Adolescent THC Exposition and vulnerability to drug abuse

Emerging evidence suggests that the use of cannabis during adolescence might lead to neurobiological changes that can affect adult brain functions and behavior[1]. Given the role of endocannabinoid system in this critical phase of life and in the expression of drug reward-related behaviors[2], the aim of this study was to investigate whether cannabis exposure during adolescence might increase reinforcing effects of abused drugs, such as nicotine, heroin and cannabinoids, in adulthood. For this purpose behavioral, neurochemical studies have been conducted. Male adolescent rats (Sprague-Dawley for nicotine and heroin studies; Lister Hooded for WIN55,212-2 studies[3]) (45 postnatal day, PND) were treated intraperitoneally with increasing doses of THC (2.5, 5 and 10 mg/kg) twice/day for 11 consecutive days. Once animals reached the adulthood (75 PND), we studied the effects of THC exposure on acquisition of nicotine (30 μg/kg/infusion), heroin (30 μg/kg/infusion) and WIN55,212-2 (12,5 μg/kg/infusion) intravenous self-administration behavior using a continuous-reinforcement (fixed-ratio (FR) 1) schedule. Faster acquisition and higher rate of drug intake was considered as index of vulnerability to drug abuse. In a different set of animals that underwent the same drug treatment, dopamine release in the shell of the nucleus accumbens (coordinates from bregma, AP: -1.7, L 0.7, V: -8.2)[4] was measured both in basal condition and after a drug challenge in order to evaluate possible modifications at the level of the mesolimbic dopaminergic system, a brain circuit crucially involved in the mechanisms of reward and dependence related to drug abuse. Behavioral data from nicotine self administration showed no significant difference between the two group of animals although the THC group showed lower, but not significant, responding with respect to the control group. On the other hand, THC exposure increased both heroin and WIN55,212-2 infusions per sessions compared to the control groups. Interestingly, neurochemical data showed a significant difference between two groups of treatment in respect to drug challenge, with a significant lower release of dopamine after nicotine (0.4mg/kg i.p.) and WIN55,212-2 (0.3mg/kg i.v.) and a significant increase after heroin (0.06mg/kg i.v.) in the THC treated animals with respect to control group. Altogether, these results seem to support the hypothesis that early cannabis exposure increased the vulnerability to heroin and cannabinoids abuse in adulthood, with different mechanisms, but not to nicotine abus

Adolescence versus adulthood: differential effects of drugs of abuse on mesolimbic dopamine transmission

Increasing evidences suggest a heightened vulnerability to drugs of abuse in adolescence. During this developmental time frame the brain undergoes extensive remodelling affecting particularly reward system. Such changes involve both mesocortical and mesolimbic pathways. There is evidence for a predominance of ventral striatum (approach system) relative to prefrontal cortex (regulatory system) that produce typical adolescent behaviors (risk-taking, novelty seeking etc.) but, although most of the studies suggest a delayed maturation of the PFC, it is still debated if dopaminergic transmission in the nucleus accumbens (NAc) of adolescents is hyper- or hypo- reactive. In rodent models, in spite of overwhelming studies on reward function, tested through conditioned place preference or self-administration paradigms, direct evidences on adolescent dopamine (DA) transmission responsiveness to drugs of abuse are limited. The aim of our study was to evaluate if there are differences in mesolimbic DA transmission between adults and adolescents after administration of different drugs of abuse through in vivo microdialysis. Male Sprague-Dawley rats of 5, 6, 7 or 10,11,12 weeks of age were implanted with dual probe, aimed at the shell and core of NAc and challenged with nicotine (0.4 mg/kg s.c.), Δ9-tetrahydrocannabinol (THC, 1.0 mg/kg i.p.), cocaine (10 mg/kg i.p.) or morphine (1.0 mg/kg s.c.) and extracellular DA levels monitored simultaneously with behaviour. Although no significant differences were observed between adolescents and adults in basal DA levels, neither in the shell and core of NAc, adolescents showed different effects depending on the drug and on the age of exposure. While no differences were observed in DA transmission responsiveness, both in the shell and in the core of NAc, after morphine or nicotine administration, rats at 6 weeks of age showed greater increase of DA levels in the NAc shell following 1.0 mg/kg i.p. of THC compared to adult rats. Moreover 5 weeks animals appear to be less sensitive to the DA increasing effects of cocaine (10 mg/kg i.p.) compared to adolescents of 6 and 7 weeks and to adults. While differences observed following THC and cocaine challenge might be explained respectively by changes occurring in endocannabinoid system during development and in DA uptake transporter (DAT) levels as reported by previous studies, these results add new insights in the development of the reward system during different stages of adolescence

