23.2 ALPHA 7 NICOTINIC MODULATORS REVERSE THE HYPERDOPAMINERGIC TONE IN THE MAM MODEL OF SCHIZOPHRENIA. (9th April 2019)

• Record Type: Journal Article
• Authors: Grace, Anthony; Neves, Gilda
• Is Part Of: Schizophrenia bulletin. Volume 45(2019)Supplement 2
• Page Start: S126
• Page End: S126
• Publication Date: 2019-04-09
• Subjects: Schizophrenia -- Periodicals; Schizophrenia -- Research -- Periodicals; 616.898005
• DOI: 10.1093/schbul/sbz022.092
• Languages: English
• ISSNs: 0586-7614

Abstract

Abstract: Background: While dopaminergic antagonists have been the mainstay of schizophrenia pharmacotherapy, they suffer from low compliance and are fraught with side effects. A more effective approach would be to intervene at the site of dysfunction within the schizophrenia brain, which increasing evidence is pointing at the limbic hippocampus. Specifically, studies have suggested aberrant alpha 7 nicotinic transmission in this region as a potential therapeutic target for schizophrenia. We examined the impact of alpha 7 nicotinic modulator drugs on the hyperdopaminergic tone characteristic of the MAM model of schizophrenia. Methods: Sprague-Dawley pregnant dams were treated with MAM or saline on GD17. In vivo recordings of VTA DA spontaneously active neurons were performed in the male adult offspring. Four drugs were tested: PNU282987 (full agonist), SSR180711 (partial agonist) NS1738 (PAM I) and PNU120596 (PAM II). Data analysis: two-way ANOVA and Bonferroni posttest. Results: Intravenous administration of PNU12 increased the number of active DA cells found in the VTA of normal rats (1.7±0.2cells/track vs 1.0±0.1cells/track in the vehicle group, n=8–11, p=0.012). In contrast, PNU28 (1.0±0.1cells/track n=8) and SSR (1.0±0.2cells/track n=8) reduced the hyperdopaminergic tone to control levels from the elevation observed in the MAM model of schizophrenia (1.7±0.1cells/track, n=10, p<0.012). This appeared to be due to an effect in the ventral hippocampus, since infusion into this area also significantly decreased the number of active DA neurons in MAM rats (PNU28 1.1±0.1cells/track; SSR 1.0±0.1cells/track vs 1.7±0.1cells/track in the vehicle group, n=8, p<0.021). In contrast when these drugs were infused into the basolateral amygdala there was an increased number of active DA neurons in control rats (PNU28 1.8±0.2cells/track; SSR 1.6±0.2cells/track vs 1.0±0.1cells/track in the vehicle group, n=8, p<0.019). Conclusions: Alpha7 agonists counterbalanced the hyperdopaminergic state of MAM rats and this effect is partially mediated by receptors in the ventral hippocampus. Our data corroborate the potential of alpha7 receptors as a therapeutic target for schizophrenia treatment.