Chronic Phenethylamine Hallucinogen Treatment Alters Behavioral Sensitivity to a Metabotropic Glutamate 2/3 Receptor Agonist

Abstract

Recent clinical studies in schizophrenic patients show that a selective agonist of group II metabotropic glutamate (mGlu) receptors has robust efficacy in treating positive and negative symptoms. Group II mGlu receptor agonists also modulate the in vivo activity of psychotomimetic drugs, reducing the ability of psychotomimetic hallucinogens to increase glutamatergic transmission. The use of mouse models provides an opportunity to investigate the dynamic action that mGlu2/3 receptors play in regulating the behavioral effects of hallucinogen-induced glutamatergic neurotransmission using genetic as well as pharmacological strategies. The current study sought to characterize the use of the two-lever drug discrimination paradigm in ICR (CD-1) mice, using the hallucinogenic 5-HT 2A/2C receptor agonist (À)-2,5-dimethoxy-4-bromoamphetamine [(À)-DOB)] as a stimulus-producing drug. The (À)-DOB discriminative stimulus was dose-dependent, generalized to the hallucinogen lysergic acid diethylamide, and was potently blocked by the 5-HT 2A receptor antagonist M100907. However, contrary to our prediction, the hallucinogen-induced discriminative stimulus was not regulated by mGlu2/3 receptors. In a series of follow-up studies using hallucinogen-induced head twitch response and phencyclidine-induced hyperlocomotion, it was additionally discovered that the repeated dosing regimen required for discrimination training attenuated the behavioral effects of the mGlu2/3 receptor agonist LY379268. Furthermore chronic studies, using a 14 day (À)-DOB treatment, confirmed that repeated hallucinogen treatment causes a loss of behavioral activity of mGlu2/3 receptors, likely resulting from persistent activation of mGlu2/3 receptors by a hallucinogen-induced hyperglutamatergic state.

Diversity of Metabotropic Glutamate Receptor–Interacting Proteins and Pathophysiological Functions

“…Both 5-HT 2A and mGlu2 receptors have been implicated in schizophrenia (Roth et al 1998;Benneyworth et al 2007Benneyworth et al , 2008. Activation of mGlu2 receptor increases affinity of 5-HT 2A receptors, whereas activation of 5-HT 2A receptors decreases mGlu2 receptor affinity.…”

Positive allosteric modulators of metabotropic glutamate 2 receptors in schizophrenia treatment

“…On the other hand, the locomotor activity induced by the mGlu 2/3 R antagonist LY341495 is attenuated in 5-HT 2A -KO mice [74]. Moreover, chronic administration of the hallucinogenic 5-HT 2A agonist 2,5-Dimethoxy-4-bromoamphetamine (DOB) in mice attenuates the behavioral effects of the mGlu 2/3 R agonist LY379268 [95] whereas chronic treatment by LY341495 decreases 5-HT 2A binding and the hallucinogenic effects of LSD [96]. …”

Agonist-Trafficking and Hallucinogens

“…heterodimers or oligomers [135,[146][147][148][149][150][151][152][153][154]. Several laboratories have shown that metabotropic glutamate receptor 2/3 (mGluR2/3) activation is able to affect the cellular [155][156][157], electrophysiological [78,117,158,159] and behavioral [155,[160][161][162][163][164] responses induced by 5-HT2AR. It has been recently reported that 5-HT2AR forms a receptor complex with mGluR2 [56].…”