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The delay in onset and treatment resistance of subpopulations of depressed patients to conventional serotonin reuptake inhibitors has lead to new drug development strategies to produce agents with improved antidepressant efficacy. We report the in vivo characterization of the novel 5-HT1A/1B autoreceptor antagonist/5-HT transporter inhibitor (6-[(1-{2-[(2-methyl-5-quinolinyl)oxy]ethyl}-4-piperidinyl)methyl]-2 H-1,4-benzoxazin-3(4 H)-one), SB-649915-B. Ex vivo binding was used to ascertain 5-HT1A receptor and serotonin transporter occupancy. 8-OH-DPAT-induced hyperlocomotion and SKF-99101-induced elevation of seizure threshold were used as markers of central blockade of 5-HT1A and 5-HT1B receptors, respectively. In vivo electrophysiology in the rat dorsal raphe and microdialysis in freely moving guinea pigs and rats were used to evaluate the functional outcome of SB-649915-B. SB-649915-B (1–10 mg/kg p.o.) produced a dose-related inhibition of 5-HT1A receptor radioligand binding and inhibited ex vivo [3H]5-HT uptake in both guinea pig and rat cortex. SB-649915-B (0.1–10 mg/kg p.o.) reversed both 8-OH-DPAT-induced hyperlocomotor activity and SKF-99101-induced elevation of seizure threshold in the rat, demonstrating in vivo blockade of both 5-HT1A and 5-HT1B receptors, respectively. SB-649915-B (0.1–3 mg/kg i.v.) produced no change in raphe 5-HT neuronal cell firing per se but attenuated the inhibitory effect of 8-OH-DPAT. Acute administration of SB-649915-B resulted in increases (approximately two- to threefold) in extracellular 5-HT in the cortex of rats and the dentate gyrus and cortex of guinea pigs. Based on these data, one may speculate that the 5-HT autoreceptor antagonist/5-HT transport inhibitor SB-649915-B will have therapeutic efficacy in the treatment of affective disorders with the potential for a faster onset of action compared to current selective serotonin reuptake inhibitors. [ABSTRACT FROM AUTHOR]

Rationale and objective: Performance on the Wisconsin Card Sorting Test (WCST), which requires patients to 'shift attention' between stimulus dimensions (sorting categories), is impaired in diseases such as schizophrenia. The rat attentional set shifting task is an analogue of the WCST. Given that 5-HT6 receptor antagonists improve cognitive performance and influence cortical neurochemistry in rats, the present study investigated the effects of 5-HT6 receptor antagonists upon attentional set shifting in rats. Methods: Rats were tested in this paradigm following sub-chronic SB-399885-T or SB-271046-A (both 10 mg kg-1 bid, p.o. for 8 days prior to testing and either 4 or 2 h prior to testing on day 9, respectively). Rats were trained to dig in baited bowls for a food reward and to discriminate based on odour or digging media (Habituation, day 8). In a single session (day 9), rats performed a series of discriminations, including reversals (REV), intra-dimensional (ID) and extra-dimensional (ED) shifts. Results: Neither compound altered performance during Habituation. On the test day, both SB-399885-T and SB-271046-A reduced the total trials to reach criterion and the total errors made when data were collapsed across all discriminations (P<0.05- 0.01). Further, both compounds significantly reduced the trials to criterion for REV-1 (P<0.05-0.01) and abolished the ID/ED shift. SB-399885-T, but not SB-271046-A, reduced trials required to complete the ED shift (P<0.05) and the number of errors made during completion of the ID (P<0.05) and ED shifts (P<0.01). Conclusion: 5-HT6 receptor antagonists improved performance in the attentional set shifting task and may have therapeutic potential in the treatment of disorders where cognitive deficits are a feature, including schizophrenia. [ABSTRACT FROM AUTHOR]

Rationale: The dopamine (DA) D3 receptor is preferentially expressed in the mesolimbic system. We have previously shown that selective D3 receptor blockade by the novel D3 antagonist SB-277011A inhibits cocaine's reinforcing action and cocaine-induced reinstatement of cocaine-seeking behavior. Objective: In the present study, we investigated whether SB-277011A similarly inhibits stress-induced reinstatement of cocaine-seeking behavior. Methods: Rats were allowed to self-administer cocaine (0.5 mg/kg per infusion, 3 h per session) for 10-14 days, followed by a once-daily extinction session for 7-14 days during which saline was substituted for cocaine. Extinction criteria were fewer than ten lever-presses per 3-h session for at least 3 consecutive days. After cocaine-seeking behavior was extinguished, each animal was tested twice for footshock-stress-induced reinstatement, once with vehicle (25% hydroxypropyl-β-cyclodextrin) and once with one of three doses of SB-277011A in counterbalanced fashion. Results: During the last 3 days of cocaine self-administration (SA), active lever-presses were approximately 100 per session under fixed-ratio 2 reinforcement (∼25 mg/kg cocaine per session). After extinction, intermittent footshock (10 min, 0.5 mA, 0.5 s on with a mean inter-shock interval of 40 s) robustly reinstated the cocaine-seeking behavior (8.4±3.6 active lever-presses in last extinction session to 35.3±5.2 in animals after footshock stress). Intraperitoneal (IP) injections of SB-277011A (3, 6, and 12 mg/kg) dose-dependently blocked stress-induced reinstatement of cocaine-seeking. Reinstatement was also blocked by microinjections of SB-277011A (1.5 µg/0.5 µl per side) bilaterally into the nucleus accumbens, but not into the dorsal striatum. Conclusions: The mesolimic DA D3an important role in mediating stress-induced reinstatement. [ABSTRACT FROM AUTHOR]