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

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Abstract

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
JournalNeuropharmacology
Volume63
Issue number8
DOIs
StatePublished - 1 Dec 2012

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Dopamine D3 Receptors
Self Administration
Cocaine
Sucrose
Locomotion
phenylpiperazine
Appointments and Schedules
Cocaine-Related Disorders
Colforsin
Adenylyl Cyclases
Reaction Time
Motivation

Keywords

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

Cite this

Cheung, T. H. C., Nolan, B. C., Hammerslag, L. R., Weber, S. M., Durbin, J. P., Peartree, N. A., ... Neisewander, J. L. (2012). Phenylpiperazine derivatives with selectivity for dopamine D3 receptors modulate cocaine self-administration in rats. Neuropharmacology, 63(8), 1346-1359. https://doi.org/10.1016/j.neuropharm.2012.08.011
Cheung, T. H.C. ; Nolan, B. C. ; Hammerslag, L. R. ; Weber, S. M. ; Durbin, J. P. ; Peartree, N. A. ; MacH, R. H. ; Luedtke, R. R. ; Neisewander, J. L. / Phenylpiperazine derivatives with selectivity for dopamine D3 receptors modulate cocaine self-administration in rats. In: Neuropharmacology. 2012 ; Vol. 63, No. 8. pp. 1346-1359.
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Cheung, THC, Nolan, BC, Hammerslag, LR, Weber, SM, Durbin, JP, Peartree, NA, MacH, RH, Luedtke, RR & Neisewander, JL 2012, 'Phenylpiperazine derivatives with selectivity for dopamine D3 receptors modulate cocaine self-administration in rats', Neuropharmacology, vol. 63, no. 8, pp. 1346-1359. https://doi.org/10.1016/j.neuropharm.2012.08.011

Phenylpiperazine derivatives with selectivity for dopamine D3 receptors modulate cocaine self-administration in rats. / Cheung, T. H.C.; Nolan, B. C.; Hammerslag, L. R.; Weber, S. M.; Durbin, J. P.; Peartree, N. A.; MacH, R. H.; Luedtke, R. R.; Neisewander, J. L.

In: Neuropharmacology, Vol. 63, No. 8, 01.12.2012, p. 1346-1359.

Research output: Contribution to journalArticle

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T1 - Phenylpiperazine derivatives with selectivity for dopamine D3 receptors modulate cocaine self-administration in rats

AU - Cheung, T. H.C.

AU - Nolan, B. C.

AU - Hammerslag, L. R.

AU - Weber, S. M.

AU - Durbin, J. P.

AU - Peartree, N. A.

AU - MacH, R. H.

AU - Luedtke, R. R.

AU - Neisewander, J. L.

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N2 - 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.

AB - 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.

KW - Cocaine addiction

KW - D3 dopamine receptors

KW - D3 selective compound

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