-
[show abstract]
[hide abstract]
ABSTRACT: Anxiety disorders represent the most common mental disturbances in the world, and they are characterized by an abnormal response to stress. Pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptor PAC1 have been proposed to play a key role in mediating the responses to stress as well as the regulation of food intake and body weight. Corticotropin-releasing factor (CRF), the major stress peptide in the brain, has been hypothesized to be involved in PACAP effects, but the reports are conflicting so far. The present study was aimed at further characterizing the behavioral effects of PACAP in rats and at determining the role of central CRF receptors. We found that intracerebroventricular PACAP treatment induced anxiety-like behavior in the elevated plus maze test and elevated intracranial self-stimulation (ICSS) thresholds; both of these effects were fully blocked by concurrent treatment with the CRF receptor antagonist D-Phe-CRF(12-41). Interestingly, the CRF antagonist had no effect on PACAP-induced increased plasma corticosterone, reduction of food intake and body weight loss. Finally, we found that PACAP increased CRF levels in the paraventricular nucleus of the hypothalamus and, importantly, in the central nucleus of the amygdala, as measured by solid phase radioimmunoassay and quantitative real-time PCR. Our results strengthen the notion that PACAP is a strong mediator of the behavioral response to stress and prove for the first time that this neuropeptide has anti-rewarding (i.e. pro-depressant) effects. In addition, we identified the mechanism by which PACAP exerts its anxiogenic and pro-depressant effects, via the recruitment of the central CRF system and independently from HPA axis activation.Neuropsychopharmacology accepted article preview online, 9 May 2013; doi:10.1038/npp.2013.113.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 05/2013; · 6.99 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Dieting and the increased availability of highly palatable food are considered major contributing factors to the large incidence of eating disorders and obesity. This study was aimed at investigating the role of the cannabinoid (CB) system in a novel animal model of compulsive eating, based on a rapid palatable diet cycling protocol. Male Wistar rats were fed either continuously a regular chow diet (Chow/Chow, control group) or intermittently a regular chow diet for 2 days and a palatable, high-sucrose diet for 1 day (Chow/Palatable). Chow/Palatable rats showed spontaneous and progressively increasing hypophagia and body weight loss when fed the regular chow diet, and excessive food intake and body weight gain when fed the palatable diet. Diet-cycled rats dramatically escalated the intake of the palatable diet during the first hour of renewed access (7.5-fold compared to controls), and after withdrawal, they showed compulsive eating and heightened risk-taking behavior. The inverse agonist of the CB1 receptor, SR141716 reduced the excessive intake of palatable food with higher potency and the body weight with greater efficacy in Chow/Palatable rats, compared to controls. Moreover, SR141716 reduced compulsive eating and risk-taking behavior in Chow/Palatable rats. Finally, consistent with the behavioral and pharmacological observations, withdrawal from the palatable diet decreased the gene expression of the enzyme fatty acid amide hydrolase in the ventromedial hypothalamus while increasing that of CB1 receptors in the dorsal striatum in Chow/Palatable rats, compared to controls. These findings will help understand the role of the CB system in compulsive eating.
Addiction Biology 04/2013; · 4.83 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Glutamate NMDA receptors mediate many molecular and behavioral effects of alcohol, and they play a key role in the development of excessive drinking. Uncompetitive NMDA receptor antagonists may, therefore, have therapeutic potential for alcoholism. The first aim was to compare the effects of the NMDA antagonists memantine and ketamine on ethanol and saccharin drinking in alcohol-preferring rats. The second aim was to determine whether the effects of the two NMDA receptor antagonists were mediated by the mammalian target of rapamycin (mTOR). TSRI Sardinian alcohol-preferring rats were allowed to self-administer either 10% w/v ethanol or 0.08% w/v saccharin, and water. Operant responding and motor activity were assessed following administration of either memantine (0-10mg/kg) or ketamine (0-20mg/kg). Finally, ethanol self-administration was assessed in rats administered with either memantine or ketamine but pretreated with the mTOR inhibitor rapamycin (2.5mg/kg). The uncompetitive NMDA receptor antagonists memantine and ketamine dose-dependently reduced ethanol drinking in alcohol-preferring rats; while memantine had a preferential effect on alcohol over saccharin, ketamine reduced responding for both solutions. Neither antagonist induced malaise, as shown by the lack of effect on water intake and motor activity. The mTOR inhibitor rapamycin blocked the effects of ketamine, but not those of memantine. Memantine and ketamine both reduce alcohol drinking in alcohol-preferring rats, but only memantine is selective for alcohol. The effects of ketamine, but not memantine, are mediated by mTOR. The results support the therapeutic potential of uncompetitive NMDA receptor antagonists, especially memantine, in alcohol addiction.
