsive-like responding per se in adulthood in a rat model of cocaine self-administration. However, whether the persisting irritability-like behavior may predispose an individual to mood-related impairments in adulthood or predict such impairments warrants further investigation.

Highlights

Cannabis is one of the most frequently used psychoactive substances in the world[1] and is the subject of major debates between proponents of the gateway hypothesis[2] and advocates of legalization
Previous studies reported that exposure to the cannabinoid receptor agonist WIN55,212-2 (WIN) during adolescence decreased the reactivity of dopaminergic neurons to WIN, produced cross-tolerance to cocaine in adolescence[14], and produced cross-sensitization to the psychomotor effects of cocaine in adolescence but not in adulthood[15]
The present study found that adolescent WIN exposure (i) increased irritability-like behavior in adolescence, which persisted into adulthood, (ii) induced cross-sensitization to the locomotor-stimulating effect of cocaine in adolescence, which did not persist into adulthood, (iii) decreased the speed of acquisition but not the rate of cocaine self-administration in adulthood, and (iv) had no effect on the escalation of cocaine self-administration in adulthood

Summary

Introduction

Cannabis is one of the most frequently used psychoactive substances in the world[1] and is the subject of major debates between proponents of the gateway hypothesis[2] and advocates of legalization. Previous studies reported that exposure to the cannabinoid receptor agonist WIN55,212-2 (WIN) during adolescence decreased the reactivity of dopaminergic neurons to WIN (i.e., tolerance), produced cross-tolerance to cocaine in adolescence[14], and produced cross-sensitization to the psychomotor effects of cocaine in adolescence but not in adulthood[15] This effect appears to be mediated by the modulation of eukaryotic initiation factors in the brain[15]. A major limitation of these preclinical studies is the use of an animal model of cocaine exposure (psychomotor sensitization) that reflects neither the direct acquisition of cocaine use (measured by self-administration) nor the compulsive nature of cocaine use disorder (measured by the escalation of self-administration) To address this issue, we tested the effect of adolescent exposure to the cannabinoid receptor agonist WIN on key addiction-related behaviors using a more complex animal model of drug addiction. The long-access model represents a comprehensive model of human addiction[21] because it produces the escalation of cocaine intake that is associated with the emergence of negative emotional states[22] and compulsive-like responding despite adverse consequence[23,24,25,26]

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Results

Conclusion