As noted above, different addictive drugs enhance reward by acting at different sites within the reward substrates of the CNS. Nicotine, ethanol, benzodiazepines, and barbiturates appear to act - transsynaptically - within somatic and dendritic regions of the "second-stage" DA neurons in the ventral tegmental area; cocaine, amphetamines, and dissociative anesthetics appear to act primarily on the axon terminal projections of the "second-stage" DA neurons within the nucleus accumbens. Opiates act on reward substrates within the ventral tegmental area, nucleus accumbens, and ventral pallidum (Gardner, 1997). The site(s) of cannabinoid action on CNS reward substrates has been addressed in several ways - some direct and some inferential. One of the direct ways used in the present author's laboratory has been to study the effects of local intracranial cannabinoid microinjections on DA levels in the nucleus accumbens as measured by in vivo brain microdialysis
(Chen et al., 1993). In those studies, we found that direct microinfusions of A9-THC into the nucleus accumbens dose-dependently enhanced accumbens DA levels. We also found that direct microinjections of A9-THC into the ventral tegmental area dose-dependently enhanced local somatodendritic DA release within the ventral tegmental area, but did not enhance nucleus accumbens DA levels (Chen et al., 1993). This suggests that locally-applied ventral tegmental area A9-THC does not alter local DA neuronal firing, and further suggests that the elevated nucleus accumbens DA levels and enhanced brain-stimulation reward produced by systemic cannabinoid administration result from local pharmacological action at or near the "second-stage" DA axon terminals in the nucleus accumbens. However, as noted above, systemic cannabinoid administration does enhance the neuronal firing of the "second-stage" DA reward neurons (French, 1997; French et al., 1997; Gessa et al., 1998). Furthermore, intracranial microinjection of the ^ opioid antagonist naloxonazine directly into the ventral tegmental area attenuates cannabinoid-induced enhancement of nucleus accumbens DA levels (Tanda et al., 1997). In addition -and puzzlingly - systemic naloxone (at doses high enough to block endogenous CNS opioid mechanisms) does not inhibit A9-THC's enhancement of "second-stage" DA neuronal firing in the ventral tegmental area-nucleus accumbens axis (French, 1997). To this reviewer, this combination of findings is frankly puzzling, as it is by no means clear why local CNS microinjections of an opioid antagonist should attenuate the cannabinoid effects, while systemic administration of an opioid antagonist (at doses clearly high enough to enter the CNS and affect local CNS circuits) fails to do so. However, trusting that all of these findings are correct, one is forced to surmise that cannabinoids enhance DA in the nucleus accumbens "second-stage" DA terminal projection area by acting at a combination of CNS loci: (1) within the nucleus accumbens - by acting on a neuronal mechanism closely linked to axon terminal DA release; (2) within the ventral tegmental area - by acting on an endogenous opioid mechanism not linked to activation of neuronal firing, but rather linked to mechanisms of DA synthesis, transport, and/or release; and (3) also within the ventral tegmental area - by acting on a non-endogenous-opioid mechanism linked to activation of "second-stage" DA neuronal firing. While this combination of putative cannabinoid sites of action is somewhat complex, it is hardly beyond possibility. Drugs acting on the CNS often act at multiple sites; indeed, more often than not. That cannabinoids should share such complexity is not surprising, at least to this reviewer.
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