Cocaine self-administration in dopamine D3 receptor knockout mice

S. Barak Caine, Morgane Thomsen, Andrew C. Barrett, Gregory T. Collins, Peter Grundt, Amy Hauck Newman, Paul Butler, Ming Xu

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28 Scopus citations


The dopamine D3 receptor has received attention over the last two decades as a target for medications development for substance abuse disorders. Results have remained mixed. Despite emergence of more D3-selective ligands, possible attribution of observed effects to D2 receptors remains a concern. Knockout mice may help shed light on mechanisms. Here we evaluated the effect of constitutive D3 receptor inactivation ("knockout") on the reinforcing effects of cocaine. We tested D3 wild-type (WT), heterozygous (D3+/-), and knockout (D3-/-), mice in acquisition and maintenance of intravenous self-administration across a broad range of cocaine doses, using a fixed ratio (FR) 1 and a progressive ratio (PR) schedule of reinforcement, along with parallel food-reinforced studies. Generally, D3-/- mice showed cocaine self-administration comparable to WT controls across assays. Moderate and nonsignificant trends toward lesser reinforcing effects of a low cocaine dose (0.32 mg/kg) were apparent in acquisition and PR studies, consistent with the idea that the D3 receptor may play a subtle role in the reinforcing effects of low cocaine doses under low FR conditions. However, those effects with cocaine self-administration were more subtle than the lower responding of D3 knockout mice observed with food-maintained behavior. In addition, the D3 antagonist PG01037 failed to affect cocaine self-administration under an FR 1 schedule in WT mice. The present data do not support a necessary role for the D3 receptor in the direct reinforcing effects of cocaine.

Original languageEnglish (US)
Pages (from-to)352-363
Number of pages12
JournalExperimental and Clinical Psychopharmacology
Issue number5
StatePublished - Oct 2012


  • Cocaine
  • Dopamine receptors
  • Food-maintained behavior
  • Knockout mice
  • Progressive ratio


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