β 2 -Adrenergic Receptor Activation Suppresses the Rat Phenethylamine Hallucinogen-Induced Head Twitch Response: Hallucinogen-Induced Excitatory Post-synaptic Potentials as a Potential Substrate

• Published in: Frontiers in pharmacology Vol. 9; p. 89
• Main Authors: Marek, Gerard J, Ramos, Brian P
• Format: Journal Article
• Language: English
• Published: Switzerland 2018
• Subjects: clenbuterol; head twitch response (HTR); layer V pyramidal neurons; medial prefrontal cortex (mPFC); excitatory post-synaptic potentials (EPSPs); epinephrine; 2,5-dimethoxy-4-iodoamphetamine (DOI); ICI-118,551
• ISSN: 1663-9812; 1663-9812

5-Hydroxytryptamine (5-HT ) receptors are enriched in layers I and Va of the rat prefrontal cortex and neocortex and their activation increases the frequency of glutamatergic excitatory post-synaptic 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 (α -adrenergic and orexin ) or suppress (metabotropic glutamate [mGlu ], adenosine A , μ-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 β -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 μM). Epinephrine (0.3-10 μM) suppressed the late EPSPs produced by electrical stimulation and DOI. The selective β -adrenergic receptor antagonist ICI-118,551 (300 nM) resulted in a rightward shift of the epinephrine concentration-response relationship. We also tested the selective β -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 β -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, β -adrenergic receptor activation reverses the effects of phenethylamine hallucinogens in the rat prefrontal cortex. While G /G -coupled GPCRs have previously been shown to suppress both the electrophysiological and behavioral effects of 5-HT receptor activation in the mPFC, the present work appears to extend this suppressant action to a G -coupled GPCR. Furthermore, the modulation of 5-HT 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.