leptin and Heroin-Dependence

Caloric restriction increases the risk of relapse in abstinent drug users. Hormones involved in the regulation of energy balance and food intake, such as leptin and ghrelin, are implicated in drug-related behaviors.. We investigated the role of leptin and ghrelin in the augmentation of heroin seeking induced by chronic food restriction.. Rats self-administered heroin (0.1 mg/kg/infusion) for 10 days followed by 14 days of drug withdrawal. During withdrawal, rats were food restricted to 90% of their original body weight or were given free access to food. In experiment 1, we measured the plasma concentrations of leptin and ghrelin following heroin self-administration and withdrawal. In experiment 2, leptin was administered centrally (2.0 or 4.0 μg; i.c.v.) prior to a heroin-seeking test under extinction conditions. High density of both leptin and ghrelin receptors was previously identified in the ventral tegmental area (VTA), suggesting a direct effect on reward and motivation. Hence, we administered leptin (experiment 3; 0.125 or 0.250 μg/side), or ghrelin receptor antagonist JMV 2959 (experiment 4; 2.0 or 10.0 μg/side) directly into the VTA prior to the heroin-seeking test.. Chronic food restriction significantly decreased plasma levels of leptin and elevated plasma levels of ghrelin. Central administration of leptin had no statistically significant effect on heroin seeking. Intra-VTA administration of either leptin or JMV 2959 dose-dependently and selectively decreased heroin seeking in the food-restricted rats.. Leptin and ghrelin transmission in the VTA can modulate the augmentation of heroin seeking induced by chronic food restriction.

Topics: Animals; Conditioning, Operant; Drug-Seeking Behavior; Food Deprivation; Ghrelin; Heroin; Heroin Dependence; Leptin; Male; Motivation; Rats; Rats, Long-Evans; Self Administration; Ventral Tegmental Area

Previous studies have shown that individuals withdrawn from chronic opiate administration undergo substantial elevations of cortisol levels with blunted corticotropin (ACTH) rhythms and that these changes persist beyond the 7-10 days of acute withdrawal symptoms. However, there are no published studies of changes in expression of clock genes or of other neuropeptides related to circadian-rhythm regulation, which may influence relapse susceptibility.. Blood samples were collected from 8 healthy control subjects and 16 heroin addicts during pharmacologically unassisted withdrawal on the 3rd, 10th, and 30th days of abstinence at 3-hour intervals for 24 hours. Outcome measures were the relative expression of clock gene mRNA (hperiod1, hperiod2, hclock) and the levels of serum cortisol, plasma ACTH, beta-endorphin (beta-EP), leptin, neuropeptide Y, interleukin-2 (IL-2), and tumor necrosis factor (TNF) in these subjects.. Compared with healthy volunteers, abstinent addicts showed disruptions in diurnal rhythms of hPER1 and hPER2 mRNA expression, along with disruptions in diurnal rhythms of cortisol, ACTH, beta-endorphin, leptin, and IL-2 release. Several of these disruptions (hPER1, hPER2, ACTH, beta-endorphin, and IL-2) persisted for the 30-day testing period, as did elevation of 24-hour levels of cortisol and decreases in 24-hour IL-2 and TNF levels.. These prolonged neurobiological changes may play a role in protracted opiate withdrawal symptoms and contribute to relapse vulnerability.

Topics: Adrenocorticotropic Hormone; Adult; Animals; beta-Endorphin; Case-Control Studies; Chronobiology Disorders; CLOCK Proteins; Drug Users; Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); Heroin Dependence; Humans; Hydrocortisone; Hypothalamus; Interleukin-2; Intracellular Signaling Peptides and Proteins; Leptin; Male; Neuropeptide Y; Nuclear Proteins; Period Circadian Proteins; Rats; RNA; Substance Withdrawal Syndrome; Time Factors; Trans-Activators; Transcription Factors; Tumor Necrosis Factor-alpha

Heroin use and withdrawal cause abnormality in the endocrine system. However, the time course of neuroendocrine alterations in heroin addicts during pharmacologically unassisted withdrawal is still unclear.. To investigate alterations in cortisol, adrenocorticotrophic hormone (ACTH), beta-endorphin (beta-EP), leptin, and neuropeptide Y (NPY) during the first month of abstinence in heroin addicts.. Twelve heroin addicts and eight matched healthy control subjects were recruited for this study. The neuroendocrine alterations and self-reported heroin craving, anxiety, and depression in heroin addicts were assessed at different time points (days 3, 10, and 30) of first month of abstinence from heroin use.. Self-reported heroin craving, anxiety, and depression in heroin addicts decreased gradually during the first month of abstinence. The cortisol levels increased from abstinence day 3 to 30, while ACTH and beta-EP levels decreased over this period in heroin addicts. The leptin and NPY levels were significantly decreased on days 3 and 10 but had normalized on day 30 of abstinence. A positive correlation between cortisol level and heroin craving, anxiety, and depression was observed, while a negative correlation was observed between beta-EP level and craving and anxiety and between leptin and depression and NPY and anxiety.. Abnormal alterations in the neuroendocrine system, including levels of cortisol, ACTH and beta-EP persist throughout the first month of abstinence. These results suggest that neuroendocrine system dysfunctions in heroin abusers is independent of the acute and protracted withdrawal syndromes, and may thus contribute to relapse to heroin use.