Behavioural brain research 03/2013; · 3.22 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Binge eating disorder is an addiction-like disorder characterized by excessive food consumption within discrete periods of time. This study was aimed at understanding the role of the opioid system within the medial prefrontal cortex (mPFC) in the consummatory and motivational aspects of binge-like eating. For this purpose, we trained male rats to obtain either a sugary, highly palatable diet (Palatable rats) or a chow diet (Chow rats) for 1 hour/day. We then evaluated the effects of the opioid receptor antagonist, naltrexone, given either systemically or site-specifically into the nucleus accumbens (NAcc) or the mPFC on a fixed ratio 1 (FR1) and a progressive ratio schedule of reinforcement for food. Finally, we assessed the expression of the genes proopiomelanocortin (POMC), pro-dynorphin (PDyn) and pro-enkephalin (PEnk), coding for the opioids peptides in the NAcc and the mPFC in both groups. Palatable rats rapidly escalated their intake by four times. Naltrexone, when administered systemically and into the NAcc, reduced FR1 responding for food and motivation to eat under a progressive ratio in both Chow and Palatable rats; conversely, when administered into the mPFC, the effects were highly selective for binge eating rats. Furthermore, we found a twofold increase in POMC and a ∼50% reduction in PDyn gene expression in the mPFC of Palatable rats, when compared to control rats; however, no changes were observed in the NAcc. Our data suggest that neuroadaptations of the opioid system in the mPFC occur following intermittent access to highly palatable food, which may be responsible for the development of binge-like eating.
Addiction Biology 01/2013; · 4.83 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND: Binge drinking is defined as a pattern of alcohol drinking that brings blood alcohol levels to 80 mg/dl or above. In this study, we pharmacologically characterized the intermittent access to 20% ethanol (EtOH) model (Wise, Psychopharmacologia 1973;29:203) in Sardinian alcohol-preferring (sP) rats to determine to which of the compounds known to reduce drinking in specific animal models this binge-like drinking was sensitive to. METHODS: Adult male sP rats were divided into 2 groups and allowed to drink either 20% v/v alcohol or water for 24 hours on alternate days (Monday, Wednesday, and Friday) or 10% v/v alcohol and water for 24 hours every day. After stabilization of their intake, both groups were administered 3 pharmacological agents with different mechanisms of action, naltrexone-an opioid receptor antagonist, SCH 39166-a dopamine D1 receptor antagonist, and R121919-a Corticotropin-Releasing Factor 1 (CRF(1) ) receptor antagonist, and their effects on alcohol and water intake were determined. RESULTS: Intermittent 20% alcohol ("Wise") procedure in sP rats led to binge-like drinking. Alcohol drinking was suppressed by naltrexone and by SCH 39166, but not by R121919. Finally, naltrexone was more potent in reducing alcohol drinking in the intermittent 20% binge-drinking group than in the 10% continuous access drinking group. CONCLUSIONS: The Wise procedure in sP rats induces binge-like drinking, which appears opioid- and dopamine-receptor mediated; the CRF(1) system, on the other hand, does not appear to be involved. In addition, our results suggest that naltrexone is particularly effective in reducing binge drinking. Such different pharmacological responses may apply to subtypes of alcoholic patients who differ in their motivation to drink, and may eventually contribute to treatment response.
