sch-23390 and Body-Weight

Herein, a novel series of multireceptor ligands was developed as polypharmacological antipsychotic agents using the designed multiple ligand approach between dopamine receptors and serotonin receptors. Among them, compound 47 possessed unique pharmacological features, exhibiting high affinities for D

Topics: Animals; Antipsychotic Agents; Body Weight; Chemistry Techniques, Synthetic; Drug Design; Ether-A-Go-Go Potassium Channels; Heterocyclic Compounds; Memory; Mice; Piperazine; Rats; Schizophrenia; Structure-Activity Relationship; Tissue Distribution

Pregabalin is useful for treating neuropathic pain, but known to increase body weight as a side effect. To investigate the mechanism of this increase in body weight, we focused on dopamine in the lateral hypothalamus (LH) and examined the effects of pregabalin on dopamine levels in the LH and food intake. The dopamine levels in the LH was gradually decreased during fasting. When the animals were fed, dopamine levels in the LH was significantly increased, indicating that dopamine levels in the LH reflects energy state. The systemic injection of pregabalin tended to decrease dopamine levels in the LH after feeding. The dopamine levels in the LH was also significantly increased by glucose injection, which was inhibited by pregabalin. These results suggest that pregabalin inhibits dopaminergic function in the LH, which might increase food intake. To make these points clear, we examined the effects of pregabalin on food intake and blood glucose levels. Pregabalin significantly increased food intake, whereas pregabalin did not affect blood glucose levels. These results indicate that pregabalin stimulates feeding behavior, but not glucose metabolism. Moreover, the non-selective dopamine receptor antagonist cis-(Z)-flupenthixol injected into the LH significantly increased food intake, though neither the dopamine D

Topics: Animals; Benzazepines; Blood Glucose; Body Weight; Dopamine; Dopamine Antagonists; Dopaminergic Neurons; Eating; Feeding Behavior; Hypothalamic Area, Lateral; Hypothalamus; Male; Mice; Mice, Inbred ICR; Microdialysis; Nucleus Accumbens; Pregabalin; Rats; Rats, Wistar; Receptors, Dopamine D1; Receptors, Dopamine D2

Methamphetamine (MA) studies in animals usually involve acute, binge, or short-term exposure to the drug. However, addicts take substantial amounts of MA for extended periods of time. Here we wished to study the effects of MA exposure on brain and behavior, using an animal model analogous to this pattern of MA intake. MA doses, 4 and 8mg/kg/day, were based on previously reported average daily freely available MA self-administration levels. We examined the effects of 16 week MA treatment on psychomotor and cognitive function in the rat using open field and novel object recognition tests and we studied the adaptations of the dopaminergic system, using in vitro and in vivo receptor imaging. We show that chronic MA treatment, at doses that correspond to the average daily freely available self-administration levels in the rat, disorganizes open field activity, impairs alert exploratory behavior and anxiety-like state, and downregulates dopamine transporter in the striatum. Under these treatment conditions, dopamine terminal functional integrity in the nucleus accumbens is also affected. In addition, lower dopamine D1 receptor binding density, and, to a smaller degree, lower dopamine D2 receptor binding density were observed. Potential mechanisms related to these alterations are discussed.

Topics: Animals; Anxiety; Benzazepines; Body Weight; Brain; Carbon Isotopes; Central Nervous System Stimulants; Cognition; Dopamine; Dopamine Antagonists; Dopamine Plasma Membrane Transport Proteins; Exploratory Behavior; Male; Methamphetamine; Psychomotor Performance; Raclopride; Rats; Rats, Sprague-Dawley; Receptors, Dopamine; Recognition, Psychology; Signal Transduction; Spiperone

Hypothyroidism affects cardiopulmonary regulation and function of dopaminergic receptors. Here we evaluated effects of 5 months of hypothyroidism on dopamine D1 receptor modulation of breathing in female hamsters using a D1 receptor antagonist SCH 23390. Euthyroid hamsters (EH) served as controls. Results indicated that hypothyroid female hamsters (HH) exhibited decreased body weights and minute ventilation (VE) following hypoxia due to decreased frequency of breathing (F). Moreover, SCH 23390 administration in HH increased VE by increasing tidal volume during exposure to air, hypoxia and following hypoxia. Relative to vehicle, SCH 23390 treatment decreased body temperature and hypoxic VE responsiveness in both groups. In EH, SCH 23390 decreased F in air, hypoxia and post hypoxia, and VE during hypoxia trended to decrease (P=0.053). Finally, expression of D1 receptor protein was not different between the two groups in any region evaluated. Thus, hypothyroidism in older female hamsters affected D1 receptor modulation of ventilation differently relative to euthyroid animals, but not expression of D1 receptors.

