The Metabotropic Glutamate (mGLU)2/3 Receptor Antagonist LY341495 [2S-2-Amino-2-(1S,2S-2-carboxycyclopropyl-1-yl)-3-(xanth-9-yl)propanoic Acid] Stimulates Waking and Fast Electroencephalogram Power and Blocks the Effects of the mGLU2/3 Receptor Agonist LY379268 [(-)-2-Oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate] in Rats

Abstract

The highly selective metabotropic glutamate (mGlu)2/3 receptor agonist LY379268 [(Ϫ)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate] completely suppresses rapid eye movement (REM) sleep and strongly depresses theta (6 -10 Hz) and high-frequency (10 -60 Hz) power in the waking and nonrapid eye movement (NREM) EEG, effects consistent with depressed brain excitation (arousal). We hypothesized the selective mGlu2/3 receptor antagonist LY341495 [2S-2-amino-2-(1S,2S-2-carboxycyclopropyl-1-yl)-3-(xanth-9-yl)propanoic acid] given alone would 1) increase arousal, producing sleep-wake EEG effects opposite those of LY379268, and 2) block/reverse the effects of LY379268 when the drugs are coadministered. Rats with implanted electrodes were injected with 1, 5, or 10 mg/kg LY341495 at hour 5.5 of the dark period. In the coadministration study the rats received the same dose of LY341495 followed 30 min later by 1 mg/kg LY379268. LY341495 alone increased waking by reducing NREM and REM sleep. LY341495 also depressed low-frequency and stimulated high-frequency EEG power. It produced a sharp spike in theta power in waking but not NREM sleep, a striking state-dependent difference in pharmacological response. These changes indicate that blocking mGlu2/3 receptors increases brain arousal. Moreover, they show that mGlu2/3 receptors actively support arousal even in the absence of heightened glutamate excitation. The coadministration experiment demonstrates that LY341495 is selective in vivo since it dose-dependently attenuates or reverses the sleep-wake EEG effects of the highly selective mGlu2/3 receptor agonist LY379268. The capacity of mGlu2/3 receptor agonists and antagonists to alter the sleep wake balance suggests they could be developed to enhance sleep or sustain arousal. Their opposing actions on theta EEG could test the putative role of these oscillations in memory consolidation.The level of brain excitation is largely determined by the balance of inhibitory and excitatory neurotransmission by GABA and glutamate. Most clinically used hypnotic and anxiolytic drugs increase inhibition by stimulating the GABA A -benzodiazepine receptor complex. Although these drugs remain our most effective hypnotics, they have serious limitations. They induce tachyphylaxis and can produce addiction and life-threatening withdrawal syndromes. These drugs also distort the sleep EEG, reducing delta power in nonrapid eye movement (NREM) sleep and increasing power in sigma and beta frequencies (cf. Feinberg et al., 2000).Drugs that reduce brain excitation by decreasing glutamate excitation rather than increasing GABA inhibition might also have useful hypnotic and anxiolytic properties. Moreover, drugs that reduce glutamate excitation might produce novel clinical profiles since they act through qualitatively different mechanisms that presumably impact different structures and synaptic distributions. Ideally, drugs that depress glutamate activity would have improved therapeutic ratios with less tachyphylaxis and lower liability for addicT...

Cognitive impairment in major depression and the mGlu2 receptor as a therapeutic target

“…Interestingly, it has also been shown that MGS0039 enhanced social recognition memory in rats, which was dependent on AMPA receptor activation (Shimazaki et al, 2007) and attenuated the learning deficit in a passive avoidance test induced in rats by olfactory bulbectomy (Palucha-Poniewiera et al, 2010). It has also been shown that LY341495 exhibits mild arousal enhancing effects in rats (Feinberg et al, 2005). Subsequently, it has been proposed that mGlu2/3 receptor antagonists may have an antidepressant profile with wakepromoting and cognition enhancing effects (Witkin and Eiler, 2006).…”

Pharmacological Stimulation of Group II Metabotropic Glutamate Receptors Reduces Cocaine Self-Administration and Cocaine-Induced Reinstatement of Drug Seeking in Squirrel Monkeys

“…An additional test in four monkeys determined the effects of 10.0 mg/kg LY341495 on cocaine self-administration in the absence of LY379268. The dose of LY341495 was selected on the basis of a previous report demonstrating central activity and antagonism of the effects of LY379268 in rodents (Feinberg et al, 2005) and on preliminary observations that the dose was well tolerated in squirrel monkeys.…”

“…LY379268 has been found to reduce locomotor activity, rapid eye movement sleep, and fast (10 -50 Hz) electroencephalographic wave recordings in rats, leading to speculation that the drug acts as a functional depressant of central arousal systems (Feinberg et al, 2002(Feinberg et al, , 2005. Observational studies in squirrel monkeys, however, revealed no significant effect of LY379268 on locomotor activity, resting posture, or other behaviors that might reflect reduced arousal.…”

Antagonism of metabotropic glutamate group II receptors in the potential treatment of neurological and neuropsychiatric disorders

“…Based upon these data, it was hypothesized that LY341495 would have the opposite effects of the mGlu2/3 receptor agonist. Indeed, LY341495 increased waking and waking EEG by reducing nREM and REM sleep [Feinberg et al, 2005]. LY341495 also depressed lowfrequency and stimulated high-frequency EEG power.…”

“…LY341495 has electroencephalogram (EEG) activating effects in rats [Feinberg et al, 2005], and Feinberg et al [2002] have found opposing EEG suppressant effects of the mGlu2/3 agonist LY379268. Indeed, the effects of LY341495 can be prevented by LY379268.…”