ssr180711 and Attention-Deficit-Disorder-with-Hyperactivity

Cognitive deficits represent a core symptom cluster in schizophrenia that are thought to reflect developmental dysregulations within a neural system involving the ventral hippocampus (VH), nucleus accumbens (NAC), and prefrontal cortex (PFC). The present experiments determined the cognitive effects of transiently inactivating VH in rats during a sensitive period of development. Neonatal (postnatal day 7, PD7) and adolescent (PD32) male rats received a single bilateral infusion of saline or tetrodotoxin (TTX) within the VH to transiently inactivate local circuitry and efferent outflow. Rats were tested as adults on an attentional set-shifting task. Performance in this task depends upon the integrity of the PFC and NAC. TTX infusions did not affect the initial acquisition or ability to learn an intra-dimensional shift. However, TTX rats required a greater number of trials than did controls to acquire the first reversal and extra-dimensional shift (ED) stages. These impairments were age and region-specific as rats infused with TTX into the VH at PD32, or into the dorsal hippocampus at PD7, exhibited performance in the task similar to that of controls. Finally, acute systemic administration of the partial α7 nicotinic acetylcholine receptor (nAChR) agonist SSR 180711 (3.0 mg/kg) eliminated the TTX-induced performance deficits. Given that patients with schizophrenia exhibit hippocampal pathophysiology and deficits in the ED stages of set-shifting tasks, our results support the significance of transient hippocampal inactivation as an animal model for studying the cognitive impairments in schizophrenia as well as the pro-cognitive therapeutic potential of α7 nAChR agonists.

Topics: Age Factors; Analysis of Variance; Anesthetics, Local; Animals; Animals, Newborn; Attention Deficit Disorder with Hyperactivity; Bridged Bicyclo Compounds, Heterocyclic; Discrimination, Psychological; Disease Models, Animal; Hippocampus; Male; Nicotinic Agonists; Odorants; Rats; Rats, Wistar; Set, Psychology; Tetrodotoxin; Touch

Nicotinic alpha7 acetylcholine receptors (alpha7 nAChR) have been shown to enhance attentional function and aspects of memory function in experimental models and in man. The protein Arc encoded by the effector immediate early gene arc or arg3.1 has been shown to be strongly implicated in long-term memory function. We have sought to determine if alpha7 nAChR mediate the stimulation of arc gene expression, and if so, where in the brain such activation may occur using semi-quantitative in situ hybridisation. Administration of the novel and selective alpha7 nAChR agonist, SSR180711 (1, 3 and 10 mg/kg) to adolescent rats, produced a dose- and time-dependent increase in the expression of Arc mRNA in the prefrontal cortex and the ventral orbital cortex. By contrast, no change in mRNA levels was detected in the parietal cortex and the CA1 of the hippocampus. These data show that alpha7 nAChR activates a subset of neurons in the rat prefrontal cortex and this activation likely is important for the attentional effects of this new class of drugs.

Topics: Acetylcholine; alpha7 Nicotinic Acetylcholine Receptor; Animals; Attention; Attention Deficit Disorder with Hyperactivity; Bridged Bicyclo Compounds, Heterocyclic; Cytoskeletal Proteins; Dose-Response Relationship, Drug; Gene Expression Regulation; In Situ Hybridization; Male; Memory; Memory Disorders; Nerve Tissue Proteins; Nicotinic Agonists; Prefrontal Cortex; Rats; Rats, Wistar; Receptors, Nicotinic; RNA, Messenger; Synaptic Transmission; Time Factors; Up-Regulation