Increased conditioned fear response and altered balance of dopamine in the shell and core of the nucleus accumbens during amphetamine withdrawal

It has been suggested that neuroadaptations within the nucleus accumbens (NAC) dopaminergic (DA) projection contribute to the negative affect associated with psychostimulant withdrawal. The present study assessed the effects of amphetamine (AMPH) withdrawal on behavioral and NAC DA responses to conditioned fear stress. Animals injected with escalating-dose AMPH (1-5mg/kg, three injections/day, 6 days) or saline (SAL) acquired a tone-shock association on withdrawal day 3 and were tested for extinction of conditioned freezing to the tone on withdrawal day 4. Extracellular levels of NAC shell and core DA were monitored using in vivo microdialysis on both days. AMPH-withdrawn animals exhibited more conditioned freezing than SAL animals during both acquisition and extinction. During acquisition, DA increased more in the shell than the core of the NAC in both AMPH and SAL groups. During extinction to the tone, shell DA increased in SAL- but not AMPH-treated animals, whereas core DA activity was greater in AMPH than SAL animals. These data demonstrate that AMPH withdrawal alters the balance between shell and core DA transmission while increasing the behavioral expression of conditioned fear. Such drug-induced neuroadaptations in the NAC stress response may be involved in the exacerbation of negative emotions associated with drug withdrawal and stimulant-induced psychosis.