Rats were allowed to self-administer heroin (50 microg/kg per inj., 14 daily sessions), cocaine (500 microg/kg per inj., 10 daily sessions) or saline. The present study was designed to evaluate the relationship between reinstatement of drug-seeking behaviour following long-term extinction of intravenous (i.v.) drug self-administration (an animal model for craving) and long-term behavioural sensitization. These data indicate that withdrawal from chronic cannabinoid administration is associated with reduced dopaminergic transmission in the limbic system, similar to that observed with other addictive drugs these changes in neuronal plasticity may play a role in drug craving and relapse into drug addiction. Conversely, SR 141716A produced a further decrease of spontaneous activity in cannabinoid-treated although it was ineffective in control rats. The administration of Delta9-THC to spontaneously withdrawn rats restored neuronal activity. In contrast, both groups showed a reduction in dopamine cells activity as indicated by extracellular single unit recordings from antidromically identified meso-accumbens dopamine neurons. Administration of the cannabinoid antagonist SR 141716A precipitated an intense behavioral withdrawal syndrome, whereas abrupt Delta9-THC suspension failed to produce overt signs of abstinence. Rats were treated chronically with the major psychoactive ingredient of hashish and marijuana, Delta9-tetrahydrocannabinol (Delta9-THC). In the present study we sought to determine whether mesolimbic dopamine neurons are involved in the neurobiologic mechanisms underlying withdrawal from chronic cannabinoid exposure. The mesolimbic dopamine system has recently been implicated in the long-term aversive consequences of withdrawal from major drugs of abuse. As OT is known to inhibit development of drug tolerance and attenuate withdrawal symptoms, we suggest that OT downregulation could play a role during the establishment of the chronic effects of Delta9-THC. No changes in cell staining were observed in the paraventricular nucleus and supraoptic nucleus. Immunohistochemistry showed a large decrease in number of OT and NPOT-stained fibers in NAc (by 59% and 52%, respectively) and VTA (by 50% and 56%, respectively).
Real-time PCR revealed a 60% and 53% reduction of OT-NP mRNA in NAc and VTA, respectively, under chronic treatment, while no changes were observed in NAc after 24 h.
7 days) to rats, downregulates the expression of oxytocin-neurophysin (OT-NP) mRNA and of OT and oxytocin-associated NP (NPOT) immunoreactivity in nucleus accumbens (NAc) and ventral tegmental area (VTA), brain areas involved in reward and addiction. We found that chronic administration of Delta9-THC (1.5 mg/kg/day, i.p. Our goal was to identify genes modulated by Delta9-tetrahydrocannabinol (Delta9-THC) treatment. Moreover, in the last decade, a large body of evidence has been accumulated on the effects of cannabinoids on brain reward processes (Fattore et al., 2001 Gardner, 2002 Gardner and Vorel, 1998 Lichtman and Martin, 2005 Maldonado, 2002 Parolaro and Rubino, 2005 Tanda and Goldberg, 2003), in which several brain regions, including the nucleus accumbens (NAc) and the ventral tegmental area (VTA) have been implicated (Gardner, 2002 Lupica et al., 2004 Pistis et al., 2001 Wise, 2000).Ĭannabinoids are widely abused drugs. After a long debate, it is now accepted that cannabinoids including D 9 -THC could be addictive, leading to the development of tolerance and dependence (Gardner and Vorel, 1998 Lichtman and Martin, 2005 Martin et al., 2004 Parolaro and Rubino, 2005 Tanda and Goldberg, 2003 and references therein). Many of the biological effects of D 9 -THC in the nervous system are regulated by signaling through the G i/o -protein-coupled CB 1 cannabinoid receptor (CB 1 -R) (Howlett, 1995(Howlett,, 2004Mukhopadhyay et al., 2002).
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