Alcoholism Clinical and Experimental Research 11/2012; · 3.34 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: RATIONALE: Impulsive behavior is categorically differentiated between impulsive action, the inability to withhold from acting out a response, and impulsive choice, the greater preference for an immediate and smaller reward over a delayed but more advantageous reward. While the effects of N-methyl-D-aspartic acid (NMDA) receptor antagonists on impulsive action have been extensively characterized, there are very few and conflicting reports on the effects of this class of drugs on impulsive choice. OBJECTIVES: Using a modified adjusting delay task, we investigated the effects of uncompetitive and competitive blockade of NMDA receptors on impulsive choice. METHODS: Male Wistar rats were trained in a modified adjusting delay task, which involved repeated choice between a low reinforcing solution delivered immediately and a highly reinforcing solution delivered after a variable delay. Rats were then administered either the NMDA receptor uncompetitive antagonists ketamine or memantine, or the competitive antagonists D-AP-5 or CGS 19755. RESULTS: Ketamine treatment dose-dependently increased impulsive choice, and this effect was selective for low-impulsive but not high-impulsive rats. Similarly, memantine treatment dose-dependently increased impulsive choice with a preferential effect for low-impulsive rats. While D-AP-5 treatment did not affect impulsive choice, CGS 19755 increased impulsivity, however, at the same doses at which it caused a marked response inhibition. CONCLUSIONS: NMDA receptor uncompetitive, but not competitive, antagonists significantly increased impulsive choice, preferentially in low-impulsive rats. These findings demonstrate that the effects of NMDA receptor blockade on impulsive choice are not generalizable and depend on the specific mechanism of action of the antagonist used.
Psychopharmacologia 10/2012; · 4.08 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The increased availability of highly palatable foods is a major contributing factor toward the development of compulsive eating in obesity and eating disorders. It has been proposed that compulsive eating may develop as a form of self-medication to alleviate the negative emotional state associated with withdrawal from highly palatable foods. This study was aimed at determining whether withdrawal from chronic, intermittent access to a highly palatable food was responsible for the emergence of depressive-like behavior. For this purpose, a group of male Wistar rats was provided a regular chow diet 7 days a week (Chow/Chow), whereas a second group of rats was provided chow for 5 days a week, followed by a 2-day access to a highly palatable sucrose diet (Chow/Palatable). Following 7 weeks of diet alternation, depressive-like behavior was assessed during withdrawal from the highly palatable diet and following renewed access to it, using the forced swim test, the sucrose consumption test, and the intracranial self-stimulation threshold procedure. It was found that Chow/Palatable rats withdrawn from the highly palatable diet showed increased immobility time in the forced swim test and decreased sucrose intake in the sucrose consumption test compared with the control Chow/Chow rats. Interestingly, the increased immobility in the forced swim test was abolished by renewing access to the highly palatable diet. No changes were observed in the intracranial self-stimulation threshold procedure. These results validate the hypothesis that withdrawal from highly palatable food is responsible for the emergence of depressive-like behavior, and they also show that compulsive eating relieves the withdrawal-induced negative emotional state.
Behavioural pharmacology 09/2012; 23(5-6):593-602. · 2.85 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Positive reinforcement (e.g., appetitive, rewarding properties) has often been hypothesized to maintain excessive intake of palatable foods. Recently, rats receiving intermittent access to high sucrose diets showed binge-like intake with withdrawal-like signs upon cessation of access, suggesting negative reinforcement mechanisms contribute as well. Whether intermittent access to high fat diets also produces withdrawal-like syndromes is controversial. The present study therefore tested the hypothesis that binge-like eating and withdrawal-like anxiety would arise in a novel model of binge eating based on daily 10-min access to a sweet fat diet (35% fat kcal, 31% sucrose kcal). Within 2-3weeks, female Wistar rats developed binge-like intake comparable to levels seen previously for high sucrose diets (~40% of daily caloric intake within 10min) plus excess weight gain and adiposity, but absent increased anxiety-like behavior during elevated plus-maze or defensive withdrawal tests after diet withdrawal. Binge-like intake was unaffected by pretreatment with the corticotropin-releasing factor type 1 (CRF(1)) receptor antagonist R121919, and corticosterone responses to restraint stress did not differ between sweet-fat binge rats and chow-fed controls. In contrast, pretreatment with the cannabinoid type 1 (CB(1)) receptor antagonist SR147778 dose-dependently reduced binge-like intake, albeit less effectively than in ad lib chow or sweet fat controls. A priming dose of the sweet fat diet did not precipitate increased anxiety-like behavior, but rather increased plus-maze locomotor activity. The results suggest that CB(1)-dependent positive reinforcement rather than CRF(1)-dependent negative reinforcement mechanisms predominantly maintain excessive intake in this limited access model of sweet-fat diet binges.
