bibp-3226 and Substance-Withdrawal-Syndrome

The role of neuropeptide Y (NPY) in the central nucleus of amygdala (CeA) in the preventive effects of acupuncture against ethanol withdrawal-induced anxiety was investigated. Rats were treated with 3g/kg/day of ethanol for 28 days, followed by 3 days of withdrawal. Bilateral acupuncture treatment at HT7 (Shen-Men), PC6 (Nei-Guan) or a non-acupoint was respectively added to the rats during the withdrawal once a day for three days. Enzyme-linked immunosorbent assays and real-time polymerase chain reaction analyses showed there was a significant decrease in NPY protein and mRNA expression in the CeA during ethanol withdrawal, which was reversed by acupuncture at HT7 but neither at PC6 nor at a non-acupoint. Acupuncture at HT7 also greatly inhibited the decrease in cAMP response element-binding protein (CREB) phosphorylation in the CeA. In elevated plus maze tests, a selective NPY Y1 receptor antagonist BIBP 3226 into the CeA before the acupuncture abolished almost completely the anxiolytic effect of acupuncture at HT7. These results suggest that acupuncture at HT7 rescues the depletion of amygdaloid NPY and reverses the decrease in CREB phosphorylation to produce anxiolytic effects during ethanol withdrawal.

Topics: Acupuncture Therapy; Amygdala; Animals; Anxiety; Arginine; Benzazepines; Cyclic AMP Response Element-Binding Protein; Ethanol; Male; Maze Learning; Neuropeptide Y; Phosphorylation; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; RNA, Messenger; Substance Withdrawal Syndrome

We investigated the role of neuropeptide Y Y(1) receptors in acute, chronic and withdrawal effects of nicotine with reference to feeding behavior. Rats were administered with nicotine, neuropeptide Y, neuropeptide Y Y(1) receptor agonist [Leu(31),Pro(34)]neuropeptide Y or antagonist BIBP3226 (N(2)-diphenylacetyl)-N-[(4-hydroxy-phenyl)-methyl]-D-arginine amide) via i.c.v. route, and food intake was measured at 2 and 6 h post-injection time-points. While acute nicotine or BIBP3226 reduced food intake, increase was observed following neuropeptide Y or [Leu(31),Pro(34)]neuropeptide Y. Nicotine-induced anorexia was antagonized by pre-treatment with neuropeptide Y or [Leu(31),Pro(34)]neuropeptide Y, and potentiated by BIBP3226. Furthermore, effects of chronic nicotine (i.p.) and its withdrawal, alone and in combination with BIBP3226 were evaluated with reference to feeding and body weight. Concurrent administration of BIBP3226 with nicotine prevented the development of tolerance to nicotine-induced anorexia, and withdrawal hyperphagia and weight gain. Moreover, acute BIBP3226 attenuated the hyperphagia following nicotine termination. Additionally, immunocytochemical profile of neuropeptide Y in the hypothalamus was studied following differential nicotine treatments. Acute nicotine treatment dramatically reduced neuropeptide Y immunoreactivity in the arcuate and paraventricular nuclei. Chronic nicotine administration decreased neuropeptide Y immunoreactivity in arcuate, but not in paraventricular nucleus. Nicotine withdrawal resulted in significant increase in the neuropeptide Y immunoreactivity in both the nuclei. Neuropeptide Y immunoreactivity in the lateral hypothalamus did not change following any of the treatments. The results suggest that neuropeptide Y in the arcuate and paraventricular nuclei of hypothalamus may be involved in acute, chronic and withdrawal effects of nicotine on the feeding behavior, possibly via neuropeptide Y Y(1) receptors.

