Marijuana and the Cannabinoids

114 Raymon and Walls
Fig. 12. The reward pathway: possible site of action of Cannabis. ∆ 9 -Tetrahydrocannabinol
may reinforce the effects of opiates and increase the firing of dopamine
neurons from the ventral tegmental area. Neurons in the dashed line are inhibitory;
neurons in the solid line are excitatory.
likely to be severe in the case of THC use because THC is highly lipophilic and slow
release from the fat tissues in chronic users should result in a tapering of the effects of
Cannabis over time. Nevertheless, rimonabant can precipitate withdrawal in animals,
indicating the involvement of CB 1 receptors in tolerance and dependence to THC (79).
When agonists are chronically used, receptors desensitize or downregulate. CB 1
receptors are downregulated after chronic exposure to THC (80), and chronic exposure
to an anandamide derivative, methanandamide, causes internalization of G protein-linked
receptors from the plasma membrane of hippocampal neurons, an effect
blocked by rimonabant (81). These findings would result in an expected reduction of
effects of cannabinoids when administered chronically. Not all effects of a drug show
the same degree of tolerance. In animals, tolerance to the hypothermic, locomotor,
analgesic, and immune-suppressant effects of cannabinoids in mice was studied (82,83).
But there is a notable absence of tolerance to cognition defects induced by THC in
animals, suggesting that impairing effects of Cannabis on learning and memory would
persist in chronic marijuana users (84). The same is true of the increased dopamine
firing in the VTA of rats, suggesting a lack of tolerance to the pleasurable effects of
Cannabis use in humans (83).
6. CANNABINOIDS AND CARDIOVASCULAR EFFECTS
Most of the research on cannabinoids has focused on the CNS, yet there are very
well-described effects of synthetic and endogenous cannabinoids in the periphery,