Physiology & Behavior 07/2012; 107(2):231-42. · 2.87 Impact Factor
-
Pietro Cottone,
Xiaofan Wang,
Jin Won Park,
Marta Valenza,
Angelo Blasio,
Jina Kwak,
Malliga R Iyer,
Luca Steardo,
Kenner C Rice,
Teruo Hayashi, Valentina Sabino
[show abstract]
[hide abstract]
ABSTRACT: Binge eating disorder is an addiction-like disorder characterized by episodes of rapid and excessive food consumption within discrete periods of time which occur compulsively despite negative consequences. This study was aimed at determining whether antagonism of Sigma-1 receptors (Sig-1Rs) blocked compulsive-like binge eating. We trained male wistar rats to obtain a sugary, highly palatable diet (Palatable group) or a regular chow diet (Chow control group), for 1 h a day under fixed ratio 1 operant conditioning. Following intake stabilization, we evaluated the effects of the selective Sig-1R antagonist BD-1063 on food responding. Using a light/dark conflict test, we also tested whether BD-1063 could block the time spent and the food eaten in an aversive, open compartment, where the palatable diet was offered. Furthermore, we measured Sig-1R mRNA and protein expression in several brain areas of the two groups, 24 h after the last binge session. Palatable rats rapidly developed binge-like eating, escalating the 1 h intake by four times, and doubling the eating rate and the regularity of food responding, compared to Chow rats. BD-1063 dose-dependently reduced binge-like eating and the regularity of food responding, and blocked the increased eating rate in Palatable rats. In the light/dark conflict test, BD-1063 antagonized the increased time spent in the aversive compartment and the increased intake of the palatable diet, without affecting motor activity. Finally, Palatable rats showed reduced Sig-1R mRNA expression in prefrontal and anterior cingulate cortices, and a two-fold increase in Sig-1R protein expression in anterior cingulate cortex compared to control Chow rats. These findings suggest that the Sig-1R system may contribute to the neurobiological adaptations driving compulsive-like eating, opening new avenues of investigation towards pharmacologically treating binge eating disorder.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 06/2012; 37(12):2593-604. · 6.99 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Existing animal models of impulsivity frequently use food restriction to increase subjects' motivation. In addition, behavioral tasks that assess impulsive choice typically involve the use of reinforcers with dissimilar caloric content. These factors represent energy-homeostasis limitations, which may confound the interpretation of results and limit the applicability of these models.
This study was aimed at validating face and convergent validities of a modified adjusting delay task, which assesses impulsive choice between isocaloric reinforcers in ad libitum fed rats.
Male Wistar rats (n = 18) were used to assess the preferredness and reinforcing efficacy of a "supersaccharin" solution (1.5% glucose/0.4% saccharin) over a 1.5% glucose solution. A separate group of rats (n = 24) was trained in a modified adjusting delay task, which involved repeated choice between the glucose solution delivered immediately and the supersaccharin solution delivered after a variable delay. To pharmacologically validate the task, the effects of the 5-HT(2A/C) receptor agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane [(±)-DOI] and the 5-HT(1A) receptor agonist (±)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide [(±)-8-OH-DPAT] on impulsive choice were then evaluated.
Supersaccharin was highly reinforcing and uniformly preferred over the glucose solution by all subjects. Rats quickly learned the task, and impulsivity was a very stable and consistent trait. DOI and 8-OH-DPAT significantly and dose dependently increased impulsive choice in this modified adjusting delay task.
We validated a rodent task of impulsive choice, which eliminates typical energy-homeostasis limitations and, therefore, opens new avenues in the study of impulsivity in preclinical feeding and obesity research.
