Dynamic changes of the endogenous cannabinoid and opioid mesocorticolimbic systems during adolescence: THC effects
Introduction
It is now well accepted that adolescence is an important period of active neural development (Rice and Barone, 2000, Charmandari et al., 2003) that may be particularly vulnerable to external insults and internal (e.g., hormonal and emotional) stress. Of growing concern is the fact that initiation of drug experimentation normally begins during adolescence (SAMHSA, 2007). Several clinical studies have linked repeated early cannabis exposure with the development of schizophrenia (Arseneault et al., 2002, van Os et al., 2002, Fergusson et al., 2003, Green et al., 2004, Veen et al., 2004) and an increased risk of other illicit drug use (Yamaguchi and Kandel, 1984, Fergusson and Horwood, 2000, Lynskey et al., 2003, Agrawal et al., 2004). While epidemiological studies have tried to evaluate underlying factors that may predispose individuals to use cannabis as well as other illicit drugs, e.g. genetic predisposition, peer-pressure, drug availability and risk-taking behavior (e.g. Hall and Lynskey, 2005), experimental animal studies have helped to provide insights into direct neurobiological alterations in the brain induced by cannabis. These alterations may contribute to the disturbance of reward neural pathways that influence the progression to future drug abuse. We recently observed in an adolescent rat model (Ellgren et al., 2007) that animals exposed to delta-9-tetrahydrocannabinol (THC; the main psychoactive ingredient of cannabis) at an early age resulted in higher intravenous heroin self-administration in adulthood. Moreover, molecular studies revealed specific alterations in the enkephalin opioid system within brain areas implicated in reward-related behavior, e.g. increased expression of proenkephalin (PENK) mRNA in the nucleus accumbens (NAc) shell and increased µ opioid receptor (µOR) activity in the ventral tegmental area. The time course of THC effects on the opioid system as well on the endogenous cannabinoids is however unknown. The aim of the present study was to explore potential neurochemical alterations during adolescent brain development in association with THC exposure that could account for the opioid reward-related disturbances observed previously in adult rats with adolescent THC use. To date, most developmental studies of the cannabinoid (Berrendero et al., 1999, Fernandez-Ruiz et al., 2000, Perez-Rosado et al., 2000, Ade and Lovinger, 2007) and opioid (Xia and Haddad, 1991, Brana et al., 1995, Georges et al., 1998) systems have focused on the embryonic and early postnatal stages. As such, another important aim of the current investigation was to assess the ontogeny of the cannabinoid and opioid systems in reward-related brain areas in the adolescent rat brain. The levels of cannabinoid receptor type 1 (CB1), mu opioid receptor (µOR), endocannabinoids (anandamide and 2-arachidonoylglycerol; 2-AG) and Met-enkephalin were analyzed in subregions of the striatum — NAc shell, NAc core, and caudate–putamen — of THC or vehicle exposed rats at ages corresponding to early (postnatal day; PND; 29), mid (PND 38) and late (PND 50) adolescence. Given the importance of the prefrontal cortex (PFC) in cognitive function and its protracted development until late adolescence/early adulthood, this cortical area was also examined.
Section snippets
Animals
Male Long–Evan rats (21 days old) were obtained from M&B Taconic, New York, USA. They were group-housed in a temperature-controlled environment on a reversed 12-h light/dark cycle (lights off at 11 a.m.) with ad libitum access to food and water. The rats were allowed to acclimate in their new environment and were handled daily for one week before the start of the experiment. All animal experiments were performed in accordance with the guidelines of The Swedish National Board for Laboratory
Endogenous cannabinoids
Concentrations of endogenous cannabinoids measured in the NAc, caudate–putamen and PFC during the adolescent period and the effect of THC exposure are shown in Fig. 1. The amount of anandamide in the NAc was found to depend on both age [F(2, 23) = 4.43, P < 0.05] and THC treatment [F(1, 23) = 10.51, P < 0.01]. Anandamide levels peaked at mid adolescence in vehicle-treated animals, where it was almost three times (165%) higher than at the early adolescence stage (43.5 vs. 16.4 pmol/g, P < 0.05) and almost
Discussion
The current results reveal clear developmental fluctuations throughout adolescence in endocannabinoid levels in the NAc and PFC, brain regions involved in reward, motivation, and cognition. The most profound alteration was the continuous increase in PFC anandamide levels throughout the adolescent period; concentrations were almost three times higher in late than early adolescence. However, the 2-AG concentrations were lower in the PFC in the later phases than in the beginning of the adolescent
Role of the funding source
This work was supported by the National Institute of Health grants DA 19350 (Y.L.H.) and DA 008863 (L.A.D.), The Danish Medical Council (H.S.H.), The Augustinus Foundation (H.S.H., S.H.H.) and Grete Sorensen. None of these organizations had any further role in any aspect of the work conducted for this study.
Contributors
Ellgren, M. Design, performed experiments and wrote the manuscript.
Artmann, A. Performed endocannabinoid experiments.
Tkalych, O. Performed peptide experiments.
Gupta, A. Assisted with opioid experiments.
Hansen, H.S. Supervised endocannabinoid experiments.
Hansen, S.H. Supervised endocannabinoid experiments.
Devi, L.A. Supervised opioid receptor experiments.
Hurd, Y.L. Design, supervised experiments and wrote the manuscript.
Conflict of interest
No conflict of interest.
Acknowledgement
We thank Mrs. Alexandra Tylec for technical assistance.
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