Topics: Animals; Benzazepines; Blotting, Western; Body Temperature; Body Weight; Carbon Dioxide; Disease Models, Animal; Dopamine Antagonists; Female; Hypothyroidism; Mesocricetus; Oxygen Consumption; Propylthiouracil; Receptors, Dopamine D1; Respiration; Tidal Volume

Binge-eating disorder is a common psychiatric disorder affecting ~2% of adults. Binge-eating was initiated in freely-fed, lean, adult, female rats by giving unpredictable, intermittent access to ground, milk chocolate over four weeks. The rats avidly consumed chocolate during 2 hr binge sessions, with compensatory reductions of normal chow intake in these sessions and the days thereafter. Bodyweights of binge-eating rats were normal. The model's predictive validity was explored using nalmefene (0.1-1.0mg/kg), R-baclofen (1.0-10mg/kg) and SB-334867 (3.0-30 mg/kg) (orexin-1 antagonist), which all selectively decreased chocolate bingeing without reducing chow intake. Sibutramine (0.3-5.0mg/kg) non-selectively reduced chocolate and chow consumption. Olanzapine (0.3-3.0mg/kg) was without effect and rolipram (1.0-10mg/kg) abolished all ingestive behaviour. The pro-drug, lisdexamfetamine (LDX; 0.1-1.5mg/kg), dose-dependently reduced chocolate bingeing by ⩽ 71% without significantly decreasing normal chow intake. Its metabolite, D-amphetamine (0.1-1.0mg/kg), dose-dependently and preferentially decreased chocolate bingeing ⩽ 56%. Using selective antagonists to characterize LDX's actions revealed the reduction of chocolate bingeing was partially blocked by prazosin (α1-adrenoceptor; 0.3 and 1.0mg/kg) and possibly by SCH-23390 (D1; 0.1mg/kg). RX821002 (α2-adrenoceptor; 0.1 and 0.3mg/kg) and raclopride (D2; 0.3 and 0.5mg/kg) were without effect. The results indicate that LDX, via its metabolite, d-amphetamine, reduces chocolate bingeing, partly by indirect activation of α1-adrenoceptors and perhaps D1 receptors.

Topics: Animals; Baclofen; Behavior, Animal; Benzazepines; Benzodiazepines; Body Weight; Bulimia; Disease Models, Animal; Eating; Feeding Behavior; Female; Idazoxan; Lisdexamfetamine Dimesylate; Naltrexone; Olanzapine; Prazosin; Prodrugs; Raclopride; Rats; Rats, Wistar; Rolipram

Obesity resistance due to elevated orexin signaling is accompanied by high levels of spontaneous physical activity (SPA). The behavioral and neural mechanisms underlying this observation have not been fully worked out. We determined the contribution of hypothalamic orexin receptors (OXRs) to SPA stimulated by orexin A (OXA), whether OXA-stimulated SPA was secondary to arousal and whether voluntary wheel running led to compensations in 24-h SPA. We further tested whether orexin action on dopamine one receptors (DA1R) in the substantia nigra (SN) plays an important role in the generation of SPA. To test this, SPA response was determined in lean and obese rats with cannulae targeted toward the rostral lateral hypothalamus (rLH) or SN. Sleep/wake states were also measured in rats with rLH cannula and electroencephalogram/electromyogram radiotelemetry transmitters. SPA in lean rats was more sensitive to antagonism of the OX1R and in the early response to the orexin 2 agonist. OXA increased arousal equally in lean and obese rodents, which is discordant from the greater SPA response in lean rats. Obesity-resistant rats ran more and wheel running was directly related to 24-h SPA levels. The OX1R antagonist, SB-334867-A, and the DA1R antagonist, SCH3390, in SN more effectively reduced SPA stimulated by OXA in obesity-resistant rats. These data suggest OXA-stimulated SPA is not secondary to enhanced arousal, propensity for SPA parallels inclination to run and that orexin action on dopaminergic neurons in SN may participate in the mediation of SPA and running wheel activity.

