<p class="first" id="P3">Chronic methamphetamine (meth) abuse often turns into a compulsive
drug-taking disorder
accompanied by persistent cognitive deficits and re-occurring psychosis. Possible
common neurobiological substrates underlying meth-induced deficits and schizophrenia
remain poorly understood. Serotonin 2A (5-HT2A) and metabotropic glutamate 2 (mGlu2)
receptors coregulate psychosis-like behaviors and cognitive function in animals. Therefore,
in the present study we examined the effects of chronic exposure to three different
drugs known to produce persistent deficits in sensorimotor gating and cognition [meth,
phencyclidine (PCP) and MK-801] on the expression of 5-HT2A and mGlu2 within the rat
medial prefrontal cortex (PFC), dorsal hippocampus (dHPC) and perirhinal cortex (PRh).
Adult male rats underwent 14 days of: (a) meth self-administration (6 hr/day), (b)
phencyclidine (PCP; 5 mg/kg, twice/day) administration, or (c) MK-801 (0.3 mg/kg,
twice/day) administration. Seven days after the discontinuation of drug administration,
tissues of interest were collected for protein expression analysis. We found that
despite different pharmacological mechanism of action, chronic meth, PCP, and MK-801
similarly dysregulated 5-HT2A and mGlu2, as indicated by an increase in the 5-HT2A/mGlu2
expression ratio in the mPFC (all three tested drugs), PRh (meth and PCP), and dHPC
(MK-801 only). Complementary changes in G-protein expression (increase in Gα
<sub>q</sub> and decrease in Gα
<sub>i</sub> were also observed in the mPFC of meth animals. Finally, we found that
5-HT2A/mGlu2
cooperation can be mediated in part by the formation of the receptor heteromer in
some, but not all cortical regions. In summary, these data suggest that a shift towards
increased availability (and G-protein coupling) of cortical 5-HT2A
<i>vs.</i> mGlu2 receptors may represent a common neurobiological mechanism underlying
the emergence
of psychosis and cognitive deficits observed in subjects with meth use disorder and
schizophrenia.
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