Pharmacology - Chronic Phenethylamine Hallucinogen Treatment Alters Behavioral Sensitivity to a Metabotropic Glutamate 2/3 Receptor Agonist (2007)

[Jatelka]

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Neuropsychopharmacology. 2007 Oct 24

Benneyworth MA, Smith RL, Sanders-Bush E.

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 (-)-2,5-dimethoxy-4-bromoamphetamine [(-)-DOB)] as a stimulus-producing drug. The (-)-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 (-)-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.

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[snapper]

The glutamate agonist angle for controlling schizophrenia is really a fantastic discovery if it bears out. It is interesting that though they found increased receptor activation (indirectly) but that their agonists did not block DOB's effect. That argues for some secondary process which is mediated at another level than the glutamine receptor. What is not valid is the analogy inferred between schizophrenia and the hallucinogenic state. they are very different and likely use different neurochemical pathways. That said, wouldn't it be handy to have some M100907 around as a trip aborter ? SWIM also wonders what drugs mGlu receptor agonists modulate, or is this an assumption in the article (SWIM finds having only abstracts frustrating sometimes !).

[Paracelsus]

Only abstracts? The full text is linked to in post #1 (I assume you know this but your last comment raised doubt).

[snapper]

Thanks Paracelsus, I didn't know to hit the second link to the PDF. It does not go into much detail about previous studies but there is one involving DOI in mice in the references which from the title found the opposite of this study (ie-glutamate modulates the effect of a seratonergic hallucinogenic). And as an FYI for those reading, ICR mice are standard lab mice - there is no special mutation relevant to this study (this was unclear in the article).