AMPA receptor involvement in 5-hydroxytryptamine2A receptor-mediated pre-frontal cortical excitatory synaptic currents and DOI-induced head shakes.
Glutamate plays an important role in the psychotomimetic effects of both channel blocking N-methyl D-aspartate (NMDA) receptor antagonists and hallucinogenic drugs which activate 5-hydroxytryptamine2A (5-HT2A) receptors. Previous work suggested that activation of non-NMDA ionotropic glutamate receptors mediates the effects of 5-HT-induced excitatory post-synaptic potentials/currents (EPSPs/EPSCs) when recording from layer V pyramidal cells in the rat medial pre-frontal cortex (mPFC). However, those effects are mediated by either alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) or kainate receptors of the iGluk5 subtype. To test whether activation of AMPA receptors is sufficient to mediate 5-HT-induced EPSCs, a 2,3-benzodiazepine that selectively blocks AMPA receptors was assessed. This selective AMPA receptor antagonist potently suppressed 5-HT-induced EPSCs. Since phenethylamine hallucinogens induce head shakes by activating 5-HT2A receptors in the mPFC and this action is modulated by glutamate, we also examined whether selective blockade of AMPA receptors would suppress DOI-induced head shakes. As predicted, we found that selective blockade of AMPA receptors suppressed DOI-induced head shakes. Given evidence that activation of AMPA receptors is an important downstream effect for both channel blocking NMDA receptor antagonists and phenethylamine hallucinogens, we also tested multiple doses of DOI with a sub-anesthetic dose of MK-801. Synergistic action between these two classes of psychotomimetic drugs was demonstrated by MK-801 enhancing DOI-induced head shakes and locomotor activity. These findings expand the dependence of both channel blocking NMDA receptor antagonists and phenethylamine hallucinogens on enhancing extracellular glutamate.
Zhang
Ce
C
Department of Psychiatry, Yale University School of Medicine, Ribicoff Research Facilities of the Connecticut Mental Health Center, New Haven, Connecticut, USA.
Marek
Gerard J
GJ
D000662:Amphetamines / Q000009:adverse effects; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D004195:Disease Models, Animal; D004347:Drug Interactions; D004569:Electroencephalography; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D005625:Frontal Lobe / Q000166:cytology*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000502:physiology*; D018091:Receptors, AMPA / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology; D014202:Tremor / Q000139:chemically induced / Q000378:metabolism*
D000662:Amphetamines; D018691:Excitatory Amino Acid Antagonists; D044402:Receptor, Serotonin, 5-HT2A; D018091:Receptors, AMPA; D012701:Serotonin; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine