neuropeptide-y and alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanol

1. The Y receptor subtype involved in the antagonism by neuropeptide Y (NPY) of intracisternal corticotropin-releasing factor (CRF)-induced inhibition of gastric acid secretion was studied in urethane-anaesthetized rats by use of peptides with various selectivity for Y1, Y2 and Y3 subtypes: NPY, a Y1, Y2 and Y3 agonist, peptide YY (PYY), a Y1 and Y2 agonist, [Leu31, Pro34]-NPY, a Y1 and Y3 agonist, NPY(3-36) and PYY(3-36), highly selective Y2 agonists and NPY(13-36) a weak Y2 and Y3 agonist. Peptides were injected intracisternally 10 min before intracisternal injection of CRF (10 micrograms) and gastric acid secretion was measured by the flushed technique for 1 h before and 2 h after pentagastrin-(10 micrograms kg-1 h-1, i.v.) infusion which started 10 min after CRF injection. 2. Intracisternal injection of CRF (10 micrograms) inhibited by 56% gastric acid secretion stimulated by pentagastrin. Intracisternal injection of NPY and PYY (0.1-0.5 microgram) did not influence the acid response to pentagastrin but blocked CRF-induced inhibition of pentagastrin-stimulated acid secretion. NPY(3-36) (0.5 microgram) and PYY(3-36) (0.25 and 0.5 microgram) also completely blocked the inhibitory action of CRF on pentagastrin-stimulated acid secretion. 3. [Leu31, Pro34]-NPY (0.5-5 micrograms) and NPY(13-36) (0.5-5 micrograms) injected intracisternally did not modify gastric acid secretion induced by pentagastrin or CRF inhibitory action. 4. The sigma antagonist, BMY 14802 (1 mg kg-1, s.c.) did not influence the acid response to pentagastrin but prevented the antagonism by PYY(3-36) (0.5 microgram) of the CRF antisecretory effect. 5. These results show that both PYY and NPY and the 3-36 forms of PYY and NPY are equipotent in blocking central CRF-induced inhibition of pentagastrin-stimulated gastric acid secretion. The structure-activity profile suggests a mediation through Y2 receptor subtype and the involvement of sigma binding sites.

Topics: Animals; Corticotropin-Releasing Hormone; Gastric Acid; Gastric Mucosa; Male; Neuropeptide Y; Peptide Fragments; Peptide YY; Peptides; Pyrimidines; Rats; Rats, Sprague-Dawley

Multiple administrations of the psychotomimetic drug, phencyclidine-HCI (PCP), decreased striatal neuropeptide Y-like immunoreactivity (NPY-LI) levels in a dose-dependent manner. Single or multiple PCP administrations decreased striatal NPY levels after 10-12 h; levels returned to control 24 h after a single dose or 58 h after multiple doses. In contrast, no significant changes were seen in nigral NPY levels with either acute or multiple-dose PCP treatments. The role of monoamine, sigma or opioid receptors in PCP-induced striatal NPY changes was evaluated. When administered alone, the alpha 1-adrenergic antagonist, prazosin, the sigma antagonist, BMY 14802, and the dopamine D2 antagonist, sulpiride decreased striatal NPY levels; however, only prazosin and the dopamine D1 antagonist, SCH 23390, significantly attenuated PCP-induced changes. Administration of the gamma-aminobutyric acid transaminase (GABA-T) inhibitors, amino-oxyacetic acid (AOAA) or gamma-vinyl-GABA (GVG, vigabatrin, MDL 71,754) alone had no effect on striatal NPY-LI levels while administration of these indirect GABA agonists prior to or concurrently with PCP treatment completely blocked PCP-induced changes in striatal NPY-LI levels. The effect of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801, on striatal NPY-LI content resembled that of PCP and was also blocked by the two indirect GABA agonists. These data suggest that NPY systems are modulated by glutamatergic activity (specifically by the NMDA receptor) and that the interaction between these two transmitter systems is mediated by GABAergic mechanisms.

