Chronic cocaine administration reduces striatal dopamine terminal density and striatal dopamine release which leads to drug-seeking behaviour

Abstract

Drug addiction is associated with altered dopamine (DA) neurotransmission in the basal ganglia. We have previously shown that chronic stimulation of the dopamine D2 receptor (D 2R) with cocaine results in reduced striatal DA terminal density. The aims of this study were to establish whether this reduction in DA terminal density results in reduced striatal DA release and increased cocaine-seeking behaviour and whether D 2R antagonism can restore the cocaine-induced alterations in DA neurotransmission and drug-seeking behaviour. Rats were housed individually and either control, cocaine, haloperidol (D 2R antagonist), or cocaine and haloperidol was administered in the drinking water for 16 weeks. Chronic cocaine treatment, which reduced striatal DA terminal density by 20%, resulted in a reduction in basal (−34%) and cocaine-evoked (−33%) striatal DA release and increased cocaine-seeking behaviour. These cocaine-mediated effects on striatal DA terminal density, DA release and drug-seeking could be prevented by co-administration with haloperidol. Basal and cocaine-evoked DA release in the striatum directly correlated with DA terminal density and with preference for cocaine. We conclude that striatal DA terminal density and DA release is an important factor in maintaining drug preference and should be considered as a factor in drug-seeking behaviour and relapse.