Phenylpiperazine derivatives with selectivity for dopamine D3 receptors modulate cocaine self-administration in rats

T. H.C. Cheung, B. C. Nolan, L. R. Hammerslag, S. M. Weber, J. P. Durbin, N. A. Peartree, R. H. MacH, R. R. Luedtke, J. L. Neisewander

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


This study examined cocaine self-administration after pretreatments with three structurally related compounds that bind selectively to dopamine D3 receptors (D3Rs) relative to the D2 receptor subtype (D2Rs) and exhibit varying intrinsic activities in the forskolin-stimulated adenylyl cyclase assay. The compounds are: a) WC10, a D3R weak partial agonist/antagonist with 42-fold D3R:D2R selectivity, b) WC26, a 51-fold selective D3R partial agonist, c) WC44, a 23-fold selective D3R agonist. Rats were stabilized on a multiple variable-interval 60-s (VI60) schedule with alternating components of sucrose (45 mg pellets) or cocaine reinforcement (0.375 mg/kg, IV) and then tested for effects of the WC compounds (0.0, 1.0, 3.0, 5.6, or 10.0 mg/kg, IP). Another cohort was trained to self-administer cocaine (0.75 mg/kg, IV) on a VI60 schedule then tested with various doses of cocaine available (0.0-1.5 mg/kg, IV) following pretreatment with WC10 (5.6 or 10.0 mg/kg) or WC44 (10.0 mg/kg). WC10 and WC26 decreased both cocaine and sucrose reinforcement rates at the 10.0 mg/kg dose, whereas WC44 decreased only cocaine reinforcement rate at this dose. Furthermore, WC26 and WC44 increased response latency for cocaine but not sucrose. In the cocaine dose-response experiment, WC10 and WC44 flattened the dose-effect function of cocaine reinforcement rate. All compounds decreased spontaneous locomotion. WC10 and WC26 also reduced cocaine-induced locomotion. These results support the targeting of D3Rs for treatments for cocaine dependence. WC26 and WC44, in particular, show promise as they increased the latency to respond for cocaine but not sucrose, suggesting selective reduction of the motivation for cocaine.

Original languageEnglish
Pages (from-to)1346-1359
Number of pages14
Issue number8
StatePublished - Dec 2012

Bibliographical note

Funding Information:
The authors thank Ms. Maria Barajas and Mr. Jeffrey Pang for their expert technical assistance with this project. We also thank Michelle Taylor for proofreading the manuscript. This work was supported by the National Institute on Drug Abuse ( DA023957 ).


  • Cocaine addiction
  • D3 dopamine receptors
  • D3 selective compound
  • Self-administration

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience


Dive into the research topics of 'Phenylpiperazine derivatives with selectivity for dopamine D3 receptors modulate cocaine self-administration in rats'. Together they form a unique fingerprint.

Cite this