Inhibition of amphetamine- and apomorphine-induced behavioural effects by neuropeptide YY1 receptor antagonist BIBO 3304

Neuropeptide Y (NPY) has an important role in the regulation of stress resp onses and feeding behaviour. There is evidence that some effects elicited b y NPY occur due to modulation of action of regular neurotransmitters. The m ain objective of the present study was to test behavioural effects of the n ovel neuropeptide Y (NPY) Y-1 receptor antagonist (R)-N-[[4-(aminocarbonyla minomethyl)-phenyl] methyl]-N-2-(diphenylacetyl)-argininamide trifluoroacet ate (BIBO 3304) on dopamine-dependent behaviour. Intracerebroventricular ad ministration of BIBO 3304 (I, 10, 50 nmol) had no effect on locomotor activ ity as measured by number of rearings and number of squares visited in an o pen field test in rats, but at 50 nmol dose defecation was significantly in creased. BIBO 3304 (10 nmol) reduced amphetamine-induced increases in horiz ontal and vertical activity whereas its S-configurated enantiomer BIBO 3457 was inactive. In an open field test BLBO 3304 (10 nmol) inhibited purposel ess running in rats sensitized to direct dopaminergic agonist apomorphine ( 0.5 mg/kg, s.c.). BIBO 3304 (10 nmol but not 1 nmol, i.c.v.) reduced fighti ng in apomorphine-induced aggression paradigm. Apomorphine-induced aggressi on was reduced by another, structurally similar, but less potent NPY Y, rec eptor antagonist BIBP 3226 (10 nmol, i.c.v.). A lower dose of BIBP 3226 (1 nmol, i.c.v.) was inactive. Concomitant administration of BIBO 3304 (10 nmo l) with low doses of apomorphine (0.5 mg/kg s.c.) over the course of 10 day s failed to prevent the development of apomorphine-induced aggressiveness. These data demonstrate that behavioural response to indirectly (amphetamine ) and directly (apomorphine) acting dopaminergic stimulants is inhibited by NPY Y-1 receptor antagonists and suggest that NPY Y-1 receptor activation might be important in pathophysiology of disorders associated with hyperact ivity of dopaminergic pathways, such as psychosis, schizophrenia and drug a buse. We propose that the effects of BIBO 3304 on amphetamine/apomorphine-i nduced locomotion and apomorphine-induced aggressiveness are due to modulat ion of postsynaptic dopaminergic responses rather than direct effects of NP Y Y-1 receptor antagonists on dopamine or NPY release. (C) 2000 Elsevier Sc ience Ltd. All rights reserved.