Psychopharmacologia 01/2012; 219(2):377-86. · 4.08 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Sigma (σ) receptors have been implicated in the behavioral and motivational effects of alcohol and psychostimulants. Sigma receptor antagonists reduce the reinforcing effects of alcohol and excessive alcohol intake in both genetic (alcohol-preferring rats) and environmental (chronic alcohol-induced) models of alcoholism. The present study tested the hypothesis that pharmacological activation of σ-receptors facilitates ethanol reinforcement and induces excessive, binge-like ethanol intake. The effects of repeated subcutaneous treatment with the selective σ-receptor agonist 1,3-di-(2-tolyl)guanidine (DTG; 15 mg/kg, twice a day for 7 days) on operant ethanol (10%) self-administration were studied in Sardinian alcohol-preferring (sP) rats. To confirm that the effect of DTG was mediated by σ-receptors, the effects of pretreatment with the selective σ-receptor antagonist BD-1063 (7 mg/kg, subcutaneously) were determined. To assess the specificity of action, the effects of DTG on the self-administration of equally reinforcing solutions of saccharin or sucrose were also determined. Finally, gene expression of opioid receptors in brain areas implicated in ethanol reinforcement was analyzed in ethanol-naive sP rats treated acutely or repeatedly with DTG, because of the well-established role of the opioid system in alcohol reinforcement and addiction. Repeatedly administered DTG progressively and dramatically increased ethanol self-administration in sP rats and increased blood alcohol levels, which reached mean values close to 100 mg% in 1 h drinking sessions. Repeated DTG treatment also increased the rats' motivation to work for alcohol under a progressive-ratio schedule of reinforcement. BD-1063 prevented the effects of DTG, confirming that σ-receptors mediate the effects of DTG. Repeated DTG treatment also increased the self-administration of the non-drug reinforcers saccharin and sucrose. Naive sP rats repeatedly treated with DTG showed increased mRNA expression of μ- and δ-opioid receptors in the ventral tegmental area. These results suggest a key facilitatory role for σ-receptors in the reinforcing effects of alcohol and identify a potential mechanism that contributes to binge-like and excessive drinking.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 02/2011; 36(6):1207-18. · 6.99 Impact Factor
-
Marisa Roberto,
Maureen T Cruz,
Nicholas W Gilpin, Valentina Sabino,
Paul Schweitzer,
Michal Bajo,
Pietro Cottone,
Samuel G Madamba,
David G Stouffer,
Eric P Zorrilla,
George F Koob,
George R Siggins,
Loren H Parsons
[show abstract]
[hide abstract]
ABSTRACT: Corticotropin-releasing factor (CRF) and gamma-aminobutyric acid (GABA)ergic systems in the central amygdala (CeA) are implicated in the high-anxiety, high-drinking profile associated with ethanol dependence. Ethanol augments CeA GABA release in ethanol-naive rats and mice.
Using naive and ethanol-dependent rats, we compared electrophysiologic effects and interactions of CRF and ethanol on CeA GABAergic transmission, and we measured GABA dialyzate in CeA after injection of CRF(1) antagonists and ethanol. We also compared mRNA expression in CeA for CRF and CRF(1) using real-time polymerase chain reaction. We assessed effects of chronic treatment with a CRF(1) antagonist on withdrawal-induced increases in alcohol consumption in dependent rats.
CRF and ethanol augmented CeA GABAergic transmission in naive rats via increased GABA release. Three CRF1 receptor (CRF(1)) antagonists decreased basal GABAergic responses and abolished ethanol effects. Ethanol-dependent rats exhibited heightened sensitivity to CRF and CRF(1) antagonists on CeA GABA release. Intra-CeA CRF(1) antagonist administration reversed dependence-related elevations in GABA dialysate and blocked ethanol-induced increases in GABA dialyzate in both dependent and naive rats. Polymerase chain reaction studies indicate increased expression of CRF and CRF(1) in CeA of dependent rats. Chronic CRF(1) antagonist treatment blocked withdrawal-induced increases in alcohol drinking by dependent rats and tempered moderate increases in alcohol consumption by nondependent rats in intermittent testing.
These combined findings suggest a key role for specific presynaptic CRF-GABA interactions in CeA in the development and maintenance of ethanol dependence.