Topics: Age Factors; Animals; Benzazepines; Benzoxazoles; Body Weight; Dopamine Antagonists; Eating; Electromyography; Eye Movements; Hypothalamus; Intracellular Signaling Peptides and Proteins; Male; Motor Activity; Naphthyridines; Neuropeptides; Obesity; Orexin Receptor Antagonists; Orexins; Rats; Rats, Sprague-Dawley; Sleep; Substantia Nigra; Urea; Wakefulness

Access to highly palatable and calorically dense foods contributes to increasing rates of obesity worldwide. Some have made the controversial argument that consumption of such foods can lead to "food addiction," yet little is known about how long-term access to highly palatable foods might alter goal-directed learning and decision making. In the following experiments, rats were given 5 weeks of continuous or restricted daily access to sweetened condensed milk (SCM) before instrumental training for food reward. Subsequently we examined whether goal-directed performance was impaired in these groups using the outcome-devaluation task. Control rats reduced responding following devaluation of the earned outcome as did those with previous continuous access to SCM. Of interest, rats with previous restricted access to SCM responded similarly under the devalued and nondevalued conditions, indicating loss of goal-directed control of responding. To identify whether the loss of goal-directed control was accompanied by differences in neuronal activity, we used c-Fos immunohistochemistry to examine the patterns of activation during devaluation testing. We observed greater c-Fos immunoreactivity in the dorsolateral striatum (DLS) and associated cortical regions in the group that received previous restricted access to SCM and demonstrated a lack of sensitivity to outcome devaluation. Infusion of the AMPA-receptor antagonist CNQX or dopamine D1-receptor antagonist SCH-23390 into the DLS before testing restored goal-directed performance in the restricted SCM group, confirming that this region is essential for habit-based performance. These results indicate that previous diet can alter subsequent learning and activity in the neural circuits that support performance.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Benzazepines; Body Weight; Conditioning, Operant; Corpus Striatum; Dopamine Antagonists; Energy Intake; Excitatory Amino Acid Antagonists; Extinction, Psychological; Food Deprivation; Food Preferences; Habits; Male; Rats; Rats, Long-Evans; Reward; Satiation; Sweetening Agents

Antipsychotic drugs are increasingly used in children and adolescents to treat a variety of psychiatric disorders. However, little is known about the long-term effects of early life antipsychotic drug (APD) treatment. Most APDs are potent antagonists or partial agonists of dopamine (DA) D₂ receptors; atypical APDs also have multiple serotonergic activities. DA and serotonin regulate many neurodevelopmental processes. Thus, early life APD treatment can, potentially, perturb these processes, causing long-term behavioural and neurobiological sequelae. We treated adolescent, male rats with olanzapine (Ola) on post-natal days 28-49, under dosing conditions that approximate those employed therapeutically in humans. As adults, they exhibited enhanced conditioned place preference for amphetamine, as compared to vehicle-treated rats. In the nucleus accumbens core, DA D₁ receptor binding was reduced, D₂ binding was increased and DA release evoked by electrical stimulation of the ventral tegmental area was reduced. Thus, adolescent Ola treatment enduringly alters a key behavioural response to rewarding stimuli and modifies DAergic neurotransmission in the nucleus accumbens. The persistence of these changes suggests that even limited periods of early life Ola treatment may induce enduring changes in other reward-related behaviours and in behavioural and neurobiological responses to therapeutic and illicit psychotropic drugs. These results underscore the importance of improved understanding of the enduring sequelae of paediatric APD treatment as a basis for weighing the benefits and risks of adolescent APD therapy, especially prophylactic treatment in high-risk, asymptomatic patients.

