Recently, it has been proposed that not only the presence but also the duration of dopamine cell neuroadaptations is an important determinant of addiction (6). As such, prolonging VTA dopamine cell plasticity extends the duration of the neuroadaptations observed in the nucleus accumbens (7). However, it is unknown if differences in the duration of drug-induced neuroadaptations contribute to increased addiction liability in “at-risk” populations. To address this question, we chose to study dopamine cell neuroadaptations after drug exposure in a model of spontaneous addiction liability: high- and low-responder (HR and LR) rats. HR and LR rats are identified according to their high or low locomotor reactivity to a novel environment. Relative to LR rats, HR rats show enhanced addiction liability in several models: acquisition of psychostimulant self-administration (8, 9), escalation of drug intake (10), sensitization (11), and impulsivity (12, but see 13).

Relative to LR rats, HRs exhibit higher drug responding in a number of models including acquisition of low dose of cocaine self-administration, escalation of drug intake, and behavioral sensitization (15). Here we designed the self-administration paradigms to minimize differences in drug intake. Thus, we used a high drug dose, a low workload to obtain the drug, and short training. Under these conditions, HRs and LRs are known to exhibit similar acquisition of self-administration behavior (10, 15, 16), which ensured that all animals acquired the operant response at a similar rate and took a similar amount of cocaine (16). Despite similar drug intake, HR rats showed a more persistent elevation in dopamine cell firing during withdrawal than LR rats. Thus, this difference is independent of learning of operant responding and of amount of drug consumed. Such prolonged drug-induced plasticity in HR rats may be viewed as a reduced ability of dopamine cells to return to baseline. In contrast, LR rats have greater elasticity and ability to return to baseline.

Recent evidence suggests that the duration of drug-induced neuroadaptations of VTA dopamine cells is critical for determining long-lasting addiction (6). Mameli et al. (7) demonstrated that manipulations that prolong neuroadaptations in excitatory synaptic drive onto VTA dopamine neurons also lead to a more persistent form of plasticity being transferred to the nucleus accumbens. Using a paradigm similar to ours, Chen et al. (17) showed that VTA neuroadaptations are longer-lasting if associated with self-administration of cocaine rather than yoked or experimenter-delivered drugs. These authors observed persistent changes in VTA excitatory synaptic strength that lasted nearly three months. Interestingly, in measurements of cell firing, baseline levels were re-established within one week of drug withdrawal (present study, and 14, 18). This indicates that an increase in the strength of excitatory synapses onto dopamine neurons does not translate into the integrated output of these cells as measured by firing activity. Thus, increases in firing rate observed during drug withdrawal may primarily depend on other mechanisms, such as changes in the function of dopamine D2 autoreceptors (14) or metabotropic glutamate receptors (7). The longer-lasting increases in excitatory synaptic strength observed by Chen et al. (18) would, instead, be important by enabling dopamine cells to fire more readily in response to salient stimuli such as drug cues (14).

01

02