Strain differences in the dose-response relationship for morphine self-administration and impulsive choice between Lewis and Fischer 344 rats.

Dose-response studies are thought to be a valuable tool to predict the most genetically drug-vulnerable individuals. However, dose-response curves for morphine self-administration have not yet been examined and nor strain differences might be evident. Therefore, this study aimed to define the dose-response curve for morphine self-administration (0.25, 0.5, 1 and 2 mg/kg) in Lewis (LEW) rats and their histocompatible Fischer-344 (F344) rats. In addition, impulsivity has been suggested as one of the genetic factors contributing most to the initiation of drug use. Therefore, the impulsive choice of both rat strains in the presence or absence of the same morphine doses was also analysed. LEW rats self-administered significantly more morphine whatever the dose tested and they exhibited greater basal impulsive choice compared with F344 rats. The F344 strain showed a preference for the dose of 0.5 mg/kg, while any of the doses used had a differential reinforcing effect in the LEW strain. The basal pattern of strain differences in impulsive choice was not affected by morphine administration. These data suggest that the LEW strain has a highly drug-vulnerable phenotype and they point to the strength of impulsivity as a pre-existing behavioural trait that might make this rat strain more vulnerable to the reinforcing effects of drugs and, therefore, to develop addiction.

Behavioral and molecular changes elicited by acute administration of SR141716 to Delta9-tetrahydrocannabinol-tolerant rats: an experimental model of cannabinoid abstinence.

Whether chronic cannabinoid consumption produces a dependent state comparable to that occurring with other drugs (e.g. the appearance of withdrawal signs when consumption is interrupted), and whether chronic cannabinoid consumption increases the risk of consuming other drugs of greater addictive power, are probably the two questions relating to cannabinoid addiction that provoke the most controversy. The present study was designed to further explore these two questions in laboratory animals. Firstly, we examined the effects of an acute challenge with SR141716 (an antagonist for the cannabinoid CB(1) receptor) in Delta(9)-tetrahydrocannabinol (Delta(9)-THC)-tolerant rats. This antagonist has been reported to precipitate a cannabinoid withdrawal syndrome. Thus, the administration of SR141716 to Delta(9)-THC-tolerant rats reduced inactivity in the open-field test and enhanced responses as tremor, turning and retropulsion-these responses that were only slightly enhanced in control rats. The administration of SR141716 increased the plasma prolactin and the corticosterone concentration in controls, but these increases were much lesser in Delta(9)-THC-tolerant rats. In addition, CRF-mRNA levels in the paraventricular hypothalamic nucleus, while reduced in SR141716-treated controls, were significantly increased in Delta(9)-THC-tolerant rats. The analysis of endocannabinoids also revealed that the administration of SR141716, which was mostly inactive in control rats, was able to reverse the changes in anandamide or 2-arachidonoylglycerol concentrations found in Delta(9)-THC-tolerant rats, in the striatum, limbic forebrain, diencephalon, cerebellum and brainstem, but not in the midbrain and hippocampus. As a second objective, we evaluated whether Delta(9)-THC-tolerant rats were more vulnerable to morphine in a self-administration paradigm. The Delta(9)-THC-tolerant and control rats self-administered morphine to a similar extent, in concordance with the similar values of dopaminergic activity in limbic and motor regions. In summary, our data indicate that Delta(9)-THC-tolerant rats were not more vulnerable to the reinforcing properties of morphine. However, they responded to the blockade of CB(1) receptors by exhibiting slightly but possibly relevant differences in behavioral, endocrine and molecular parameters compared to the response in non-tolerant rats. This is indicative of the existence of a withdrawal syndrome in cannabinoid-tolerant rats that is mild compared with abstinence in opioid-dependent rats.