Biological psychiatry 05/2010; 67(9):831-9. · 8.93 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Adaptations in the anterior cingulate cortex (ACC) have been implicated in alcohol and drug addiction. To identify genes that may contribute to excessive drinking, here we performed microarray analyses in laser microdissected rat ACC after a single or repeated administration of an intoxicating dose of alcohol (3 g/kg). Expression of the small G protein K-ras was differentially regulated following both single and repeated alcohol administration. We also observed that voluntary alcohol intake in K-ras heterozygous null mice (K-ras(+/-)) did not increase after withdrawal from repeated cycles of intermittent ethanol vapor exposure, unlike in their wild-type littermates. To identify K-ras regulated pathways, we then profiled gene expression in the ACC of K-ras(+/-), heterozygous null mice for the K-ras negative regulator Nf1 (Nf1(+/-)) and wild-type mice following repeated administration of an intoxicating dose of alcohol. Pathway analysis showed that alcohol differentially affected various pathways in a K-ras dependent manner - some of which previously shown to be regulated by alcohol - including the insulin/PI3K pathway, the NF-kappaB, the phosphodiesterases (PDEs) pathway, the Jak/Stat and the adipokine signaling pathways. Altogether, the data implicate K-ras-regulated pathways in the regulation of excessive alcohol drinking after a history of dependence.
Brain research 04/2010; 1339:1-10. · 2.46 Impact Factor
-
Pietro Cottone, Valentina Sabino,
Marisa Roberto,
Michal Bajo,
Lara Pockros,
Jennifer B Frihauf,
Eva M Fekete,
Luca Steardo,
Kenner C Rice,
Dimitri E Grigoriadis,
Bruno Conti,
George F Koob,
Eric P Zorrilla
[show abstract]
[hide abstract]
ABSTRACT: Dieting to control body weight involves cycles of deprivation from palatable food that can promote compulsive eating. The present study shows that rats withdrawn from intermittent access to palatable food exhibit overeating of palatable food upon renewed access and an affective withdrawal-like state characterized by corticotropin-releasing factor-1 (CRF(1)) receptor antagonist-reversible behaviors, including hypophagia, motivational deficits to obtain less palatable food, and anxiogenic-like behavior. Withdrawal was accompanied by increased CRF expression and CRF(1) electrophysiological responsiveness in the central nucleus of the amygdala. We propose that recruitment of anti-reward extrahypothalamic CRF-CRF(1) systems during withdrawal from palatable food, analogous to abstinence from abused drugs, may promote compulsive selection of palatable food, undereating of healthier alternatives, and a negative emotional state when intake of palatable food is prevented.
Proceedings of the National Academy of Sciences 11/2009; 106(47):20016-20. · 9.68 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Urocortin 1 (Ucn 1) is an endogenous peptide related to the corticotropin-releasing factor (CRF). Ucn 1 is mainly expressed in the perioculomotor area (pIII), and its involvement in alcohol self-administration is well confirmed in mice. In other species, the relationship between the perioculomotor Ucn 1-containing population of neurons (pIIIu) and alcohol consumption needs further investigation. The pIII also has a significant subpopulation of dopaminergic neurons. Because of dopamine's (DA) role in addiction, it is important to evaluate whether this subpopulation of neurons contributes to addiction-related phenotypes. Furthermore, the effects of gender on the relationship between Ucn 1 and tyrosine hydroxylase (TH) in pIII and alcohol preference in rats have not been previously assessed.
To address these issues, we compared 2 Sardinian alcohol-preferring sublines of rats, a population maintained at the Scripps Research Institute (Scr:sP) and a population maintained at University of Camerino-Marchigian Sardinian preferring rats (msP), to corresponding nonselectively bred Wistar rats of both sexes. Ucn 1- and TH-positive cells were detected on coronal midbrain sections from 6- to 8-week-old alcohol-naïve animals using brightfield and fluorescent immunohistochemistry. Ucn 1- and TH-positive cells in pIII were counted in the perioculomotor area, averaged across 2 to 3 sets, and binned into 3 bregma levels.
