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Dopamine transporter knockdown by antisense oligonucleotides attenuates reinstatement of cocaine self-administration after extinction Schachter, Michael Eli


Mice lacking the dopamine transporter (DAT) self-administer cocaine (Rocha et al., 1998). However, in DAT knockout mice a variety of compensatory changes may occur, including increased basal dopamine levels, decreased dopamine receptor number and behavioral hyperactivity. In the present cocaine self-administration study, we attempted to reduce these confounds by knocking down DAT expression in adult Long-Evans rats using phosphorothioate antisense oligonucleotides targeting DAT mRNA. Animals were trained to self-administer a low-dose of cocaine (0.1 mg/infusion, FR2, TO30s) after which drug seeking was extinguished (50-110 hours) by substituting saline for cocaine. Next, half the rats were treated with DAT antisense (1 nmol/day for 6 days) bilaterally into the VTA using osmotic minipumps, and half the rats received a missense control sequence. On the sixth day of antisense/missense-administration, reinstatement of drug taking was assessed following one infusion of cocaine (0.1 mg/infusion) (priming). Drug taking was also assessed without priming on two subsequent days. DAT antisense resulted in a significant (42%) reduction in DAT binding in the nucleus accumbens, assessed using [3H]WIN 35,428. Rats treated with DAT antisense responded selectively on the drug-appropriate lever during the first session following extinction. However discriminant responding was completely disrupted by the second session and on the final trial, cocaine self-administration was significantly reduced. Drug taking in the missense group was comparable to pre-extinction levels. These data suggest that cocaine's interaction with DAT is a necessary component of its reinforcing properties.

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