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

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.

Display variability and spatial organization as contributors to the pigeon's discrimination of complex visual stimuli.

Three experiments assessed the contributions of display variability and spatial organization to the pigeon's discrimination of 16-icon visual displays. After training to discriminate 4 x 4 arrays of same and different computer icons, 4 pigeons were shown testing displays that systematically manipulated the variability of the depicted icons and their spatial organization on the display screen. Display variability and spatial organization each reliably controlled the pigeon's behavior. These seemingly separate effects could be collectively explained by the pigeon's discriminating the amount of variability or entropy in localized regions of the display.