Topics: Age Factors; Animals; Animals, Newborn; Benzamides; Benzazepines; Benzodiazepines; Body Weight; Conditioning, Operant; Dopamine; Dopamine Antagonists; Follow-Up Studies; Male; Nucleus Accumbens; Olanzapine; Protein Binding; Rats; Rats, Long-Evans; Reward; Selective Serotonin Reuptake Inhibitors; Tritium

Tesofensine is a novel monoamine reuptake inhibitor that inhibits both norepinephrine, 5-HT, and dopamine (DA) reuptake function. Tesofensine is currently in clinical development for the treatment of obesity, however, the pharmacological basis for its strong effect in obesity management is not clarified. Using a rat model of diet-induced obesity (DIO), we characterized the pharmacological mechanisms underlying the appetite suppressive effect of tesofensine. DIO rats treated with tesofensine (2.0 mg/kg, s.c.) for 16 days showed significantly lower body weights than vehicle-treated DIO rats, being reflected by a marked hypophagic response. Using an automatized food intake monitoring system during a 12 h nocturnal test period, tesofensine-induced hypophagia was investigated further by studying the acute interaction of a variety of monoamine receptor antagonists with tesofensine-induced hypophagia in the DIO rat. Tesofensine (0.5-3.0 mg/kg, s.c.) induced a dose-dependent and marked decline in food intake with an ED(50) of 1.3 mg/kg. The hypophagic response of tesofensine (1.5 mg/kg, s.c.) was almost completely reversed by co-administration of prazosin (1.0 mg/kg, alpha(1) adrenoceptor antagonist) and partially antagonized by co-administration of SCH23390 (0.03 mg/kg, DA D(1) receptor antagonist). In contrast, tesofensine-induced hypophagia was not affected by RX821002 (0.3 mg/kg, alpha(2) adrenoceptor antagonist), haloperidol (0.03 mg/kg, D(2) receptor antagonist), NGB2904 (0.1 mg/kg, D(3) receptor antagonist), or ritanserin (0.03 mg/kg, 5-HT(2A/C) receptor antagonist). Hence, the mechanism underlying the suppression of feeding by tesofensine in the obese rat is dependent on the drug's ability to indirectly stimulate alpha(1) adrenoceptor and DA D(1) receptor function.

Topics: Adrenergic alpha-Antagonists; Animals; Appetite Depressants; Benzazepines; Body Weight; Bridged Bicyclo Compounds, Heterocyclic; Diet; Disease Models, Animal; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Interactions; Eating; Feeding Behavior; Male; Obesity; Prazosin; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-1; Receptors, Dopamine D1; Signal Transduction; Time Factors

Caffeine exacerbates the acute toxicity of 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') in rats characterised by hyperthermia, tachycardia and lethality. Depletion of central catecholamine stores and dopamine D(1) receptor blockade have been reported to attenuate the ability of caffeine to exacerbate MDMA-induced hyperthermia.. Here, we investigate whether dopamine D(1) and D(2) receptors mediate the effects of caffeine on MDMA-induced changes in body temperature, heart rate and locomotor activity.. All parameters were recorded continuously in individually housed rats using bioradiotelemetry from 1 h prior to 4 h following caffeine (10 mg/kg, s.c.) and/or MDMA (10 mg/kg, s.c.) administration.. Co-administration of caffeine with MDMA provoked a switch from MDMA-induced hypothermia and bradycardia to hyperthermia and tachycardia without influencing MDMA-induced hyperlocomotion. Pre-treatment with a specific dopamine D(1/5) antagonist SCH 23390 (1 mg/kg) enhanced MDMA-induced hypothermia and blocked the ability of caffeine to provoke a switch from MDMA-induced hypothermia to hyperthermia. Furthermore, SCH 23390 blocked MDMA-induced hyperactivity and the ability of caffeine to promote a tachycardic response to MDMA. By contrast, pre-treatment with the selective D(2) antagonist, sulpiride (100 mg/kg) blocked MDMA-induced hypothermia, failed to influence the ability of caffeine to promote tachycardia whilst enhancing MDMA-induced hyperactivity.. Our results highlight the importance of dopamine D(1) and D(2) receptors in shaping the behavioural and physiological response to MDMA and suggest that the ability of caffeine to provoke MDMA-induced toxicity is associated with the promotion of dopamine D(1) over D(2) receptor-related responses.

Topics: Analysis of Variance; Animals; Behavior, Animal; Benzazepines; Body Weight; Caffeine; Central Nervous System Stimulants; Dopamine Agents; Drug Interactions; Hallucinogens; Heart Rate; Locomotion; Male; N-Methyl-3,4-methylenedioxyamphetamine; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1; Sulpiride; Time Factors