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The opioid-mesolimbic-dopamine circuitry operates between ventral tegmental area (VTA) and nucleus accumbens (Acb) and serves as a major reward pathway. We hypothesized that the neuropeptide cocaine- and amphetamine-regulated transcript (CART) is involved in the natural reward action mediated by the circuitry. Therefore, the modulation of opioid-mesolimbic-dopamine reward circuitry by CART was investigated using pellet self-administration paradigm in operant chamber. Morphine administered bilaterally in shell region of Acb (AcbSh) significantly increased active lever pressings and pellet self-administration. While CART given bilaterally in the AcbSh significantly increased pellet self-administration, CART antibody produced no effect. Morphine induced pellet self-administration was potentiated by CART, and antagonized by CART antibody administered in AcbSh. A close interaction between dopamine and CART systems was observed. Several tyrosine hydroxylase (marker for dopamine) immunoreactive fibers were seen contacting CART neurons in the AcbSh. Intraperitoneal administration of pramipexole, a dopamine agonist, increased pellet self-administration. The effect was blocked by prior treatment with CART antibody targeted at AcbSh. CART-immunoreactive cells and fibers in the AcbSh, and cells but not fibers in hypothalamic paraventricular nucleus (PVN), were significantly increased in the animals trained in operant chamber. However, CART-immunoreactive profile in the medial forebrain bundle, VTA and arcuate nucleus of hypothalamus did not respond. We suggest that CART, released from the axonal terminals in the framework of AcbSh, may serve as the final output of the endogenous opioid-mesolimbic-dopamine circuitry that processes natural reward., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

We investigated the role of endogenous neuropeptide Y (NPY) system in nicotine-mediated improvement of learning and memory in rat model of Alzheimer's disease (AD). Intracerebroventricular (icv) colchicine treatment induced AD-like condition in rats and showed increased escape latency (decreased learning), and amnesic condition in probe test in Morris water maze. In these rats, nicotine (0.5mg/kg, intraperitoneal), NPY (100 ng/rat, icv) or NPY Y1 receptor agonist [Leu(31), Pro(34)]-NPY (0.04 ng/rat, icv) decreased escape latency by 54.76%, 55.81% and 44.18%, respectively, on day 4 of the acquisition. On the other hand, selective NPY Y1 receptor antagonist, BIBP3226 (icv) produced opposite effect (44.18%). In the probe test conducted at 24h time point, nicotine, NPY or [Leu(31), Pro(34)]-NPY increased the time spent by 72.72%, 44.11% and 26.47%, respectively; while BIBP3226 caused reduction (8.82%). It seems that while NPY or [Leu(31), Pro(34)]-NPY potentiated, BIBP3226 attenuated the learning and memory enhancing effects of nicotine. Brains of colchicine treated rats showed significant reduction in NPY-immunoreactivity in the nucleus accumbens shell (cells 62.23% and fibers 50%), bed nucleus of stria terminalis (fibers 71.58%), central nucleus of amygdala (cells 74.33%), arcuate nucleus (cells 70.97% and fibers 69.65%) and dentate gyrus (cells 58.54%). However, in these rats nicotine treatment for 4 days restored NPY-immunoreactivity to the control level. We suggest that NPY, perhaps acting via NPY Y1 receptors, might interact with the endogenous cholinergic system and play a role in improving the learning and memory processes in the rats with AD-like condition., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Since estradiol exercises inhibitory effect on food intake, we wanted to find out if this influence of estradiol is mediated by cocaine- and amphetamine-regulated transcript peptide (CART), a well established anorectic agent in the brain. Ovariectomized (OVX) rats, replaced with estradiol to produce estrous-phase like conditions, showed a significant decrease in food intake as compared with that in OVX controls. Intracerebroventricular (icv) administration of CART (0.5-1 μg/rat) to OVX rats, resulted in a dose-dependent reduction in the food intake. The lower dose (0.25 μg) had no effect, and was considered subeffective. In estradiol replaced OVX rats, CART at subeffective dose, further reduced food intake. However, CART failed to reduce food intake in estradiol replaced OVX rats pretreated with anti-estrogenic agent tamoxifen (3 mg/kg, subcutaneous). Administration of CART antibody (1:500 dilution/rat, i.c.v.) significantly