Adolescence versus adulthood: differential effects of drugs of abuse on mesolimbic and nigrostriatal dopamine transmission

Increasing evidence suggests a heightened vulnerability to drugs of abuse in adolescence. During this developmental time frame the brain undergoes extensive remodelling affecting particularly reward system. Such changes involve both mesocortical and mesolimbic pathways. There is evidence for a predominance of ventral striatum (approach system) relative to prefrontal cortex (regulatory system) that produce typical adolescent behaviors (risk-taking, novelty seeking etc.) but, although most of the studies suggest a delayed maturation of the PFC, it is still debated if dopaminergic (DA) transmission in the nucleus accumbens (NAc) of adolescents is hyper- or hypo- responsive. In rodent models, in spite of overwhelming studies on reward function, tested through conditioned place preference or self-administration paradigms, direct evidence on adolescent DA transmission responsiveness to drugs of abuse is limited. The aim of our study was to evaluate differences in mesolimbic DA transmission between adults and adolescent rats and its responsiveness to different drugs of abuse through in vivo microdialysis. Male Sprague-Dawley rats of 5, 6, 7 or 10,11,12 weeks of age were implanted with dual probe, aimed at the shell and core of NAc and challenged with nicotine, Δ9-tetrahydrocannabinol (THC), cocaine, or morphine and extracellular DA levels monitored simultaneously with behaviour. Although no significant differences were observed between adolescents and adults in basal DA levels, neither in the shell nor in the core of NAc, adolescents showed different effects depending on the drug and age of exposure. While no differences were observed in DA transmission responsiveness, both in the shell and in the core of NAc, after cocaine administration, adolescent rats showed greater increase of extracellular DA in the NAc shell following nicotine, THC and morphine compared with adult rats. Moreover behavioral activation was significantly different in adolescent compared with adult rats. While differences observed following THC might be explained by changes occurring in endocannabinoid systems during development, differences following nicotine might be related to differential expression of nicotinic receptors. In conclusion, these results while adding new insight in the development of the reward system during different stages of adolescence provide a likely explanation of the gateway effect of nicotine and THC toward abuse of other illicit substances

Mesolimbic dopamine transmission of adolescent and adult rats are differentially affected by drugs of abuse

Increasing evidences suggest a heightened vulnerability to drugs of abuse in adolescence. During this developmental time frame the brain undergoes extensive remodelling affecting particularly reward system. Such changes involve both mesocortical and mesolimbic pathways. There is evidence for a predominance of ventral striatum (approach system) relative to prefrontal cortex (regulatory system) that produce typical adolescent behaviors (risk-taking, novelty seeking etc.) but, although most of the studies suggest a delayed maturation of the PFC, it is still debated if dopaminergic transmission in the nucleus accumbens (NAc) of adolescents is hyper- or hypo- reactive. In rodent models, in spite of overwhelming studies on reward function, tested through conditioned place preference or self-administration paradigms, direct evidences on adolescent dopamine (DA) transmission responsiveness to drugs of abuse are limited. In order to assess differences in mesolimbic DA transmission between adults and adolescents and its responsiveness to different drugs of abuse we used in vivo microdialysis. Male Sprague-Dawley rats of 5, 6, 7 or 10,11,12 weeks of age were implanted with dual probe, aimed at the shell and core of NAc and challenged with nicotine (0.4 mg/kg s.c.), Δ9-tetrahydrocannabinol (THC, 1.0mg/kg i.p.), cocaine (10 mg/kg i.p.) or morphine (1.0 mg/kg s.c.) and extracellular DA levels monitored simultaneously with behaviour. Although no significant differences were observed between adolescents and adults in basal DA levels, neither in the shell and core of NAc, adolescents showed different effects depending on the drug and on the age of exposure. While no differences were observed in DA transmission responsiveness, both in the shell and in the core of NAc, after morphine or nicotine administration, rats at 6 weeks of age showed greater increase of DA levels in the NAc shell following 1.0 mg/kg i.p. of THC compared to adult rats. Moreover 5 weeks animals appear to be less sensitive to the DA increasing effects of cocaine (10 mg/kg i.p.) compared to adolescents of 6 and 7 weeks and to adults. The differences observed after THC and cocaine challenge might be explained respectively by changes in endocannabinoid system during development and in DA uptake transporter (DAT) levels as reported by previous studie