Hallucinogenic 5-HT_2A receptor (5-HT_2AR) agonists-induced head-twitch response (HTR) is regulated by G_s signaling pathway. Formation of heterodimers between 5-HT_2AR and metabotropic glutamate mGlu2 receptor (mGluR2) is essential for the hallucinogenic 5-HT_2AR agonist-induced HTR. In order to investigate the effects of mGluR2 agonists and inverse agonists on hallucinogenic 5-HT_2AR agonists DOM-induced HTR, C57BL/6 mice were pretreated with mGluR2 agonists (LY379268, LY354740, LY404039) or the inverse agonist LY341495, and the HTR was manually counted after administering DOM immediately. IP-One (IP1) HTRF assay and cAMP assay were performed to evaluate the effect of LY341495 or LY354740 on DOM-induced G_q and G_s activation in Human Embryonic Kidney-293 (HEK-293) T-type cells co-expressing 5-HT_2AR and mGluR2. The results showed that DOM-induced HTR in mice was dose-dependently inhibited by LY379268, LY354740, and LY404039, while it was dose-dependently enhanced by LY341495. Moreover, LY341495 reversed the inhibitory effect of LY354740 on DOM-induced HTR. In HEK-293T cells co-expressing 5-HT_2AR and mGluR2, DOM-induced cAMP level was decreased by LY354740 and increased by LY341495, but DOM-induced IP1 level was not regulated by LY354740 or LY341495. The regulation of DOM-induced HTR by mGluR2 agonists and inverse agonists is closely related to 5-HT_2AR-mediated G_s signaling pathway. In HEK-293T cells co-expressing 5-HT_2AR and mGluR2 A677S/A681P/A685G mutant (mGluR2 3 A mutant), DOM-induced cAMP level was not regulated by LY354740, but was significantly enhanced by LY341495. The 5-HT_2AR/mGluR2 heterodimers is critical for DOM-induced HTR and cAMP level, both of which are inhibited by mGluR2 agonists and enhanced by mGluR2 inverse agonists.

01 Jun 2023·Psychopharmacology

Metabotropic glutamate group II receptor activation in the ventrolateral dorsal striatum suppresses incentive motivation for cocaine in rats.

Article

Author: Samaha, Anne-Noël ; Khoo, Shaun Yon-Seng

RATIONALEAfter a history of intermittent cocaine intake, rats develop patterns of drug use characteristic of substance use disorder. The dorsal striatum is involved in the increased pursuit of cocaine after intermittent drug self-administration experience. Within the dorsal striatum, chronic cocaine use changes metabotropic glutamate type II receptor (mGlu_2/3) density and function.OBJECTIVESWe examined the extent to which activity at Glu_2/3 receptors mediates responding for cocaine after intermittent cocaine use.METHODSMale (n = 11) and female (n = 10) Wistar rats self-administered 0.25 mg/kg/infusion cocaine during 10 daily intermittent access (IntA) sessions (5 min ON/25 min OFF, for 5 h/session). We then examined the effects of microinjections of the mGlu_2/3 receptor agonist LY379268 (0, 1, and 3 µg/hemisphere) into the ventrolateral part of the dorsal striatum on cocaine self-administration under a progressive ratio schedule of reinforcement.RESULTSAcross 10 IntA sessions, the sexes showed similar levels of cocaine intake. In females only, locomotion significantly increased over sessions, suggesting that female rats developed psychomotor sensitization to self-administered cocaine. After 10 IntA sessions, intra-dorsal striatum LY379268 significantly reduced breakpoints achieved for cocaine, active lever presses, and cocaine infusions earned under progressive ratio. LY379268 had no effects on locomotion or inactive lever presses, indicating no motor effects.CONCLUSIONSThese results suggest that mGlu_2/3 receptor activation in the ventrolateral dorsal striatum suppresses incentive motivation for cocaine, and this holds promise for new treatments to manage substance use disorder.

01 Mar 2023·PsychopharmacologyQ3 · MEDICINE

Metabotropic group II glutamate receptors mediate cue-triggered increases in reward-seeking behaviour

Q3 · MEDICINE

Article

Author: Samaha, Anne-Noël ; Marsault, Justine ; Robinson, Mike J F ; Garceau, Caroline

RATIONALEReward-associated cues can invigorate reward-seeking actions via Pavlovian-to-instrumental transfer (PIT). Glutamatergic neurotransmission mediates the appetitive effects of reward-associated cues. We characterized the expression of PIT and its mediation by metabotropic group II glutamate (mGlu_2/3) receptor activity in female and male rats.OBJECTIVESAcross the sexes, we used PIT procedures to determine (i) cue-triggered increases in instrumental responding for water reward (experiment 1) and (ii) the respective influences of the mGlu_2/3 receptor agonist LY379268 and thirst satiation on this effect (experiment 2).METHODSWater-restricted female and male Sprague-Dawley rats learned to lever press for water. Separately, they learned that one of two auditory stimuli predicts free water (CS + vs CS -). On PIT test days, the CS + and CS - were presented independent of instrumental responding, and we measured effects on lever pressing under extinction (no water). In experiment 1, we characterized PIT across the sexes. In experiment 2, we measured PIT after systemic LY379268 administration (0, 0.3 and 1 mg/kg) and thirst satiation, respectively.RESULTSFemale and male rats showed similar PIT, with CS + but not CS - presentations potentiating water-seeking behaviour. LY379268 (1 mg/kg) attenuated CS + evoked increases in both water-associated lever pressing and conditioned approach to the water port. Thirst satiation attenuated both water-seeking and CS + evoked conditioned approach behaviour.CONCLUSIONSThe sexes show similar cue-triggered increases in reward seeking, and thirst satiation suppresses both water-seeking and cue-triggered anticipation of water reward. Finally, across the sexes, mGlu_2/3 receptor activity mediates cue-triggered increases in reward seeking.

100 Deals associated with LY-379268

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Indication	Highest Phase	Country/Location	Organization	Date
Nervous System Diseases	Preclinical	GB	Eli Lilly & Co.	-
Nervous System Diseases	Preclinical	US	Eli Lilly & Co.	-
Schizophrenia	Preclinical	US	Eli Lilly & Co.	-

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