Recent cloning of K ϩ channel ␤ subunits revealed that these cytoplasmic polypeptides can dramatically alter the kinetics of current inactivation and promote efficient glycosylation and surface expression of the channel-forming ␣ subunits. Here, we examined the expression, distribution, and association of two of these ␤ subunits, Kv␤1 and Kv␤2, in adult rat brain. In situ hybridization using cRNA probes revealed that these ␤-subunit genes are heterogeneously expressed, with high densities of Kv␤1 mRNA in the striatum, CA1 subfield of the hippocampus, and cerebellar Purkinje cells, and high densities of Kv␤2 mRNA in the cerebral cortex, cerebellum, and brainstem. Immunohistochemical staining using subunit-specific monoclonal and affinity-purified polyclonal antibodies revealed that the Kv␤1 and Kv␤2 polypeptides frequently co-localize and are concentrated in neuronal perikarya, dendrites, and terminal fields, and in the juxtaparanodal region of myelinated axons. Immunoblot and reciprocal co-immunoprecipitation analyses indicated that Kv␤2 is the major ␤ subunit present in rat brain membranes, and that most K ϩ channel complexes containing Kv␤1 also contain Kv␤2. Taken together, these data suggest that Kv␤2 is a component of almost all K ϩ channel complexes containing Kv1 ␣ subunits, and that individual channels may contain two or more biochemically and functionally distinct ␤-subunit polypeptides.

Recent data has suggested that the 5-hydroxytryptamine (5-HT) 1A receptor is involved in cognitive processing. A novel 5-HT 1A receptor antagonist, 4-cyano-N-{2R-[4-(2,3-dihydrobenzo[1,4]-dioxin-5-yl)-piperazin-1-yl]-propyl}-N-pyridin-2-yl-benzamide HCl (lecozotan), which has been characterized in multiple in vitro and in vivo pharmacological assays as a drug to treat cognitive dysfunction, is reported. In vitro binding and intrinsic activity determinations demonstrated that lecozotan is a potent and selective 5-HT 1A receptor antagonist. Using in vivo microdialysis, lecozotan (0.3 mg/kg s.c.) antagonized the decrease in hippocampal extracellular 5-HT induced by a challenge dose (0.3 mg/kg s.c.) of 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT) and had no effects alone at doses 10-fold higher. Lecozotan significantly potentiated the potassium chloride-stimulated release of glutamate and acetylcholine in the dentate gyrus of the hippocampus. Chronic administration of lecozotan did not induce 5-HT 1A receptor tolerance or desensitization in a behavioral model indicative of 5-HT 1A receptor function. In drug discrimination studies, lecozotan (0.01-1 mg/kg i.m.) did not substitute for 8-OH-DPAT and produced a dose-related blockade of the 5-HT 1A agonist discriminative stimulus cue. In aged rhesus monkeys, lecozotan produced a significant improvement in task performance efficiency at an optimal dose (1 mg/kg p.o.). Learning deficits induced by the glutamatergic antagonist MK-801 [(Ϫ)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate] (assessed by perceptually complex and visual spatial discrimination) and by specific cholinergic lesions of the hippocampus (assessed by visual spatial discrimination) were reversed by lecozotan (2 mg/kg i.m.) in marmosets. The heterosynaptic nature of the effects of lecozotan imbues this compound with a novel mechanism of action directed at the biochemical pathologies underlying cognitive loss in Alzheimer's disease.The multiplicity of biological data associated with the 5-hydroxytryptamine (5-HT) 1A receptor subtype, since its discovery by radioligand binding in 1981 (Pedigo et al., 1981) and subsequent cloning in 1988 (Fargin et al., 1988), implicates this receptor in numerous behavioral and physiological functions, including cognition, psychosis, feeding/satiety, temper-

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