An animal model of female adolescent cannabinoid exposure elicits a long-lasting deficit in presynaptic long-term plasticity

Highlights

• We used female mice to model adolescent cannabinoid exposure.

• We examine changes presynaptic long-term potentiation (LTP).

• Endocannabinoid-LTP and mGluR2/3-LTP are impaired in model for adolescent cannabinoid exposure.

• Adolescent CB1R agonist exposure triggers cognitive deficiency.

Abstract

Cannabis continues to be the most accessible and popular illicit recreational drug. Whereas current data link adolescence cannabinoid exposure to increased risk for dependence on other drugs, depression, anxiety disorders and psychosis, the mechanism(s) underlying these adverse effects remains controversial. Here we show in a mouse model of female adolescent cannabinoid exposure deficient endocannabinoid (eCB)-mediated signaling and presynaptic forms of long-term depression at adult central glutamatergic synapses in the prefrontal cortex. Increasing endocannabinoid levels by blockade of monoacylglycerol lipase, the primary enzyme responsible for degrading the endocannabinoid 2-arachidonoylglycerol (2-AG), with the specific inhibitor JZL 184 ameliorates eCB-LTD deficits. The observed deficit in cortical presynaptic signaling may represent a neural maladaptation underlying network instability and abnormal cognitive functioning. Our study suggests that adolescent cannabinoid exposure may permanently impair brain functions, including the brain's intrinsic ability to appropriately adapt to external influences.

Introduction

Cannabis is the most prevalent illicit recreational drug. A total of 2.6–5% of the world's population (119–224 million people) consume cannabis, whereas 0.3–0.4% of the population consume cocaine (UNODC, 2012). On exposure to cannabis, individuals experience a variety of psychoactive effects including a general alteration of conscious perception, euphoria, impaired social interactions, disrupted memory and learning, and occasionally anxiety and paranoia. Cannabis abuse is considered to be a significant environmental risk for neuropsychiatric disorders (Arseneault et al., 2004). It is presently accepted that many mental illnesses, including psychosis, are the result of abnormal and synergistic interactions between multiple genes and environmental factors. For example, genetic variation in the gene COMT is itself a well-characterized risk factor for schizophrenia (Goldberg et al., 2003). It has been demonstrated that the relative risk of developing psychosis following the use of cannabis is increased in people carrying a common polymorphism within the COMT (Val158Met allele) gene, but this effect was observed only in people who used cannabis during adolescence (Caspi et al., 2005). While current data link adolescent cannabis abuse to increased risk for dependence on other drugs, depression, anxiety disorders and psychosis (Arseneault et al., 2004), the mechanism(s) underlying these adverse effects remains controversial.

In the brain, cannabis exerts its psychological effects through direct binding of its active ingredient, Δ⁹-tetrahydrocannabinol (THC) (Mechoulam and Gaoni, 1965) to the G-protein-coupled, type 1-cannabinoid receptor (CB1R) (Howlett et al., 2002, Matsuda et al., 1990) expressed on presynaptic terminals (Freund et al., 2003, Gerdeman and Lovinger, 2001, Huang et al., 2001, Katona et al., 1999, Katona et al., 2006). Endogenous ligands of CB1R, which are referred as to endocannabinoids (eCBs), act as retrograde signals inhibiting neurotransmitter release (Choi and Lovinger, 1997a, Choi and Lovinger, 1997b). 2-arachidonoylglycerol (2-AG) is most abundant endogenous ligand of CB1R in the brain (Stella et al., 1997). In fact, the eCB system represents a major activity-dependent regulatory system in the central nervous system and has been implicated in multiple brain functions, including synaptic plasticity and the homeostatic regulation of network activity patterns (Freund et al., 2003, Gerdeman and Lovinger, 2003, Piomelli, 2003, Raver et al., 2013, Sales-Carbonell et al., 2013). CB1R-mediated decreased probability of neurotransmitter release underlies transient, depolarization-induced synaptic inhibition (Wilson and Nicoll, 2001), long-term depression (Choi and Lovinger, 1997b) and the postnatal development of corticostriatal synapses (Choi and Lovinger, 1997b).

During adolescence, the prefrontal cortex (PFC), one of the latest regions of the brain to mature, undergoes significant developmental modification of its circuits that can be translated to cognitive, emotional and behavioral progression (Gogtay et al., 2004). Although the behavioral effects of administration of CB1R agonists during adolescence have been studied (Raver et al., 2013, Realini et al., 2011, Rubino et al., 2009, Rubino et al., 2008, Zamberletti et al., 2014), the possible permanent effects of CB1R hyperactivity during adolescence on mPFC network physiology are still unclear. Studies of adult female rats exposed to THC during adolescence revealed altered behaviors including anhedonia, behavioral despair, reduced sociability, deficits in spatial-working and object recognition memory, as well as sensitization to phencyclidine locomotor-activating effects (Realini et al., 2011, Rubino et al., 2009, Rubino et al., 2008, Zamberletti et al., 2014). Similarly treated male rats also developed abnormal behavior in adulthood but behavioral changes were less complex and limited to cognitive deficits (Rubino et al., 2009, Rubino et al., 2008). In addition, exposure to cannabinoids during adulthood was ineffective in producing this phenotype in female rats (Realini et al., 2011).

To detect potential prefrontal maladaptations triggered by adolescent cannabinoid exposure, we tested multiple forms of presynaptic plasticity at the cortical layer (L)2/3 to L5 (L2/3→L5) glutamatergic synapse in the mPFC of adult female mice treated sub-chronically during adolescence with the cannabinoid agonist, WIN55,212-2 and investigated the effects of this treatment on presynaptic plasticity in the adult. We found that two types of long-term depression (LTD), LTD mediated by metabotropic glutamate receptors 2/3 (mGluR2/3) and LTD mediated by CB1Rs, were deficient in adulthood in mice treated with WIN55,212-2. Over-activation of the CB1R during adolescence could therefore lead to permanent developmental changes in the expression of presynaptic LTD in the mPFC at excitatory synapses. These observations could be linked to a maladaptation of the mPFC network during a critical period of cortical development and may underlie the alteration of gamma oscillations in adults after adolescent CB1R stimulation, as found in earlier studies(Raver et al., 2013, Sales-Carbonell et al., 2013, Skosnik et al., 2012).