Chronic drug exposure-induced neurochemical changes in systems that are implicated in acute drug reward are called within-system neuroadaptations. Within-system neuroadaptations can be defined as those in which “the primary cellular response element to the drug…adapt[s] to neutralize the drug’s effects; persistence of the opposing effects after the drug disappears… produce[s] the withdrawal response.”68 Such changes include decreases in dopaminergic and serotonergic transmission in the nucleus accumbens during drug withdrawal as measured by in-vivo microdialysis in rats69 and brain imaging studies in humans, in which amphetamine-induced or methylphenidate-induced striatal dopamine responses are 50% lower in detoxified abusers and 80% lower in active abusers, and accompanied by lower self-reports of the drug’s rewarding effects relative to non-drug-abusing controls.25,35,61,70 Other observed changes include increases in μ opioid receptor responsivity during opioid withdrawal,71,72 and decreases in GABAergic and increases in NMDA glutamatergic transmission in the nucleus accumbens.73,74 Differential regional changes in nicotinic receptor function in the nucleus accumbens and ventral tegmental area in nicotine, alcohol, and other addictions have also been reported, implicating α4β2 nicotinic receptor subtypes.19,44 Such decreases in reward system function might
