Chronic Cannabinoid Administration Research Articles

Effects of SR 141716A after acute or chronic cannabinoid administration in dogs

The effects of N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1 H-pyrazole-3-carboxamide HCl (SR 141716A), a specific cannabinoid receptor antagonist, were assessed in the dog static ataxia test after either acute treatment with two cannabinoid receptor agonists, Δ 9-tetrahydrocannabinol and arachidonylethanolamide (anandamide), or chronic treatment with Δ 9-tetrahydrocannabinol. As previously reported, acute intravenous (i.v.) injected Δ 9-tetrahydrocannabinol produced dose-dependent cannabinoid effects, including marked static ataxia, prancing, loss of muscle tone, and incoordination. The behavioral profile of anandamide was distinctly different in that it produced a loss of muscle tone and considerable sedation with little static ataxia, prancing, or incoordination. Despite these qualitative differences between the two agonists, SR 141716A blocked the acute behavioral effects of both drugs indicating a cannabinoid receptor mechanism of action. Interestingly, SR 141716A was able to precipitate a withdrawal syndrome in Δ 9-tetrahydrocannabinol-tolerant dogs, but failed to produce any observable effects in dogs receiving chronic vehicle injections. Acute toxicity caused by anandamide, which was not blocked by SR 141716A, precluded conducting dependence studies with this drug. The Δ 9-tetrahydrocannabinol precipitated withdrawal syndrome included diarrhea, vomiting, excessive salivation, decreases in social behavior, and increases in restless behavior and trembling. This is the first demonstration of a precipitated withdrawal syndrome in a non-rodent species.

Mesolimbic dopaminergic decline after cannabinoid withdrawal.

The mesolimbic dopamine system has recently been implicated in the long-term aversive consequences of withdrawal from major drugs of abuse. In the present study we sought to determine whether mesolimbic dopamine neurons are involved in the neurobiologic mechanisms underlying withdrawal from chronic cannabinoid exposure. Rats were treated chronically with the major psychoactive ingredient of hashish and marijuana, Delta9-tetrahydrocannabinol (Delta9-THC). 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. 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. The administration of Delta9-THC to spontaneously withdrawn rats restored neuronal activity. Conversely, SR 141716A produced a further decrease of spontaneous activity in cannabinoid-treated although it was ineffective in control rats. 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.

Chronic administration of cannabinoids regulates proenkephalin mRNA levels in selected regions of the rat brain

This study was designed to examine the interactions between the cannabinoid and enkephalinergic systems in the rat brain. To this aim, we have examined the effects of subchronic (5 days) administration (10 mg·kg −1·day −1; i.p.) of Δ 9-tetrahydrocannabinol (THC) or R-methanandamide (AM356) and chronic (18 days) administration with the synthetic cannabinoid receptor agonist CP-55,940 (1 mg·kg −1·day −1; i.p.) on proenkephalin (PENK) mRNA levels in several brain regions of the rat. Twenty micrometer brain sections from striatum, nucleus accumbens, paraventricular nucleus, ventromedial nucleus, periaqueductal grey matter and mammillary nucleus were hybridized with an oligonucleotide probe complementary to PENK using in situ hybridization technique. Subchronic administration of THC or AM356 increased PENK mRNA levels in the ventromedial nucleus of the hypothalamus, (82%) and (39%), in the periaqueductal grey matter, (97%) and (49%), and mammillary nucleus, (43%) and (9%), respectively. In contrast, both drugs were without effect in the striatum and nucleus accumbens. On the other hand, chronic administration of CP-55,940 increased PENK mRNA levels in the striatum (44%), nucleus accumbens (25%), paraventricular (31%) and ventromedial nuclei of the hypothalamus (41%). These results revealed that chronic cannabinoid administration increases opioid gene expression in the rat central nervous system and suggest an interaction between the cannabinoid and enkephalinergic systems that may be part of a molecular integrative response to behavioral and neurochemical alterations that occur in cannabinoid drug abuse.

Chronic cannabinoid administration alters cannabinoid receptor binding in rat brain: a quantitative autoradiographic study

The active ingredient of marijuana is(−)-Δ 9-tetrahydrocannabinol(Δ 9-THC).Δ 9-THC and other natural and synthetic cannabinoids such as CP-55, 940 inhibit spontaneous activity and produce catalepsy in animals in a receptor-mediated fashion. Tolerance develops to the motor effects ofΔ 9-THC after repeated administration. To test the hypothesis that tolerance is mediated by changes in cannabinoid receptor binding characteristics, we used quantitative in vitro autoradiography of [ 3H]CP-55, 940 binding to striatal brain sections from rats treated either chronically or acutely withΔ 9-THC, CP-55, 940, or the inactive natural cannabinoid cannabidiol. In the chronic condition, rats were given daily i.p. injections ofδ 9-THC (10 mg/kg), cannabidiol (10 mg/kg), or CP-55, 940 (1, 3, or 10 mg/kg) for 2 weeks and sacrificed 30 min after the last injection. In the acute condition, animals received a single dose (10 mg/kg) prior to sacrifice. Rats developed tolerance to the inhibitory effects ofΔ 9-THC and CP-55, 940, assayed in an open field on days 1, 7, and 14. Cannabidiol had no effect on behavior. Densitometry of [ 3H]CP-55, 940 binding to brain sections showed thatδ 9-THC- and CP-55, 940-treated animals had homogeneous decreases in binding in all structures measured at the selected striatal level. Cannabidiol had no effect on binding. Analysis of binding parameters showed that alterations in the acute condition were attributed to changes in affinity (K D), whereas the major changes in the chronic condition were attributed to a lowering of capacity (B max). The effects in the 1, 3, and 10 mg/kg CP-55, 940 conditions were dose-dependent and paralleled the behavioral data showing that the animals given the highest dose developed the greatest degree of tolerance. The data suggest that tolerance to cannabinoids results at least in part from agonist-induced receptor down-regulation.