Author: D'Errico, Giovanna ; Bruno, Valeria ; Nicoletti, Ferdinando ; Pittaluga, Anna ; Busceti, Carla Letizia ; Battaglia, Giuseppe ; Castaldi, Sonia ; Di Menna, Luisa ; Taddeucci, Alice ; Fornai, Francesco

Cognitive dysfunction is associated with methamphetamine use disorder (MUD). Here, we used genetic and pharmacological approaches to examine the involvement of either Group 2 metabotropic glutamate (mGlu2) or mGlu3 receptors in memory deficit induced by methamphetamine in mice. Methamphetamine treatment (1 mg/kg, i.p., once a day for 5 d followed by 7 d of withdrawal) caused an impaired performance in the novel object recognition test in wild-type mice, but not in mGlu2−/−or mGlu3−/−mice. Memory deficit in wild-type mice challenged with methamphetamine was corrected by systemic treatment with selectively negative allosteric modulators of mGlu2 or mGlu3 receptors (compounds VU6001966 and VU0650786, respectively). Methamphetamine treatment in wild-type mice caused large increases in levels of mGlu2/3 receptors, the Type 3 activator of G-protein signaling (AGS3), Rab3A, and the vesicular glutamate transporter, vGlut1, in the prefrontal cortex (PFC). Methamphetamine did not alter mGlu2/3-mediated inhibition of cAMP formation but abolished the ability of postsynaptic mGlu3 receptors to boost mGlu5 receptor-mediated inositol phospholipid hydrolysis in PFC slices. Remarkably, activation of presynaptic mGlu2/3 receptors did not inhibit but rather amplified depolarization-induced [3H]-D-aspartate release in synaptosomes prepared from the PFC of methamphetamine-treated mice. These findings demonstrate that exposure to methamphetamine causes changes in the expression and function of mGlu2 and mGlu3 receptors, which might alter excitatory synaptic transmission in the PFC and raise the attractive possibility that selective inhibitors of mGlu2 or mGlu3 receptors (or both) may be used to improve cognitive dysfunction in individuals affected by MUD.

01 Jun 2024·Pharmacology Biochemistry and Behavior

mGlu2 and mGlu3 receptor negative allosteric modulators attenuate the interoceptive effects of alcohol in male and female rats

Article

Author: Landavazo, Antonio ; Tyler, Ryan E ; Van Voorhies, Kalynn ; Besheer, Joyce ; Blough, Bruce E

RATIONALEThe subjective effects of alcohol are associated with alcohol use disorder (AUD) vulnerability and treatment outcomes. The interoceptive effects of alcohol are part of these subjective effects and can be measured in animal models using drug discrimination procedures. The newly developed mGlu₂ and mGlu₃ negative allosteric modulators (NAMs) are potential therapeutics for AUD and may alter interoceptive sensitivity to alcohol.OBJECTIVESTo determine the effects of mGlu₂ and mGlu₃ NAMs on the interoceptive effects of alcohol in rats.METHODSLong-Evans rats were trained to discriminate the interoceptive stimulus effects of alcohol (2.0 g/kg, i.g.) from water using both operant (males only) and Pavlovian (male and female) drug discrimination techniques. Following acquisition training, an alcohol dose-response (0, 0.5, 1.0, 2.0 g/kg) experiment was conducted to confirm stimulus control over behavior. Next, to test the involvement of mGlu₂ and mGlu₃, rats were pretreated with the mGlu₂-NAM (VU6001966; 0, 3, 6, 12 mg/kg, i.p.) or the mGlu₃-NAM (VU6010572; 0, 3, 6, 12 mg/kg, i.p.) before alcohol administration (2.0 g/kg, i.g.).RESULTSIn Pavlovian discrimination, male rats showed greater interoceptive sensitivity to 1.0 and 2.0 g/kg alcohol compared to female rats. Both mGlu₂-NAM and mGlu₃-NAM attenuated the interoceptive effects of alcohol in male and female rats using Pavlovian and operant discrimination. There may be a potential sex difference in response to the mGlu₂-NAM at the highest dose tested.CONCLUSIONSMale rats may be more sensitive to the interoceptive effects of the 2.0 g/kg alcohol training dose compared to female rats. Both mGlu₂_-and mGlu₃_-NAM attenuate the interoceptive effects of alcohol in male and female rats. These drugs may have potential for treatment of AUD in part by blunting the subjective effects of alcohol.

14 Sep 2017·ACS Medicinal Chemistry LettersQ3 · MEDICINE

Design and Synthesis of mGlu₂NAMs with Improved Potency and CNS Penetration Based on a Truncated Picolinamide Core

Q3 · MEDICINE

Article

Author: Conn, P. Jeffrey ; Bollinger, Katrina A. ; Chang, Sichen ; Cho, Hyekyung P. ; Bubser, Michael ; Blobaum, Anna L. ; Jones, Carrie K. ; Brassard, Christopher J. ; Engers, Julie L. ; Rodriguez, Alice L. ; Emmitte, Kyle A. ; Felts, Andrew S. ; Niswender, Colleen M. ; Lindsley, Craig W. ; Weiner, Rebecca L.

Herein, we detail the optimization of the mGlu₂ negative allosteric modulator (NAM), VU6001192, by a reductionist approach to afford a novel, simplified mGlu₂ NAM scaffold. This new chemotype not only affords potent and selective mGlu₂ inhibition, as exemplified by VU6001966 (mGlu₂ IC₅₀ = 78 nM, mGlu₃ IC₅₀ > 30 μM), but also excellent central nervous system (CNS) penetration (K_p = 1.9, K_p,uu = 0.78), a feature devoid in all previously disclosed mGlu₂ NAMs (K_ps ≈ 0.3, K_p,uus ≈ 0.1). Moreover, this series, based on overall properties, represents an exciting lead series for potential mGlu₂ PET tracer development.

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