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Rationale: Obesity is a leading public health problem worldwide. Multiple lines of evidence associate deficits in the brain reward circuit with obesity., Objective: Whether alterations in brain reward sensitivity precede or are a consequence of obesity is unknown. This study aimed to investigate both innate and obesity-induced differences in the sensitivity to the effects of an indirect dopaminergic agonist., Methods: Rats genetically prone to diet-induced obesity (DIO) and their counterpart diet-resistant (DR) were fed a chow diet, and their response to D-amphetamine on intracranial self-stimulation and food intake were assessed. The same variables were then evaluated after exposing the rats to a high-fat diet, after DIO rats selectively developed obesity. Finally, gene expression levels of dopamine receptors 1 and 2 as well as tyrosine hydroxylase were measured in reward-related brain regions., Results: In a pre-obesity state, DIO rats showed innate decreased sensitivity to the reward-enhancing and anorectic effects of D-amphetamine, as compared to DR rats. In a diet-induced obese state, the insensitivity to the potentiating effects of D-amphetamine on intracranial self-stimulation (ICSS) threshold persisted and became more marked in DIO rats, while the anorectic effects were comparable between genotypes. Finally, innate and obesity-induced differences in the gene expression of dopamine receptors were observed., Conclusions: Our results demonstrate that brain reward deficits antedate the development of obesity and worsen after obesity is fully developed, suggesting that these alterations represent vulnerability factors for its development. Moreover, our data suggests that the reward-enhancing and anorectic effects of D-amphetamine are dissociable in the context of obesity.

Rationale: 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., Objectives: 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., Methods: 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., Results: 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., Conclusions: 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.

Rationale and Objectives: 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., Material and Methods: 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., Results: 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., Conclusions: The results implicate the Sig-1R system in alcohol drinking, identifying a potential therapeutic target for the treatment of alcohol use disorders.

Rationale: Increased opioidergic activity is thought to increase the propensity to consume ethanol. However, the dose monotonicity and receptor subtype for this effect remain uncertain. 14-methoxymetopon is a centrally acting, selective micro opioid receptor agonist with greater systemic antinociceptive potency than morphine and a putatively improved therapeutic index., Objective: To determine whether 14-methoxymetopon influenced voluntary ethanol intake in Sardinian alcohol-preferring (sP) rats., Methods: Male sP rats with continuous 2-bottle choice access to ethanol (10% v/v) or water were subjects. The effects of systemic 14-methoxymetopon administration (2, 5, 12.25, 30 micro/kg, s.c.) on 4-h ethanol intake were determined. The ability of naltrexone (50 micro/kg, s.c.), an opioid antagonist, to block actions of 14-methoxymetopon (12.25, 30 micro/kg, s.c.) was examined as were the effects of 14-methoxymetopon (12.25 micro/kg, s.c.) on self-administered blood alcohol levels (BALs) and clearance of a passive ethanol bolus (1 g/kg). Finally, the effects of central 14-methoxymetopon administration (0.0003-100 ng, i.c.v.) on 4-h ethanol intake were evaluated., Results: Systemic 14-methoxymetopon very potently and dose-dependently suppressed ethanol and food intake for 30 min, followed by a greater, longer-lasting, and behaviorally specific increase in ethanol intake. The increased ethanol intake led to threefold higher BALs, was naltrexone-reversible, and not due to altered ethanol clearance. Intracerebroventricular 14-methoxymetopon administration rapidly altered ethanol intake per an inverted U-shaped dose-response function, increasing it at a 10 pg dose, while suppressing it at a 10,000-fold higher dose., Conclusions: The novel mu analgesic increases ethanol intake, a potential therapeutic liability, and results suggest a non-monotonic influence of brain mu opioid receptor stimulation on ethanol intake.

