Spinal 5-HT2A receptors regulate cutaneous sympathetic vasomotor outflow in rabbits and rats; relevance for cutaneous vasoconstriction elicited by MDMA (3,4-methylenedioxymethamphetamine, "Ecstasy") and its reversal by clozapine.
We determined whether spinal 5-hydroxytryptamine 2A (5-HT2A) receptors contribute to resting cutaneous sympathetic vasomotor activity, and to increases in activity elicited by electrical stimulation of the medullary raphe/parapyramidal region, and whether these receptors are involved in the cutaneous vasoconstricting action of systemically administered MDMA (3,4-methylenedioxymethamphetamine, "Ecstasy") and its reversal by clozapine. Experiments were conducted in urethane-anesthetized rabbits and rats. Administration of the 5-HT2A antagonist, trans-4-((3Z)3-[(2-Dimethylaminoethyl)oxyimino]-3-(2-fluorophenyl)propen-1-yl)-phenol, hemifumarate (SR 46349B, 0.1 mg/kg, i.v.) inhibited resting ear pinna sympathetic vasomotor nerve discharge and reduced the extent to which raphe/parapyramidal electrical stimulation caused ear pinna (rabbit) and tail (rat) artery blood flow to fall. Clozapine (0.125-0.5 mg/kg, i.v.) also reduced the fall in ear pinna blood flow elicited by raphe/parapyramidal stimulation. In rabbits, after inactivation of raphe/parapyramidal function by local microinjection of muscimol (1 nmol in 100 nl), the 5-HT2A agonist R(-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI, 50 microg/kg, i.v.) increased ear pinna sympathetic nerve activity from 3+/-2% to 129+/-5% of pre-muscimol levels (P<0.01, n=6), and this increase was abolished by section of the ipsilateral cervical sympathetic nerve trunk. MDMA (2 mg/kg, i.v.) after muscimol decreased ear pinna blood flow from 33+/-10 to 2+/-1 cm/s (P<0.01, n=5) and increased ear pinna sympathetic nerve activity from 8+/-4% to 120+/-41% of pre-muscimol levels (P<0.01, n=6). The MDMA-elicited increase in nerve activity was abolished by SR 46349B. Data suggest that spinal 5-HT2A receptors contribute to sympathetically induced cutaneous vasoconstriction regulated by raphe/parapyramidal neurons in the brainstem, and that these receptors contribute to the cutaneous vasoconstricting action of MDMA and its reversal by clozapine.
Ootsuka
Youichirou
Y
Department of Human Physiology, School of Medicine, Flinders University, Bedford Park, South Australia 5042, Australia. yoichiro.otsuka@flinders.edu.au
Nalivaiko
Eugene
E
Blessing
William W
WW
D000818:Animals; D003024:Clozapine / Q000494:pharmacology*; D004431:Ear, External / Q000098:blood supply; D005464:Fluorobenzenes / Q000008:administration & dosage; D007275:Injections, Intravenous; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010636:Phenols / Q000008:administration & dosage; D011817:Rabbits; D011903:Raphe Nuclei / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000502:physiology*; D012702:Serotonin Antagonists / Q000008:administration & dosage; D012867:Skin / Q000098:blood supply*; D013131:Spine / Q000378:metabolism*; D013623:Tail / Q000098:blood supply; D018617:Ultrasonography, Doppler, Pulsed; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology*; D014666:Vasomotor System / Q000187:drug effects / Q000502:physiology
D005464:Fluorobenzenes; D010636:Phenols; D044402:Receptor, Serotonin, 5-HT2A; D012702:Serotonin Antagonists; C076033:SR 46349B; D003024:Clozapine; D018817:N-Methyl-3,4-methylenedioxyamphetamine