Reduced cortical serotonin 5-HT2A receptor binding and glutamate activity in high compulsive drinker rats. (December 2018)

• Record Type: Journal Article
• Authors: Mora, Santiago; Merchán, Ana; Vilchez, Olga; Aznar, Susana; Klein, Anders Bue; Ultved, Lene; Campa, Leticia; Suñol, Cristina; Flores, Pilar; Moreno, Margarita
• Is Part Of: Neuropharmacology. Volume 143(2018)
• Page Start: 10
• Page End: 19
• Publication Date: 2018-12
• Subjects: Compulsivity -- Schedule-induced polydipsia -- Serotonin -- Glutamate -- 5-HT2A receptor -- Prefrontal cortex; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2018.09.004
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Serotonin2A receptors and glutamate signaling have been implicated in the pathophysiology and treatment of compulsive spectrum disorders. Schedule-Induced Polydipsia (SIP), characterized by excessive drinking under intermittent food reinforcement schedules, is a valid model for studying the compulsive phenotype in rats. We explored the expression, function, and neurochemistry of 5-HT2A receptors in the frontal cortex (FC) of rats with individual differences to compulsivity. Rats were selected for high (HD) versus low (LD) drinking on SIP. First, we measured 5-HT2A, 5-HT1A, and mGlu2/3 receptors and serotonin transporter binding in different brain regions. Second, we assessed the effect of microinfusion into the medial prefrontal cortex (mPFC) of the 5-HT2A/C receptor agonist DOI, the mGlu2/3 agonist LY379268, and the combination of DOI with the 5-HT2A receptor antagonist M100907 and the 5-HT2C receptor antagonist SB242084. Finally, we measured the serotonin and glutamate efflux in mPFC in basal condition and after DOI local application. The compulsive HD rats showed a specific reduction of 5-HT2A receptor binding in FC compared to LD rats. The highest dose of DOI reduced compulsive drinking in HD rats on SIP, whereas LY379268 did not induce any significant effect. The 5-HT2A receptor antagonist M100907 reversed the DOI induced reduction on compulsive drinking in HD rats while blocking the 5-HT2C receptor did not affect SIP. Compulsive HD rats showed increased serotonin and decreased glutamate efflux in basal conditions that were modified by the DOI application. These findings indicate that reduced 5-HT2A receptor binding and glutamate neurochemical mechanisms may underlie compulsive behavior vulnerability. Highlights: Reduced cortical 5-HT2A receptors in high compulsive drinker rats. Intra-mPFC 5-HT2A/C agonist DOI decreased compulsive drinking in HD rats on SIP. Intra-mPFC 5-HT2A antagonist M100907 reversed the effect of DOI in HD rats on SIP. Increased serotonin and reduced glutamate output in mPFC in compulsive drinker rats. Cortical DOI application increased glutamate mPFC output in compulsive drinker rats.