Since endogenous CNS opioid mechanisms are so clearly involved in mediating at least some cannabinoid effects on CNS reward substrates, it might logically be asked whether endogenous CNS cannabinoid systems are involved in mediating opioid effects on CNS reward substrates. There is little work addressing this possibility, but the few published studies are highly provocative to this reviewer's mind, notably the facts that morphine's rewarding properties and its ability to enhance nucleus accumbens DA are both markedly reduced in knockout mice lacking the CBX cannabinoid receptor (Ledent et al., 1999; Mascia, 1999; Cossu et al., 2001). In contrast, CBX receptor knockout mice retain their normal responses to the rewarding effects of cocaine, d-amphetamine, and nicotine - as assessed by intravenous self-administration (Cossu et al., 2001). Furthermore, CBX receptor knockout mice also retain their normal responses to the DA-enhancing effects of cocaine, as assessed by in vivo brain microdialysis (Mascia et al., 1999).
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