Results demonstrated increased average counts of Ucn 1-positive cells in the middle bregma level in preferring male rats compared to Wistar controls and no difference in TH-positive cell counts in pIII. In addition, fluorescent double labeling revealed no colocalization of Ucn 1-positive and TH-positive neurons. Ucn 1 but not TH distribution was influenced by gender with female animals expressing more Ucn 1-positive cells than male animals in the peak bregma level.
These findings extend previous reports of increased Ucn 1-positive cell distribution in preferring lines of animals. They indicate that Ucn1 contributes to increased alcohol consumption across different species and that this contribution could be gender specific. The results also suggest that Ucn1 regulates positive reinforcing rather than aversive properties of alcohol and that these effects could be mediated by CRF(2) receptors, independent of direct actions of DA.
Alcoholism Clinical and Experimental Research 09/2009; 33(11):1956-65. · 3.34 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Sigma receptors have been implicated in appetitive effects of psychostimulants and in high levels of ethanol intake. This study tested the hypothesis that the sigma-1 receptor subtype (Sig-1R) may modulate ethanol intake.
The effects of acute and repeated treatment with the potent, selective Sig-1R antagonist NE-100 on ethanol intake (10%) were studied in adult, male Sardinian alcohol-preferring (sP) rats, a model of genetic predisposition to high ethanol drinking. To assess the specificity of action, the acute effects of NE-100 on intake of an equally preferred sucrose solution and of a higher concentration of ethanol that sP rats did not prefer over water (28%), were determined. Finally, the ability of NE-100 administration to prevent the increased ethanol intake that occurs after deprivation was evaluated.
Acute treatment with NE-100 dose-dependently (10-30 mg/kg) reduced 1- and 3-h intake of 10% ethanol solution in sP rats, while increasing concurrent water intake and not affecting food intake. NE-100 (17.8-30 mg/kg) comparably reduced intake of the 28% ethanol solution, while not suppressing 1.25% sucrose solution intake, suggesting selectivity of action against ethanol intake. Acute NE-100 (30 mg/kg) also prevented an increase in ethanol intake after a 7-day deprivation period. Repeated, daily NE-100 (30 mg/kg) treatment continued to reduce 24-h ethanol intake across 7 days of administration, with some, but incomplete, tolerance, evident by day 6.
The results implicate the Sig-1R system in alcohol drinking, identifying a potential therapeutic target for the treatment of alcohol use disorders.
Psychopharmacologia 06/2009; 205(2):327-35. · 4.08 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Defeat is a social stressor involving subordination by a threatening conspecific. Type 2 corticotropin-releasing factor receptors (CRF(2)) are abundant in brain regions implicated in defeat responses and are putative stress-related molecules. The present study sought to determine whether neuroactivation and CRF(2) expression co-occurred at brain region or cellular levels following acute defeat. Male "intruder" Wistar rats were placed into the cage of an aggressive "resident" Long-Evans rat (n=6). Upon defeat, intruders (n=6) were placed in a wire-mesh chamber and were returned to the resident's cage for an additional 75 min. Controls (n=6) were handled and returned to their home cage for the same duration. Coronal brain sections were stained for an immediate early gene product, Fos, as a neuronal activation marker. Combined immunohistochemistry with in situ hybridization was performed on a subset of brain sections from defeated intruders to visualize Fos immunoreactivity and CRF(2) mRNA jointly. Defeated rats had fivefold, sevenfold, and 10-fold more Fos-positive cells than controls in the arcuate, ventromedial nucleus of the hypothalamus, and medial amygdala post-defeat. Significant colocalization of CRF(2) mRNA and Fos-positive cells was observed in the posterior medial amygdala but not in the arcuate nucleus or ventromedial hypothalamus. The results indicate CRF(2) receptor-positive neurons in the posterior medial amygdala are involved in the neural response to social defeat.
Neuroscience 05/2009; 162(1):5-13. · 3.38 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Activation of sigma-1 receptors (Sig-1R) reportedly has antidepressant-like action. Limited data suggest that Sig-1Rs also modulate anxiety-related behaviors. The present experiments measured depressive-like, anxiety-like and motor behavior in Sig-1R knockout mice and their wildtype littermates. Sig-1R knockout mutants showed increased immobility in the forced swimming test, a depressive-like phenotype, but normal anxiety-like behavior in the elevated plus-maze and light/dark box tests and normal locomotor activity. The results further suggest that Sig-1Rs inversely modulate depressive-like behavior.
