One hour, but not six hours, of daily access to self-administered cocaine results in elevated levels of the dopamine transporter

Abstract

We have previously shown that brief (1 h) and extended (6 h) daily access to IV cocaine self-administration produce different behavioral and neural consequences following 2 weeks of drug withdrawal. Brief daily access produced stable consumption of the drug and, after withdrawal, a sensitized locomotor response and an enhanced c-Fos labeling to a single cocaine challenge. In contrast, extended daily cocaine self-administration produced escalation of drug consumption over trials but no enhanced behavioral or neurochemical response after withdrawal. Cocaine affects dopaminergic (DA) function by binding to the presynaptic transporter and thereby preventing reuptake of the neurotransmitter-an action thought to be responsible for the drug's reinforcing properties. In an extension of our previous work, the current study, using receptor autoradiography, compared binding (by [3H]WIN35428) of the dopamine transporter (DAT) in animals having experienced either brief or extended daily access to cocaine over 8 days, followed by 14 days of withdrawal. DAT densities were found to increase in the nucleus accumbens core (N.Acc Core) and the dorsal striatum (but not in the N.Acc shell, medial prefrontal cortex (mPFC), or ventral tegmental area (VTA)) of the 1-h, but not 6-h, subjects. In other words, elevations in DAT density were not associated with the 6-h access group, the group that models patterns of drug-use in human addicts, and therefore are likely to be independent of the neuroadaptations that occur in the "addictive" process. Such conclusions are also consistent with brain-imaging studies of human cocaine addicts. Additional research will be needed to identify the specific neural changes relevant to addiction.

Fig. 1

Self-administration patterns—this figure illustrates mean number of self-administered cocaine infusions during the first hour of each trial (panel A) and throughout the session (panel B) on the first and last day of the 8 days of self-administration post-training. *Signifies significant difference between first and last day (P < 0.004).

Fig. 2

Sample DAT autoradiographs—schematics of all the brain areas sampled and their coordinates are illustrated in panel A. Panel B includes sample autoradiographs of sections including the nucleus accumbens and striatum of representative animals from the Saline, Coc1h, and Coc6h groups. Squares designate the approximate area from which measurements were taken (lower medial square—N.Acc Shell; lower lateral square—N.Acc Core; upper square—Dorsal Striatum).

Fig. 3

DAT Density—Mean density of the DAT in the N.Acc core (panel A) and the dorsal striatum (panel B) of the Sal, Coc1h, and Coc6h subjects. *Signifies a significant difference between the Coc1h and Sal condition (P < 0.05); #Signifies a significant difference between the Coc1h and Coc6h conditions (P < 0.04).