Behavioural and biochemical responses following activation of midbrain dopamine pathways by receptor selective neurokinin agonists.
Preferential activation of mesolimbic and nigro-striatal dopamine (DA) pathways by receptor-selective and peptidase-resistant neurokinin (NK) agonists is reported. The DA cell body region of the mesolimbic pathway appears to be activated by NK agonists selective for NK-1 and NK-3 receptors whereas the DA cell bodies in the substantia nigra are under an excitatory NK-2 receptor-mediated influence. Stimulation of the mesolimbic DA pathway by NK-1 (Ava[L-Pro9,N-Me-Leu10]SP (7-11) [GR73632]) or NK-3 (Senktide) agonists increase locomotor activity. Additional studies showed that this elevated motor response observed after intra-VTA infusion of GR73632 was accompanied by a corresponding increase in DA turnover in the terminal fields of this pathway. Similarly, unilateral activation of the nigro-striatal DA pathway by NK-2 selective agonists (Ava (D-Pro9) SP (7-11) [GR51667] or [Lys3,Gly8,R-Lac-Leu9]NKA (3-10) [GR64349]) elicit contralateral rotational activity and an increase in DA turnover in the ipsilateral striatum. The rotational response was attenuated by prior administration of an NK-2 antagonist (cyclo (Gln, Trp, Phe, Gly, Leu, Met)] L-659877]) into the nigra. Peripheral injection of haloperidol, a DA antagonist, also blocked the NK-2 agonist induced rotations.
Elliott
P J
PJ
Department of Neuropharmacology, Glaxo Group Research Ltd, Ware, Herts, UK.
Mason
G S
GS
Stephens-Smith
M
M
Hagan
R M
RM
D000595:Amino Acid Sequence; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004298:Dopamine / Q000378:metabolism*; D006220:Haloperidol / Q000494:pharmacology; D008032:Limbic System; D008297:Male; D008636:Mesencephalon / Q000187:drug effects* / Q000378:metabolism; D008969:Molecular Sequence Data; D009043:Motor Activity / Q000187:drug effects*; D009434:Neural Pathways; D015288:Neurokinin A / Q000031:analogs & derivatives* / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017981:Receptors, Neurotransmitter / Q000378:metabolism; D018039:Receptors, Tachykinin; D013373:Substance P / Q000031:analogs & derivatives* / Q000494:pharmacology; D013378:Substantia Nigra / Q000187:drug effects; D013681:Tegmentum Mesencephali / Q000187:drug effects / Q000378:metabolism
D010446:Peptide Fragments; D017981:Receptors, Neurotransmitter; D018039:Receptors, Tachykinin; C054724:senktide; C068032:GR 73632; C068031:neurokinin A (3-10), lysyl(3)-glycyl(8)-R-lactam-leucine(9)-; C071463:delta-Ava-Pro(9)-substance P (7-11); D013373:Substance P; D015288:Neurokinin A; D006220:Haloperidol; D004298:Dopamine