Lysergic acid diethylamide and [−]-2,5-dimethoxy-4-methylamphetamine increase extracellular glutamate in rat prefrontal cortex

Hallucinogens such as LSD and DOM increase extracellular glutamate in the prefrontal cortex of rats, as shown by in vivo microdialysis. LSD (0.1 mg/kg) caused a time-dependent rise in glutamate that was blocked by a 5-HT(2A) antagonist. DOM (0.6 mg/kg) raised glutamate to 206% above controls. Direct application of LSD to the prefrontal cortex via reverse dialysis also rapidly increased glutamate, which remained elevated after infusion stopped. These findings suggest that enhanced glutamate release is a shared mechanism in the action of hallucinogens.

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Abstract

The ability of hallucinogens to increase extracellular glutamate in the prefrontal cortex (PFC) was assessed by in vivo microdialysis. The hallucinogen lysergic acid diethylamide (LSD; 0.1 mg/kg, i.p.) caused a time-dependent increase in PFC glutamate that was blocked by the 5-HT(2A) antagonist M100907 (0.05 mg/kg, i.p.). Similarly, the 5-HT(2A/C) agonist [-]-2,5-dimethoxy-4-methylamphetamine (DOM; 0.6 mg/kg, i.p.), which is a phenethylamine hallucinogen, increased glutamate to 206% above saline-treated controls. When LSD (10 microM) was directly applied to the PFC by reverse dialysis, a rapid increase in PFC glutamate levels was observed. Glutamate levels in the PFC remained elevated after the drug infusion was discontinued. These data provide direct evidence in vivo for the hypothesis that an enhanced release of glutamate is a common mechanism in the action of hallucinogens.