attenuated estradiol-induced anorexia in the OVX rats. While estradiol replacement significantly increased CART-immunoreactivity in the cells/fibers of paraventricular nucleus (PVN) of OVX rats, fibers in the anteroventral periventricular nucleus (AVPV), and cells/fibers in the arcuate nucleus (ARC) showed considerable reduction. These changes were attenuated following concurrent injection of tamoxifen to the estradiol replaced OVX rats. However, CART-immunoreactive cells/fibers in the periventricular area did not respond to any of the treatments. We suggest that estradiol treatment might influence the hypothalamic CART system in a site specific manner. While increased CART activity in the PVN might produce anorexia, reduction of CART in ARC and AVPV might represent a compensatory homeostatic response., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Introduction: Stereotaxic administration of neuroactive agents, either in ventricles, or targeted at specific intracranial sites, is a widely employed strategy for neurological studies in rodents. Surgical implantation of cannula on the skull is particularly useful in chronic treatments. We describe a simple, inexpensive and reliable method to fabricate a cannula system for delivery of drugs at the targeted sites in the brain of rat or mouse., Methods: The system consists of a guide cannula made from a hypodermic needle (24 gauge), a stainless steel wire (30 gauge) that serves as a dummy cannula, and an internal cannula made of stainless steel needle (30 gauge) taken from a hypodermic syringe. The cannula can be implanted by routine stereotaxic procedure and used for acute or chronic drug administration to conscious, free moving animals., Results: With a view to test the system for accuracy, the guide cannula was stereotaxically implanted, and neuropeptide Y was directly delivered into the lateral ventricle. These rats showed a significant increase in food intake. Another set of rats were cannulated for chronic protocol, wherein ethanol was delivered directly into the ventral tegmental area. In operant chamber, these rats showed increased ethanol self-administration. The proposed cannula takes around 5 min to fabricate and costs less than a dollar., Conclusion: We feel that it may serve as an economical and reliable tool in neuropharmacological and neurobehavioral studies., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: Although hyperphagia and body weight gain are well-recognized consequences of social isolation, the underlying mechanisms are not understood. The aim of this work is to test the possibility that the endogenous cocaine- and amphetamine-regulated transcript peptide (CART) may be involved in the process., Design: Socially isolated rats were screened for increase in food intake and body weight, and the modifications of these parameters by CART were evaluated. Furthermore, isolated animals were re-socialized and screened for reversal of these effects. Response of the endogenous CART system, in certain hypothalamic nuclei of the isolated and re-socialized rats, was evaluated with immunohistochemistry., Subjects: Fifty days old naive male Sprague-Dawley rats were used., Measurements: The effects of CART/CART antibody on the social isolation and subsequent re-socialization on feeding and body weight changes were monitored. Moreover, the immunohistochemical response of endogenous CART system to social isolation and re-socialization was analyzed morphometrically., Results: While social isolation of rats for a period of 6 weeks caused progressive increase in food consumption and body weight gain, these rats showed a significant reduction in food intake and body weight when injected daily with CART via intracerebroventricular (i.c.v.) route, for the following 7 days. The re-socialization of isolated rats reduced food intake and body weight to the control levels. These effects of re-socialization were attenuated by immunoneutralization of the endogenous CART by i.c.v. CART antibody. Social isolation also resulted in a drastic reduction in CART immunoreactivity in the cells and/or fibers in the hypothalamic areas like dorsomedial, ventromedial, lateral, paraventricular and arcuate nuclei, recognized for their role in feeding. On the other hand, the CART immunoreactivity profile was fully restored following 7 days of re-socialization of the isolation-reared rats., Conclusion: Social isolation might down-regulate the hypothalamic CART-containing system, which in turn may lead to increase in food intake and body weight.

