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

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-sec (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.

Comparison of the Binding and Functional Properties of Two Structurally Different D2 Dopamine Receptor Subtype Selective Compounds

“…22,31 Development of D2 and D3 receptor subtype selective compounds would provide the pharmacological tools to enable the neuroscience community to better understand the role of these two receptor subtypes in complex behavioral and physiological processes. Furthermore, D2-like receptor subtype selective compounds of varying intrinsic activity have the potential for development of (a) pharmacotherapeutic agents for the treatment of neurological disorders, 6 neuropsychiatric disease, 32 and psychostimulant abuse, 33 and (b) neuroimaging agents to study the differential expression and regulation of D2-like dopamine receptors. 34,35 We initially assumed that ligand binding selectivity would be achieved by developing compounds capable of exploiting differences in contact residues between these two structurally related receptor subtypes.…”

Reduction of Cocaine Self-Administration and D3 Receptor-Mediated Behavior by Two Novel Dopamine D3 Receptor-Selective Partial Agonists, OS-3-106 and WW-III-55

“…We found that three of these compounds-WC10, WC26, and WC44-reduced cocaine self-administration (Cheung et al, 2012). Although the response rate under sucrose reinforcement was also reduced, the latency to respond (i.e., the time between lever insertion and the first response on the active lever) increased as a function of dose for WC26 and WC44 when the reinforcer was cocaine but not when the reinforcer was sucrose.…”

“…Systemic cocaine, OS-3-106, WW-III-55, and their vehicles were given intraperitoneally, and 7-OH-DPAT and its vehicle were given subcutaneously. OS-3-106 and WW-III-55 were injected 5 minutes before the start of the test session, based on our previous study showing that arylamide phenylpiperazines attenuated L-DOPAinduced dyskinesia (Kumar et al, 2009) and reduced locomotor activity (Cheung et al, 2012) within this time frame.…”

“…The dopamine D3 receptor (D3R) subtype is a target for developing novel therapeutic agents for the treatment of psychostimulant addiction (Levant, 1997;Luedtkea and Mach, 2003;Joyce and Millan, 2005;Le Foll et al, 2005;Newman et al, 2005;Heidbreder and Newman, 2010;Blaylock and Nader, 2012;Cheung et al, 2012). One unique attribute of the D3R is that its level of expression is much higher in the mesolimbic pathway than in other dopaminergic pathways (Bouthenet et al, 1991;Murray et al, 1994;Levant, 1997), and the mesolimbic pathway has been implicated in drug addiction (Wise, 2004;Kalivas and Volkow, 2005).…”

“…Although the response rate under sucrose reinforcement was also reduced, the latency to respond (i.e., the time between lever insertion and the first response on the active lever) increased as a function of dose for WC26 and WC44 when the reinforcer was cocaine but not when the reinforcer was sucrose. It has been proposed that the selective increase in response latency for cocaine reflects a decrease in the motivation to seek cocaine (Olmstead et al, 2000;Cheung et al, 2012).…”