In this study we show that animals with higher addiction liability exhibit more persistent VTA neuroadaptations after drug exposure than their counterparts with lower addiction liability. Specifically, withdrawal from cocaine self-administration produced an increase in firing and bursting of VTA dopamine cells in all animals, but this increase was longer lasting in HR rats compared with LR rats.
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
), 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.
) 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.
) 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.
) would, instead, be important by enabling dopamine cells to fire more readily in response to salient stimuli such as drug cues (14
This is the first study, to our knowledge, that examines VTA neuroadaptations in a naturally occurring population of individuals with differential reactivity to drugs of abuse. Studies that use pharmacological or genetic manipulations have shown that changing dopamine cell excitability can modify addiction-related behaviors (1
). However, such studies are not designed to detect mechanisms that confer addiction risk in the natural population. Our finding that rats with elevated addiction liability show prolonged neuroadaptations of dopamine cell activity suggests that such plasticity contributes to addiction.