While nicotine treatment to rodents causes a transient anorexia and persistent weight loss, withdrawal produces hyperphagia and weight gain. Herein, we test the hypothesis that endogenous anorectic peptide cocaine- and amphetamine-regulated transcript (CART) may be involved in these nicotine triggered physiological disturbances. In acute study, an anorectic effect of intraperitoneal nicotine was significantly potentiated by intracerebroventricular pre-treatment with CART at 2 and 4 h post-injection time-points. In chronic study, following an initial reduction, food intake, but not body weight, was progressively restored to normal. On the other hand, termination of chronic nicotine treatment resulted in significant hyperphagia and weight gain. These effects of nicotine were abolished if the rats were concomitantly treated with CART. An immunohistochemical profile of hypothalamic CART was studied following different nicotine treatment conditions. Acute nicotine treatment caused a significant increase above control in the CART-immunoreactive cells and fibers in the hypothalamic paraventricular (PVN) and fibers in the arcuate (ARC) nuclei. However, chronic nicotine administration had no effect on the CART-immunoreactivity in the PVN and ARC. While nicotine withdrawal reduced the population of CART-immunoreactive cells and fibers in the PVN, the immunoreactivity in the ARC fibers was increased. The results suggest that hypothalamic CART may process the acute, chronic and withdrawal effects of nicotine on feeding and body weight., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Aim: We investigated the involvement of cocaine- and amphetamine-regulated transcript peptide (CART) in spatial learning and memory., Main Methods: Rats were intracerebroventricularly injected with CART or CART-antibody, with or without intraperitoneal scopolamine, for a period of 4 days, during which they were subjected to the acquisition protocol in Morris water maze (MWM). In retrieval protocols, at 24 h and 15 days post-acquisition time points similar treatments were given to trained rats and subjected to MWM. The response of endogenous CART system to the training as well as retrieval sessions in MWM was evaluated with immunohistochemistry., Key Findings: CART-administered rats showed a significant reduction in escape latency from day 1 through 4 days of acquisition; the rats spent more time in the platform quadrant in MWM during the retrieval protocol. CART-antibody or scopolamine produced an opposite effect. The effects of scopolamine were attenuated by CART, and potentiated by CART-antibody. CART-immunoreactivity in the arcuate and paraventricular nuclei, central nucleus of amygdala, bed nucleus of stria terminalis, accumbens shell, dentate gyrus (DG), and thalamic paraventricular nucleus (PVT), but not in the cornu ammonis 1-3 of hippocampus, was significantly increased following 4 days of training, and at 24 h retrieval time point in MWM. The changes were blocked by scopolamine. At 15 days retrieval time point, the immunoreactivity profiles resembled those in naïve control., Significance: While CART seems to promote spatial learning and memory, navigational experiences in MWM up regulates the endogenous CART systems in extended amygdala, hypothalamus, DG and PVT., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Cocaine- and amphetamine-regulated transcript peptide (CART) is a major anorectic agent present in the hypothalamus. We investigated the possible role of CART in mammary cancer-induced anorexia and body weight loss in rats. Mammary carcinogenesis was induced in the female Sprague-Dawley rats by intraperitoneal injection of N-methyl-N-nitrosourea (MNU). Following administration of MNU, rats progressively showed a reduction in food intake and body weight. Fourteen weeks after MNU treatment, rats were injected daily with CART or CART-antibody intracerebroventricularly for 5days, and food intake and body weight were monitored (g) before the next injection time-point. In normal rats, while a distinct anorexia and weight loss was observed following CART administration, injection of CART-antibody produced opposite effects. However, both the agents failed to produce any significant alterations in food intake and body weight of mammary tumor-bearing animals. An immunohistochemical application of antibodies against CART to the brain sections of cancerous rats showed a reduced immunoreactivity in the hypothalamic dorsomedial, ventromedial, lateral, paraventricular and arcuate nuclei. The results suggest that, cancerous condition might down-regulate the CART system in the hypothalamus. Alternatively, reduction in hypothalamic CART activity might be a counter-regulatory strategy to reverse food under-consumption or body mass erosion., (Copyright © 2010 Elsevier Inc. All rights reserved.)

