Chronic methamphetamine self-administration dysregulates 5-HT2A and mGlu2 receptor expression in the rat prefrontal and perirhinal cortex: Comparison to chronic phencyclidine and MK-801

Abstract

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 co-regulate 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 (mPFC), dorsal hippocampus (dHPC) and perirhinal cortex (PRh). Adult male rats underwent 14 days of: (a) meth self-administration (6 h/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 and decrease in Gα) 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 vs. 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.

Voluntary oral methamphetamine increases memory deficits and contextual sensitization during abstinence associated with decreased PKMζ and increased κOR in the hippocampus of female mice

“…In our VOMA study, low consumers consumed on average 2.09 mg/kg MA/day (±0.44 SEM) over the last 18 days of VOMA, whereas high consumers consumed on average 8.11 mg/kg MA/day (±1.24 SEM) over the last 18 days of VOMA. Previous studies have found that self-administration of MA gradually increases over a 1-week period at the same average rate in rats (Hámor et al, 2018; Krasnova et al, 2010; Rogers et al, 2008), but these reports failed to describe individual differences or MA-preferences in these animals. Recently, an emerging body of work has reported potential genetic contributions to MA-preferences using a drinking model (Shabani et al, 2016).…”

Interclass GPCR heteromerization affects localization and trafficking

“…These two receptors participate in brain processes such as perception, cognition, and sensorimotor gating and have been implicated under psychiatric conditions such as schizophrenia, depression, and alcoholism [reviewed in (40)(41)(42)]. Our previous findings (43)(44)(45)(46)(47), along with other studies (48)(49)(50)(51), suggest that 5-HT 2A R and mGluR2 can form heteromeric complexes in living mammalian cells and ex vivo in rodent models. This molecular proximity, however, has not been observed in cells coexpressing 5-HT 2A R and mGluR3 (43)(44)(45)(46)(47).…”

Modulation of the Serotonergic Receptosome in the Treatment of Anxiety and Depression: A Narrative Review of the Experimental Evidence

“…In addition, these receptors have other mechanisms that regulate their signaling, such as the formation of homo and heteromeric complexes with other metabotropic receptors such as mGlu 2 and D 2 [ 50 , 51 ]. The interaction between 5-HT 2A and mGlu 2 can be attested by the synergistic effect between 5-HT 2A antagonist antipsychotic drugs and mGlu 2 agonists, and also by the documented co-localization of these receptors [ 52 , 53 ].…”