Topics: Adrenocorticotropic Hormone; Adult; Analysis of Variance; Anxiety; beta-Endorphin; Case-Control Studies; Depression; Heroin; Heroin Dependence; Humans; Hydrocortisone; Leptin; Male; Neuropeptide Y; Neurosecretory Systems; Patient Selection; Psychiatric Status Rating Scales; Radioimmunoassay; Substance Withdrawal Syndrome; Time Factors

Heroin addiction markedly affects the nutritional and metabolic status and frequently leads to malnutrition. The aim of our study was to compare circulating concentration of adipose tissue-derived hormones leptin, adiponectin and resistin in 12 patients with heroin addiction before and after one-year methadone maintenance treatment with the group of 20 age- and body mass index-matched healthy subjects. Basal serum leptin and adiponectin levels in heroin addicts were significantly decreased (3.4+/-0.4 vs. 4.5+/-0.6 ng/ml and 18.9+/-3.3 vs. 33.9+/-3.1 ng/microl, respectively; p 0.05) while serum resistin concentrations were increased compared to healthy subjects (10.1+/-1.2 vs. 4.6+/-0.3 ng/ml; p 0.05). Moreover, positive correlation of serum leptin levels with body mass index was lost in the addicts in contrast to control group. One year of methadone maintenance treatment normalized serum leptin, but not serum adiponectin and resistin concentrations. In conclusion, circulating concentrations of leptin, adiponectin and resistin are markedly altered in patients with chronic heroin addiction. These alterations appear to be relatively independent of nutritional status and insulin sensitivity.

Topics: Adipocytes; Adiponectin; Adult; Body Mass Index; Chronic Disease; Female; Heroin Dependence; Hormones; Hormones, Ectopic; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Male; Methadone; Narcotics; Nutritional Status; Resistin

The aim of the study was to explore the influence of heroin addiction and one year methadone maintenance treatment respectively on serum leptin levels.. 14 heroin addicted subjects (9 men and 5 women) with average age 27.1 years (variation 22-38 years) and 17 control healthy subjects were included into the study. Mean duration of heroin addiction was 9 years. The subjects were treated for one year with mean daily dose of 90 mg of methadone. Serum leptin levels were measured by enzymoimmunoassay, the rest of the biochemical parameters was measured by standard laboratory methods. Body Mass Index (BMI) was calculated by conventional method (kg/m2). Statistical analysis was performed using t test and paired t test. Serum leptin levels in heroin addicts (7.08 +/- 2.80 ng/ml) did not significantly differ from those of control group (6.10 +/- 1.23 ng/ml). One year of methadone maintenance treatment significantly increased serum leptin levels to 12.10 +/- 3.17 ng/ml vs control group (< 0.05). The same was true for BMI which increased significantly from basal 21.47 +/- 2.54 to 24.61 +/- 2.82 (< 0.05).. Long term addiction to heroin did not change serum leptin levels as compared with control group. One year of methadone maintenance treatment significantly increased serum leptin levels as well as BMI values. We suggest that the increase in serum leptin levels could be explained by the restoration of hypopituitary-hypothalamo-adrenal and/or hypopituitary-hypothalamo-gonadal axis by methadone maintenance treatment. Alternatively, the improvement of nutritional status with subsequent decrease in the infectious complications may be involved.

Topics: Adult; Body Mass Index; Female; Heroin Dependence; Humans; Leptin; Male; Methadone; Narcotics

Studies in rats have shown that intermittent footshock stress reinstates drug seeking after prolonged drug-free periods. Recently, we found that another environmental stressor, acute 1 d food deprivation, potently reinstates heroin seeking in rats. Here we report that this effect of food deprivation can be blocked by leptin, a hormone involved in the regulation of energy balance and food intake. Rats were trained to self-administer heroin (0.05-0.1 mg/kg, i.v., per infusion, three 3 hr sessions per day) for 8-10 d. The heroin-reinforced behavior was then extinguished for 10-13 d, during which lever presses had no reinforced consequences. Subsequently, rats were tested for reinstatement after 1 d of food deprivation (experiment 1) or exposure to intermittent footshock (15 min, 0.6 mA) and heroin priming injections (0.25 mg/kg, s.c.) (experiment 2). Acute food deprivation reinstated heroin seeking, an effect that was attenuated by leptin (2 or 4 microgram/rat, i.c.v.; two infusions, given 21 hr and 20-30 min before the start of the test sessions). In contrast, leptin had no effect on reinstatement of heroin seeking induced by intermittent footshock or priming injections of heroin. These data indicate that food deprivation can provoke relapse to heroin seeking via a leptin-dependent mechanism, which is not involved in relapse induced by footshock stress or reexposure to heroin.

Topics: Animals; Behavior, Animal; Disease Models, Animal; Electroshock; Food Deprivation; Heroin; Heroin Dependence; Injections, Intraventricular; Injections, Subcutaneous; Leptin; Male; Rats; Rats, Long-Evans; Secondary Prevention; Self Administration; Stress, Physiological; Treatment Outcome