AUTHOR=Marek Gerard J. , Ramos Brian P. 

TITLE=β2-Adrenergic Receptor Activation Suppresses the Rat Phenethylamine Hallucinogen-Induced Head Twitch Response: Hallucinogen-Induced Excitatory Post-synaptic Potentials as a Potential Substrate

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 9 - 2018

YEAR=2018

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2018.00089

DOI=10.3389/fphar.2018.00089

ISSN=1663-9812

ABSTRACT=5-Hydroxytryptamine2A (5-HT2A) receptors are enriched in layers I and Va of the rat prefrontal cortex and neocortex  and their activation increases the frequency of glutamatergic excitatory postsynaptic potentials/currents (EPSP/Cs) onto layer V pyramidal cells.  A number of other G-protein coupled receptors (GPCRs) are also enriched in cortical layers I and Va and either induce (1-adrenergic and orexin2) or suppress (metabotropic glutamate2 [mGlu2], adenosine A1, -opioid) both 5-HT-induced EPSCs and head twitches or head shakes induced by the phenethylamine hallucinogen 2,5-dimethoxy-4-iodoamphetamine (DOI).  Another neurotransmitter receptor also localized to apparent thalamocortical afferents to layers I and Va of the rat prefrontal cortex and neocortex is the 2-adrenergic receptor.  Therefore, we conducted preliminary electrophysiological experiments with rat brain slices examining the effects of epinephrine on electrically-evoked EPSPs following bath application of DOI (3 M).  Epinephrine (0.3-10 M) suppressed the late EPSPs produced by electrical stimulation and DOI.   The selective 2-adrenergic receptor antagonist ICI-118,551 (300 nM) resulted in a rightward shift of the epinephrine concentration-response relationship.  We also tested the selective 2-adrenergic receptor agonist clenbuterol and the antagonist ICI-118,551 on DOI-induced head twitches.  Clenbuterol (0.3-3 mg/kg, i.p.) suppressed DOI(1.25 mg/kg, i.p.)-induced head twitches.  This clenbuterol effect appeared to be at least partially reversed by the selective 2-adrenergic receptor antagonist ICI-118,553 (0.01-1 mg/kg, i.p.), with significant reversal at doses of 0.1 and 1 mg/kg.  Thus, 2-adrenergic receptor activation reverses the effects of phenethylamine hallucinogens in the rat prefrontal cortex.  While Gi/Go-coupled GPCRs have previously been shown to suppress both the electrophysiological and behavioral effects of 5-HT2A receptor activation in the mPFC, the present work appears to extend this suppressant action to a Gs-coupled GPCR.  Furthermore, the modulation of 5-HT2A receptor activation induced glutamate release onto mPFC layer V pyramidal neurons apical dendrites by a range GPCRs in rat brain slices appears to results in behaviorally salient effects of relevance when screening for novel CNS therapeutic drugs.