AMPA Receptor Potentiation can Prevent Ethanol-Induced Intoxication

Abstract

We present a substantial series of behavioral and imaging experiments, which demonstrate, for the first time, that increasing AMPA receptor-mediated neurotransmission via administration of potent and selective biarylsulfonamide AMPA potentiators LY404187 and LY451395 reverses the central effects of an acutely intoxicating dose of ethanol in the rat. Using pharmacological magnetic resonance imaging (phMRI), we observed that LY404187 attenuated ethanol-induced reductions in blood oxygenation level dependent (BOLD) in the anesthetized rat brain. A similar attenuation was apparent when measuring local cerebral glucose utilization (LCGU) via C 14 -2-deoxyglucose autoradiography in freely moving conscious rats. Both LY404187 and LY451395 significantly and dose-dependently reversed ethanol-induced deficits in both motor coordination and disruptions in an operant task where animals were trained to press a lever for food reward. Both prophylactic and acute intervention treatment with LY404187 reversed ethanol-induced deficits in motor coordination. Given that LY451395 and related AMPA receptor potentiators/ampakines are tolerated in both healthy volunteers and elderly patients, these data suggest that such compounds may form a potential management strategy for acute alcohol intoxication.

Alternative Splicing of AMPA Subunits in Prefrontal Cortical Fields of Cynomolgus Monkeys Following Chronic Ethanol Self-Administration

“…The mechanisms of kainate receptor regulation during alcoholism and other forms of synaptic plasticity is far less understood than AMPA or NMDA regulation. Previous studies have indicated that the intoxicating and reinforcing effects of ethanol are mediated in part by the effects on AMPA and kainate receptors (Valenzuela and Cardoso, 1999; Backstrom and Hyytia, 2004; Sanchis-Segura et al, 2006; Jones et al, 2008; Stuber et al, 2008). For example, acute ethanol decreases AMPA and kainate receptor-mediated currents in a variety of limbic brain regions (Weiner et al, 1999; Crowder et al, 2002; Carta et al, 2003; Moykkynen et al, 2003; Stuber et al, 2008).…”

Metabotropic and ionotropic glutamate receptors as potential targets for the treatment of alcohol use disorder

“…LY404187 and LY451395, both selective biarylsulfonaminde AMPA agonists, were found to reverse the acute intoxication induced by alcohol consumption. In addition, both compounds significantly reversed the loss of motor coordination and operant task disruption induced by ethanol (Jones et al, 2008). Thus, AMPA receptor antagonists may have an important role as a possible therapeutic compounds for managing acute ethanol intoxication (Jones et al, 2008).…”

New medications for drug addiction hiding in glutamatergic neuroplasticity

“…120 In a rodent model of acute alcohol administration, an ampakine (LY404187) reversed the effects of acute ethanol intoxication on locomotor and operant behavior, and on brain activity (reversed decreases in blood oxygen level-dependent magnetic resonance signal after 0.6 g kg −1 ethanol and attenuated the decreases in glucose metabolism after 2.0 g kg −1 ethanol). 121 Common among these three studies is the inhibition of some effects associated with the acute drug administration, thereby posing ampakines as potential treatments for acute intoxication in emergency room settings. Ampakines also have neuroprotective effects, which are mediated in part by inducing BDNF, and LY503430 and LY404187 were neuroprotective in an animal model of Parkinson’s disease (6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity), even when the treatment was delayed for 14 days after the lesion was established.…”