Cannabinoid Withdrawal Effects On Cns Reward Substrates

Whereas administration of addictive drugs produces enhancement of electrical brain-stimulation reward and mesoaccumbens DA, withdrawal from such drugs produces inhibition of electrical brain-stimulation reward and depletion of DA in CNS reward loci (see, e.g. Kokkinidis et al., 1980; Cassens et al., 1981; Schaefer and Michael, 1986; Frank et al., 1988; Kokkinidis and McCarter, 1990; Parsons et al., 1991; Robertson et al., 1991; Pothos et al., 1991; Rossetti et al., 1992; Schulteis et al., 1994; Spanagel et al., 1994; Wise and Munn, 1995). Based on such findings, elevations in brain-stimulation reward thresholds and DA depletion in CNS reward substrates have been proposed as the underlying neural basis for post-drug-use anhedonia and drug craving (Dackis and Gold, 1985; Koob et al., 1989; Markou and Koob, 1991). As noted by Wise and Munn (1995), "dopamine depletion and... attendant subsensitivity of the reward system offers a withdrawal symptom that may be more significant for drug self-administration than classic [physical withdrawal]... symptoms" and "subsensitivity of the reward system... is more obviously linked to the habit-forming property of drugs rather than to correlated side effects." Importantly, since elevations in brain-stimulation reward thresholds and correlated DA depletion in CNS reward substrates - unlike physical withdrawal symptoms - offer a set of withdrawal symptoms common to opiates, psychostimulants, and ethanol, they may constitute the long-sought common denominator for addiction.

Koob and colleagues have proposed yet another common denominator of withdrawal from addictive drugs - elevations of corticotropin-releasing factor (CRF) in the central nucleus of the amygdala (Merlo Pich et al., 1995; Koob, 1996). This is a provocative hypothesis, since the amygdala has been suggested to mediate neural substrates of fear and anxiety (Le Doux et al., 1988; Davis, 1992) and - as noted above - to mediate neural substrates of an emotional memory system that facilitates stimulus-reward learning (Cador et al., 1989; Everitt et al., 1989; Gaffan, 1992) and drug-seeking behavior (Hiroi and White, 1991; White and Hiroi, 1993).

Cannabinoids appear to interact with these CNS substrates of drug withdrawal in a fashion strikingly similar to that shown by other addictive drugs. The present author has reported that significant elevations in brain-stimulation reward thresholds (i.e., inhibition of CNS reward substrates) are seen during acute withdrawal from low doses of A9-THC (Gardner and Lepore, 1996; Gardner and Vorel, 1998). And Rodriguez de Fonseca and colleagues (1997) have shown that acute cannabinoid withdrawal is accompanied by marked CRF elevations in the central nucleus of the amygdala, with maximal CRF elevations correlated with maximal cannabinoid withdrawal signs. These data suggest that cannabinoid withdrawal - at least with respect to effects on CNS reward substrates - is strikingly similar to that seen with other addictive drugs.

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Getting to Know Anxiety

Getting to Know Anxiety

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