Rationale: The role of positive vs negative ethanol reinforcement in ethanol intake of Sardinian alcohol-preferring (sP) rats is unclear., Objectives: To test the hypothesis that spontaneous ethanol self-administration of sP rats was sensitive to the opioid receptor antagonist naltrexone, whereas withdrawal-induced, but not spontaneous, ethanol self-administration would be sensitive to corticotropin-releasing factor(1) (CRF(1)) antagonists, implicating differential roles for positive and negative reinforcement, respectively., Methods: Male sP rats operantly (FR1, 30 min/day) self-administered ethanol (10% v/v) until responding stabilized. One group (n=11) was made ethanol dependent through intermittent ethanol vapor exposure. Both nondependent (n = 10) and dependent rats received the CRF(1) antagonist LWH-63 (5, 10, and 20 mg/kg, s.c.). Separate nondependent sP rats (n = 10) received the opioid antagonist naltrexone (16, 50, 150, and 450 microg/kg, s.c.). Finally, CRF(1) antagonists (MJL-1-109-2, LWH-63, and R121919) were studied for their actions on home-cage ethanol drinking in nondependent sP rats (n = 6-8/group) under continuous, limited-access, or stressed conditions., Results: Naltrexone potently reduced ethanol self-administration in nondependent sP rats. LWH-63 reduced heightened ethanol self-administration of vapor-sensitive, dependent sP rats. CRF(1) antagonists did not reduce ethanol intake in nondependent sP rats. R121919 (10 mg/kg, s.c.) retained antistress activity in sP rats, blunting novelty stress-induced suppression of ethanol intake., Conclusions: Spontaneous ethanol self-administration of sP rats was opioid dependent with CRF(1) receptors implicated in withdrawal-induced drinking. Opioid and CRF(1) receptors play different roles in ethanol reinforcement and perhaps the ethanol addiction cycle. Such distinctions may apply to subtypes of alcoholic patients who differ in their motivation to drink and ultimately treatment response.

It has been shown that glucocorticoids have a suppressant effect on the thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) in young men. To assess whether this effect of corticosteroids is also present in aged individuals, six young subjects (aged 26-32 years) and six elderly men (aged 68-75 years) underwent, in random order, at 1 week intervals, three TRH stimulation tests 30 min after IV administration of placebo and 2 mg and 4 mg dexamethasone phosphate. Elderly men showed higher basal plasma levels of TSH (P less than 0.02) and lower plasma levels of FT3 (P less than 0.03) and FT4 (P less than 0.01). The TSH response to TRH was significantly lower in aged subjects than in young ones (P less than 0.009). Moreover, 2 mg dexamethasone significantly blunted the TSH response to TRH in young men (P less than 0.0001), but not in the elders. The inhibitory effect of the glucocorticoid on the TRH-induced TSH secretion, in aged subjects, was evident only after 4 mg dexamethasone administration (P less than 0.0001). These data confirm that glucocorticoids have an inhibitory role on the thyrotropic axis and show, for the first time, that normal elderly men are hyporesponsive to this suppressant effect of corticosteroids.

Evidence has been provided for impaired neurotransmitter functioning in the brain of elderly subjects. In order to assess central GABAergic transmission, the activity of the hypothalamic GABA system may be investigated by basal growth hormone (GH) response to the GABAergic drug sodium valproate (SV). For this purpose 15 healthy men (aged 19-81 years) received orally 800 mg SV or placebo tablets on two different occasions, 1 week apart. Blood samples were collected before and after drug administration for determining GH and SV plasma levels. A clear-cut increase in plasma GH was observed following SV (P less than 0.001 in young persons, P less than 0.005 in old subjects), but in the aged subjects this rise was statistically lower than in the young men (P less than 0.001 at t = 90 min). No difference was observed in basal GH levels and in SV plasma concentrations between elderly and young subjects. delta GH (= maximum post-SV GH level minus baseline GH value) was significantly inversely related to age (r = -0.90, P less than 0.001). These results may suggest an impaired hypothalamic-pituitary responsiveness to a pharmacological challenge enhancing endogenous GABA tone in the elderly.

Sodium valproate, a GABAergic agent (800 mg), and placebo were administered orally, as a single dose, to nine chronic schizophrenics with tardive dyskinesia (TD), seven chronic schizophrenics without TD and ten healthy controls, according to a double blind design. Blood samples were collected before and after drug administration, to determine plasma prolactin concentrations. Sodium valproate decreased plasma prolactin levels in healthy subjects (P less than 0.001) and in schizophrenic patients with TD (P less than 0.001), but not in chronic schizophrenics without TD. Moreover, in dyskinetic subjects, the maximum per cent decrease of plasma prolactin from basal value was positively correlated to the score of the abnormal involuntary movement scale (r = 0.724, P less than 0.02). Although the neural or biochemical substrate underlying the different responses of plasma prolactin to sodium valproate in schizophrenics with and without TD remains unclear, these results provide the first neuroendocrine evidence able to differentiate dyskinetic subjects from those without TD within a schizophrenic population.