We investigated the role of corticotropin-releasing factor type 2 (CRF(2)) receptors in acute, chronic and withdrawal effects of nicotine on feeding behavior in rats. Nicotine was injected intraperitoneally, whereas CRF, CRF(2) receptors agonist urocortin-1 or selective antagonist astressin2-B were administered directly into the hypothalamic paraventricular nucleus (PVN). In acute studies, nicotine, CRF or urocortin-1 produced dose dependent anorexia at 2 and 4h post-injection time-points, however, astressin2-B did not alter the food intake. Prior treatment of CRF or urocortin-1 potentiated the anorectic effect of nicotine, while astressin2-B showed opposite response. Chronic administration of nicotine produced tolerance to anorexia and caused persistent weight loss. However, concomitant treatment with CRF or urocortin-1 resulted in early tolerance to nicotine-induced anorexia. In the same set of animals, while CRF pre-treatment potentiated the weight reducing effect of nicotine, urocortin-1 failed to do so. Although abrupt termination of chronic nicotine treatment caused hyperphagia and weight gain, administration of CRF or urocortin-1 prevented these effects. These results suggest that CRF(2) receptors, within the framework of PVN, may contribute to the acute, chronic and withdrawal responses of nicotine on feeding and body weight.

Aims: Neuropeptide Y (NPY) is widely distributed throughout the brain and has been implicated in some of the actions of ethanol. The aim of the present study was to characterize the subtypes of NPY receptors in ethanol induced sedation, tolerance and withdrawal hyper-excitability., Main Methods: The loss of righting reflex paradigm was used to record the sleep duration in mice., Key Findings: The acute administration of ethanol (3-4g per kg, i.p., 20%v/v) resulted in marked sedation. While prolonged ethanol consumption led to the development of tolerance, the mice showed hyper-excitability following ethanol withdrawal. Prior acute intracerebroventricular (i.c.v.) injection of NPY (5-20 ng per mouse) or NPY Y1 and Y5 receptors agonist [Leu(31), Pro(34)]-NPY (0.02-0.2 ng per mouse) potentiated ethanol induced sedation. On the other hand, administration of selective NPY Y1 receptor antagonist BIBP3226 (5 ng per mouse, i.c.v.) inhibited ethanol induced sedation. Chronic concomitant treatment of NPY (20 ng per mouse, i.c.v.) or [Leu(31), Pro(34)]-NPY (0.2 ng per mouse, i.c.v.) to ethanol-fed groups prevented the development of tolerance and attenuated withdrawal hyper-excitability. Moreover, acute treatment of NPY (5 ng per mouse, i.c.v.) or [Leu(31), Pro(34)]-NPY (0.02 ng per mouse, i.c.v.) reversed the peak ethanol withdrawal hyper-excitability., Significance: The results underscore a role for NPY Y1 and Y5 receptors in the ethanol induced sedation, tolerance and withdrawal hyper-excitability. We suggest that modulation of NPY Y1 and Y5 receptors may be a strategy to address the ethanol withdrawal conditions.

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.

Aims: Weight gain is a common outcome of antipsychotics therapy in schizophrenic patients. However, the underlying neuronal mechanisms are unclear. The present study was undertaken to investigate the role of GABA(A) receptors within the framework of nucleus accumbens shell (AcbSh) in haloperidol-induced hyperphagia and body weight gain in sated rats., Main Methods: In acute studies, GABA(A) receptor agonists muscimol, diazepam or antagonist bicuculline were administered by AcbSh route, alone or in combination with haloperidol (intraperitoneal/ip). Immediately after these treatments, preweighed food was offered to the animals at commencement of dark phase. Cumulative food intake was measured at 2 and 6 h post-injection time-points. Furthermore, effects of subacute haloperidol treatment, alone or in combination with muscimol, diazepam or bicuculline, on food intake and body weight were investigated., Key Findings: While acute treatment with haloperidol, muscimol or diazepam dose dependently stimulated the food intake, bicuculline suppressed the same. Prior administration of muscimol (20 ng/rat, intra-AcbSh) and diazepam (5 microg/rat, intra-AcbSh) significantly potentiated, whereas bicuculline (40 ng/rat, intra-AcbSh) negated the hyperphagic effect of acute haloperidol (0.005 or 0.01 mg/kg/rat, ip). Subacute administration of haloperidol (0.01 mg/kg/rat/day, ip) for 15 days produced increase in food intake and body weight. Although, concomitant administration of muscimol (20 ng/rat/day, intra-AcbSh) or diazepam (5 microg/rat/day, intra-AcbSh) markedly enhanced, bicuculline (40 ng/rat/day, intra-AcbSh) prevented the subacute haloperidol-induced hyperphagia and weight gain., Significance: The results of present study suggest that increased food intake and body weight following haloperidol treatment in rats, may be mediated via AcbSh GABA(A) receptors.