Increased DA release with repeated drug exposure supports theories suggesting that drugs of abuse modify normally adaptive circuitry to be more responsive to drug stimuli and thus less flexible (Berridge and Robinson, 1998; Everitt and Robbins, 2005; Goldstein and Volkow, 2002; Kalivas, 2008). Drug-seeking behavior following repeated drug use is thought to be driven by a persistent, maladaptive allostatic state (Koob and Le Moal, 1997) and/or by altered attribution of incentive salience (Berridge and Robinson, 1998) rather than by drug-associated positive reinforcement. Additional work is required to determine how these addiction model interpretations map onto humans, and congruence across species remains a largely unaddressed, but increasingly recognized, chasm between clinical and pre-clinical data sets. The molecular mechanisms central to rodent synaptic plasticity following psychostimulant exposure highlighted in this review may also be predictive of clinically-relevant and pharmacologically-tractable targets for treatment of human psychostimulant addiction.
