title: Stress-induced increase of cortical dopamine metabolism: attenuation by a tachykinin NK1 receptor antagonist.
abstract: The present study examined the potential role of tachykinin NK1 receptors in modulating immobilisation stress-induced increase of dopamine metabolism in rat medial prefrontal cortex. In agreement with previous studies, 20 min immobilisation stress significantly increased medial prefrontal cortex dopamine metabolism as reflected by the concentration of the dopamine metabolite dihydroxyphenylacetic acid (DOPAC). Pretreatment with the high affinity, selective, tachykinin NK1 receptor antagonist (3(S)-(2-methoxy-5-(5-trifluoromethyltetrazol-1-yl)-phenylmethyl amino)-2(S)-phenylpiperidine) ((S)-GR205171, 10 mg/kg, s.c.), a dose that in ex vivo binding studies extensively occupied rat brain tachykinin NK1 receptors for approximately 60 min, significantly attenuated the stress-induced increase of mesocortical DOPAC concentration without affecting cortical DOPAC levels per se. In contrast, pretreatment of animals with the less active enantiomer (R)-GR205171 (10 mg/kg, s.c.), which demonstrated negligible tachykinin NK1 receptor occupancy ex vivo, failed to affect either basal or stress-induced DOPAC concentration in medial prefrontal cortex. Furthermore, pretreatment of animals with the benzodiazepine/GABAA receptor antagonist, flumazenil (15 mg/kg, i.p.), did not affect the ability of (S)-GR205171 to attenuate the increase of medial prefrontal cortex DOPAC concentration by acute stress. Results demonstrate that the selective tachykinin NK1 receptor antagonist, (S)-GR205171, attenuated the stress-induced activation of mesocortical dopamine neurones by a mechanism independent of the benzodiazepine modulatory site of the GABAA receptor.
authors.affiliation: Merck, Sharp and Dohme, The Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, CM20 2QR, Essex, UK. Peter_Hudson@Merck.com
authors.forename: Peter H
authors.initials: PH
authors.lastname: Hutson
authors.forename: Shil
authors.initials: S
authors.lastname: Patel
authors.forename: Mark T
authors.initials: MT
authors.lastname: Jay
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Barton
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D013312:Stress, Physiological / Q000378:metabolism*; D013777:Tetrazoles / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D018040:Receptors, Neurokinin-1; D013777:Tetrazoles; C103207:vofopitant; D004298:Dopamine