Relapse to cocaine-seeking after hippocampal theta burst stimulation.

Treatment efforts for cocaine addiction are hampered by high relapse rates. To map brain areas underlying relapse, we used electrical brain stimulation and intracranial injection of pharmacological compounds after extinction of cocaine self-administration behavior in rats. Electrical stimulation of the hippocampus containing glutamatergic fibers, but not the medial forebrain bundle containing dopaminergic fibers, elicited cocaine-seeking behavior dependent on glutamate in the ventral tegmental area. This suggests a role for glutamatergic neurotransmission in relapse to cocaine abuse. The medial forebrain bundle electrodes supported intense electrical self-stimulation. These findings suggest a dissociation of neural systems subserving positive reinforcement (self-stimulation) and incentive motivation (relapse).

Cannabinoid transmission and reward-related events.

The reward/reinforcement circuitry of the mammalian brain consists of synaptically interconnected neurons associated with the medial forebrain bundle, linking the ventral tegmental area, nucleus accumbens, and ventral pallidum. Electrical stimulation of this circuit supports intense self-stimulation in animals and, in humans, produces intense pleasure or euphoria. This circuit is strongly implicated in the neural substrates of drug addiction and in such addiction-related phenomena as withdrawal dysphoria and craving. This circuit is also implicated in the pleasures produced by natural rewards (e.g., food, sex). Cannabinoids are euphorigenic in humans and have addictive liability in vulnerable persons, but were long considered "anomalous" drugs of abuse, lacking pharmacological interaction with these brain reward substrates. It is now clear, however, that cannabinoids activate these brain substrates and influence reward-related behaviors. From these actions, presumably, derive both the abuse potential of cannabinoids and the possible clinical efficacy in dysphoric states.

Conditioned place preference induced by delta 9-tetrahydrocannabinol: comparison with cocaine, morphine, and food reward.

The rewarding property of delta 9-tetrahydrocannabinol (THC), the psychoactive constituent of marijuana and hashish, was studied using the conditioned place preference paradigm, and compared to that of cocaine, morphine, and food reward. The results of Experiment 1 demonstrated that 2.0 and 4.0 mg/kg doses produced a reliable shift in preference for the THC-paired compartment. The THC place preference observed at 2.0 and 4.0 mg/kg was nearly equivalent to that produced by low doses of cocaine (5.0 mg/kg), morphine (4.0 mg/kg), and food in non food-deprived animals. The second experiment used a different conditioning procedure that included a washout period for THC. The results of Experiment 2 demonstrated that a THC place preference could be obtained using a lower dose of THC (1.0 mg/kg), and that this THC place preference was equivalent to that produced by 10 mg/kg cocaine. At higher doses (2.0 and 4.0 mg/kg), THC produced a dose-dependent place aversion. These results suggest that THC's action on brain reward substrates, previously demonstrated by electrical brain stimulation reward, in vivo brain microdialysis, and in vivo brain electrochemistry studies, reflects itself behaviorally in increased appetitive motivational value for environmental stimuli associated with ingestion of marijuana and hashish.