Behavioural brain research 12/2008; 198(2):472-6. · 3.22 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Sigma-Receptors (SigRs) have been implicated in behavioral and appetitive effects of psychostimulants and may also modulate the motivating properties of ethanol. This study tested the hypothesis that SigRs modulate ethanol reinforcement and contribute to excessive ethanol intake. The effects of subcutaneous treatment with the potent, selective Sig-1R antagonist BD-1063 on operant ethanol self-administration were studied in two models of excessive drinking-Sardinian alcohol-preferring (sP) rats and acutely withdrawn ethanol-dependent Wistar rats-and compared to ethanol self-administration in nondependent Wistar controls. To assess the specificity of action, the effects of BD-1063 on self-administration of an equally reinforcing saccharin solution were determined in Wistar and sP rats. Gene expression of Sig-1R in reward-related brain areas implicated in ethanol reinforcement was compared between ethanol-naive sP and Wistar rats and withdrawn ethanol-dependent Wistar rats. BD-1063 dose dependently reduced ethanol self-administration in sP rats (3.3-11 mg/kg) and withdrawn, dependent Wistar rats (4-11 mg/kg) at doses that did not modify mean ethanol self-administration in nondependent Wistar controls. BD-1063 did not reduce concurrent water self-administration and did not comparably suppress saccharin self-administration, suggesting selectivity of action. BD-1063 also reduced the breakpoints of sP rats to work for ethanol under a progressive-ratio reinforcement schedule. Ethanol-naive sP rats and 24-h withdrawn, dependent Wistar rats showed reduced Sig-1R mRNA expression in the nucleus accumbens. The results suggest that SigR systems may contribute to innate or ethanol-induced increases in susceptibility to self-administer high ethanol levels, identifying a potential neuroadaptive mechanism contributing to excessive drinking and a therapeutic target for alcohol abuse and dependence.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 11/2008; 34(6):1482-93. · 6.99 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: σ-Receptors (SigRs) have been implicated in behavioral and appetitive effects of psychostimulants and may also modulate the motivating properties of ethanol. This study tested the hypothesis that SigRs modulate ethanol reinforcement and contribute to excessive ethanol intake. The effects of subcutaneous treatment with the potent, selective Sig-1R antagonist BD-1063 on operant ethanol self-administration were studied in two models of excessive drinking—Sardinian alcohol-preferring (sP) rats and acutely withdrawn ethanol-dependent Wistar rats—and compared to ethanol self-administration in nondependent Wistar controls. To assess the specificity of action, the effects of BD-1063 on self-administration of an equally reinforcing saccharin solution were determined in Wistar and sP rats. Gene expression of Sig-1R in reward-related brain areas implicated in ethanol reinforcement was compared between ethanol-naive sP and Wistar rats and withdrawn ethanol-dependent Wistar rats. BD-1063 dose dependently reduced ethanol self-administration in sP rats (3.3–11 mg/kg) and withdrawn, dependent Wistar rats (4–11 mg/kg) at doses that did not modify mean ethanol self-administration in nondependent Wistar controls. BD-1063 did not reduce concurrent water self-administration and did not comparably suppress saccharin self-administration, suggesting selectivity of action. BD-1063 also reduced the breakpoints of sP rats to work for ethanol under a progressive-ratio reinforcement schedule. Ethanol-naive sP rats and 24-h withdrawn, dependent Wistar rats showed reduced Sig-1R mRNA expression in the nucleus accumbens. The results suggest that SigR systems may contribute to innate or ethanol-induced increases in susceptibility to self-administer high ethanol levels, identifying a potential neuroadaptive mechanism contributing to excessive drinking and a therapeutic target for alcohol abuse and dependence.Keywords: sigma receptor antagonist, alcohol or ethanol, abstinence or withdrawal, dependence or addiction or alcoholism, self-administration, Sardinian alcohol-preferring rats
Neuropsychopharmacology 10/2008; 34(6):1482-1493. · 7.99 Impact Factor
