Reduced cortical serotonin 5-HT2A receptor binding and glutamate activity in high compulsive drinker rats

Santiago Mora; Ana Merchán; Olga Vilchez; Susana Aznar; Anders Bue Klein; Lene Ultved; Leticia Campa; Cristina Suñol; Pilar Flores; Margarita Moreno

doi:10.1016/j.neuropharm.2018.09.004

Reduced cortical serotonin 5-HT_2A receptor binding and glutamate activity in high compulsive drinker rats

Santiago Mora, Ana Merchán, Olga Vilchez, Susana Aznar, Anders Bue Klein, Lene Ultved, Leticia Campa, Cristina Suñol, Pilar Flores, Margarita Moreno^*

^*Corresponding author for this work

7 Citations (Scopus)

Abstract

Serotonin_2A 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-HT_2A 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-HT_2A, 5-HT_1A, and mGlu_2/3 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-HT_2A/C receptor agonist DOI, the mGlu_2/3 agonist LY379268, and the combination of DOI with the 5-HT_2A receptor antagonist M100907 and the 5-HT_2C 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-HT_2A 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-HT_2A receptor antagonist M100907 reversed the DOI induced reduction on compulsive drinking in HD rats while blocking the 5-HT_2C 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-HT_2A receptor binding and glutamate neurochemical mechanisms may underlie compulsive behavior vulnerability.

Original language	English
Journal	Neuropharmacology
Volume	143
Pages (from-to)	10-19
Number of pages	10
ISSN	0028-3908
DOIs	https://doi.org/10.1016/j.neuropharm.2018.09.004
Publication status	Published - 2018

Keywords

5-HT receptor
Compulsivity
Glutamate
Prefrontal cortex
Schedule-induced polydipsia
Serotonin

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10.1016/j.neuropharm.2018.09.004

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@article{32fd89ec31a243bca5f355639afa4f9d,

title = "Reduced cortical serotonin 5-HT2A receptor binding and glutamate activity in high compulsive drinker rats",

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.",

keywords = "5-HT receptor, Compulsivity, Glutamate, Prefrontal cortex, Schedule-induced polydipsia, Serotonin",

author = "Santiago Mora and Ana Merch{\'a}n and Olga Vilchez and Susana Aznar and Klein, {Anders Bue} and Lene Ultved and Leticia Campa and Cristina Su{\~n}ol and Pilar Flores and Margarita Moreno",

year = "2018",

doi = "10.1016/j.neuropharm.2018.09.004",

language = "English",

volume = "143",

pages = "10--19",

journal = "Neuropharmacology",

issn = "0028-3908",

publisher = "Pergamon Press",

}

TY - JOUR

T1 - Reduced cortical serotonin 5-HT2A receptor binding and glutamate activity in high compulsive drinker rats

AU - Mora, Santiago

AU - Merchán, Ana

AU - Vilchez, Olga

AU - Aznar, Susana

AU - Klein, Anders Bue

AU - Ultved, Lene

AU - Campa, Leticia

AU - Suñol, Cristina

AU - Flores, Pilar

AU - Moreno, Margarita

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

KW - 5-HT receptor

KW - Compulsivity

KW - Glutamate

KW - Prefrontal cortex

KW - Schedule-induced polydipsia

KW - Serotonin

U2 - 10.1016/j.neuropharm.2018.09.004

DO - 10.1016/j.neuropharm.2018.09.004

M3 - Journal article

C2 - 30201211

AN - SCOPUS:85054767997

SN - 0028-3908

VL - 143

SP - 10

EP - 19

JO - Neuropharmacology

JF - Neuropharmacology

ER -