Topics: 4-Aminobutyrate Transaminase; Adrenergic beta-Antagonists; Aminocaproates; Aminooxyacetic Acid; Animals; Benzazepines; Carbazoles; Corpus Striatum; Dioxanes; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Administration Schedule; Idazoxan; Male; Naloxone; Neuropeptide Y; Phencyclidine; Prazosin; Psychotropic Drugs; Putamen; Pyrimidines; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; Time Factors; Vigabatrin

In an in vivo electrophysiological paradigm, we have shown in the companion paper that neuropeptide Y (NPY) potentiates N-methyl-D-aspartate (NMDA)-induced neuronal activation via a non-Y1, non-Y2, non-Y3 receptor subtype, in the rat CA3 dorsal hippocampus. Because sigma ligands have also been shown to potentiate NMDA-induced activation and because NPY and peptide YY have been reported to have high affinity for sigma binding sites, the present study was carried out to assess the possibility that the modulation of the NMDA response by NPY might be mediated by a sigma receptor. In the same electrophysiological paradigm, low doses of haloperidol and alpha-(4-fluorophenyl)-4-(5-fluoro-2- pyrimidinyl)-1-piperazine butanol, two antagonists of sigma receptors, reversed the potentiation of the NMDA response induced by NPY, [Leu31, Pro34]NPY or NPY13-36 and blocked the suppressant effect of desamido-NPY on the NMDA response. In contrast, spiperone, which has low affinity for sigma sites, was ineffective in suppressing NPY, as well as desamido-NPY-induced modulation of the NMDA response. In our model, peptide YY, which acts as a NPY antagonist by suppressing the potentiation of the NMDA response induced by NPY, also antagonized the potentiation of the NMDA response induced by the administration of low doses of di(2-tolyl)guanidine and (+)N-cyclopropyl-methyl-N-,methyl-1,4- diphenyl-1-ethyl-but-3-en-1-ylamine hydrochloride, two high-affinity sigma agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Cinnamates; Cyclopropanes; Drug Synergism; Guanidines; Haloperidol; Hippocampus; Male; N-Methylaspartate; Neuropeptide Y; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; Receptors, sigma; Spiperone

1. The central interactions between the sigma ligand, JO 1784, [(+)-N-cyclopropylmethyl-N-methyl-1,4-diphenyl-1-ethylbut-3- en-1-ylamine hydrochloride], or neuropeptide Y (NPY) and corticotropin-releasing factor (CRF)-induced inhibition of gastric acid secretion were investigated in rats anaesthetized with urethane. Drugs were injected intracisternally (i.c.) or into specific hypothalamic nuclei. Gastric acid secretion was measured by the flushed technique under basal and pentagastrin (10 micrograms kg-1 h-1, i.v.) stimulated conditions. 2. Intracisternal injection of CRF (10 micrograms), bombesin (0.1 microgram) and human recombinant interleukin-1 beta (hIL-1 beta, 0.1 microgram) inhibited gastric acid response to pentagastrin by 72%, 56% and 62%, respectively. NPY (0.5 microgram) or JO 1784 (0.5 microgram) injected i.c. did not alter acid secretion but completely prevented the inhibitory effect of CRF. The antagonistic effect of NPY and JO 1784 against CRF was dose-related (0.01-0.5 microgram) and peptide-specific since NPY and JO 1784 did not alter the antisecretory action of bombesin or hIL-1 beta. 3. The putative sigma receptor antagonist, BMY 14802, (1 mg kg-1, s.c.) did not influence pentagastrin-stimulated acid secretion nor CRF-induced inhibition of gastric acid secretion; however, BMY 14802 administered s.c. 20 min before JO 1784 or NPY, abolished the antagonistic effect of both JO 1784 and NPY. 4. CRF (3 micrograms) microinjected into the hypothalamic paraventricular nucleus (PVN) and the lateral hypothalamus (LH) inhibited pentagastrin-stimulated gastric acid secretion by 61% and 51%; NPY (0.03 micrograms) or JO 1784 (0.03 micrograms) microinjected into the PVN had no effect by themselves but blocked CRF antisecretory action.There were more VPBs (220 +/- 75), a higher incidence of VT (60%) and more episodes of VT (11.5 +/- 6.0 compared to 0.7 +/- 0.3 episodes in the preconditioned dogs not given L-NAME); none of the animals survived reperfusion (incidence of VF 100%). The improvement in the severity of the degree of inhomogeneity which resulted from preconditioning was abolished by L-NAME administration.5. L-NAME itself elevated blood pressure (from 96 +/- 5 mmHg diastolic to 119 +/- 7 mmHg), reduced heart rate (from 155 +/- 7 to 144 +/- 4 beats min-') but did not change LVEDP, LVdP/dt,,,,, coronary blood flow, ST-segment elevation or the degree of inhomogeneity of conduction. When given 10 min before the prolonged coronary artery occlusion in

Topics: Animals; Bombesin; Cinnamates; Cisterna Magna; Corticotropin-Releasing Hormone; Cyclopropanes; Dose-Response Relationship, Drug; Gastric Acid; Humans; Interleukin-1; Male; Microinjections; Neuropeptide Y; Paraventricular Hypothalamic Nucleus; Pentagastrin; Psychotropic Drugs; Pyrimidines; Rats; Rats, Sprague-Dawley