Topics: Animals; Arginine; Body Weight; Dose-Response Relationship, Drug; Drug Combinations; Eating; Fluorescent Antibody Technique, Indirect; Immunohistochemistry; Injections, Intraventricular; Male; Microinjections; Neuropeptide Y; Nicotine; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; Substance Withdrawal Syndrome; Time Factors

Although morphine is a potent antinociceptive agent, its chronic use developed tolerance in neuropathic pain (NP). Furthermore, opioid antagonist naloxone attenuated the antinociceptive effect of neuropeptide Y (NPY). The present study investigated the role of NPY and NPY Y1/Y5 receptors in acute and chronic actions of morphine in neuropathic rats using thermal paw withdrawal test and immunocytochemistry. In acute study, intracerebroventricular (icv) administration of morphine, NPY or NPY Y1/Y5 receptors agonist [Leu(31),Pro(34)]-NPY produced antinociception, whereas selective NPY Y1 receptors antagonist BIBP3226 caused hyperalgesia. While NPY or [Leu(31),Pro(34)]-NPY potentiated, BIBP3226 attenuated morphine induced antinociception. Chronic icv infusion of morphine via osmotic minipumps developed tolerance to its antinociceptive effect, and produced hyperalgesia following withdrawal. However, co-administration of NPY or [Leu(31),Pro(34)]-NPY prevented the development of tolerance and withdrawal hyperalgesia. Sciatic nerve ligation resulted in significant increase in the NPY-immunoreactive (NPY-ir) fibers in ventrolateral periaqueductal gray (VLPAG) and locus coeruleus (LC); fibers in the dorsal part of dorsal raphe nucleus (DRD) did not respond. While chronic morphine treatment significantly reduced NPY-ir fibers in VLPAG and DRD, morphine withdrawal triggered significant augmentation in NPY-immunoreactivity in the VLPAG. NPY-immunoreactivity profile of LC remained unchanged in all the morphine treatment conditions. Furthermore, removal of sciatic nerve ligation reversed the effects of NP, increased pain threshold and restored NPY-ir fiber population in VLPAG. NPY, perhaps acting via Y1/Y5 receptors, might profoundly influence the processing of NP information and interact with the endogenous opioid system primarily within the framework of the VLPAG.

Topics: Analgesics, Opioid; Animals; Arginine; Behavior, Animal; Drug Tolerance; Hyperalgesia; Male; Morphine; Neuropeptide Y; Pain Measurement; Peripheral Nervous System Diseases; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; Sciatic Nerve; Substance Withdrawal Syndrome

Tobacco addiction is a chronic disorder that is characterized by dysphoria upon smoking cessation and relapse after periods of abstinence. Previous research suggests that Neuropeptide Y (NPY) and Y1 receptor agonists attenuate negative affective states and somatic withdrawal signs. The aim of the present experiments was to investigate the effects of NPY and the specific Y1 receptor agonist [D-His(26)]-NPY on the deficit in brain reward function and somatic signs associated with nicotine withdrawal in rats. The intracranial self-stimulation procedure was used to assess the effects of nicotine withdrawal on brain reward function as this procedure can provide a quantitative measure of emotional states in rodents. Elevations in brain reward thresholds are indicative of a deficit in brain reward function. In the first experiment, NPY did not prevent the elevations in brain reward thresholds associated with precipitated nicotine withdrawal and elevated the brain reward thresholds of the saline-treated control rats. Similar to NPY, [D-His(26)]-NPY did not prevent the elevations in brain reward thresholds associated with precipitated nicotine withdrawal and elevated the brain reward thresholds of the saline-treated control rats. Neither NPY nor [D-His(26)]-NPY affected the response latencies. In a separate experiment, it was demonstrated that the specific Y1 receptor antagonist BIBP-3226 prevented the NPY-induced elevations in brain reward thresholds. NPY attenuated the overall somatic signs associated with precipitated nicotine withdrawal. [D-His(26)]-NPY did not affect the overall somatic signs associated with precipitated nicotine withdrawal, but decreased the number of abdominal constrictions. Both NPY and [D-His(26)]-NPY attenuated the overall somatic signs associated with spontaneous nicotine withdrawal. These findings indicate that NPY and [D-His(26)]-NPY attenuate somatic nicotine withdrawal signs, but do not prevent the deficit in brain reward function associated with precipitated nicotine withdrawal. In addition, NPY decreases the sensitivity to rewarding electrical stimuli via an Y1 dependent mechanism.

Topics: Animals; Arginine; Brain; Drug Implants; Electric Stimulation; Electrodes, Implanted; Male; Neuropeptide Y; Nicotine; Nicotinic Agonists; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Reward; Self Stimulation; Substance Withdrawal Syndrome