5-hydroxytryptamine medications for the treatment of obesity.

The central 5-hydroxytryptamine (5-HT; serotonin) system represents a fundamental component of the brain's control of energy homeostasis. Medications targeting the 5-HT pathway have been at the forefront of obesity treatment for the past 15 years. Pharmacological agents targeting 5-HT receptors (5-HTR), in combination with genetic models of 5-HTR manipulation, have uncovered a role for specific 5-HTRs in energy balance and reveal the 5-HT2 C R as the principal 5-HTR mediating this homeostatic process. Capitalising on this neurophysiological machinery, 5-HT2 C R agonists improve obesity and glycaemic control in patient populations. The underlying therapeutic mechanism has been probed using model systems and appears to be achieved primarily through 5-HT2 C R modulation of the brain melanocortin circuit via activation of pro-opiomelanocortin neurones signalling at melanocortin4 receptors. Thus, 5-HT2 C R agonists offer a means to improve obesity and type 2 diabetes, which are conditions that now represent global challenges to human health.

Melanocortin-3 receptors are involved in adaptation to restricted feeding.

The central nervous melanocortin system forms a neural network that maintains energy homeostasis. Actions involving neural melanocortin-3 receptors (MC3Rs) regulate the expression rhythms in ingestive behaviors and metabolism anticipating nutrient intake. Here, we characterized the response of Mc3r knockout (Mc3r(-/-)) and wild type (WT) mice to a restricted feeding (RF) schedule where food access was limited to a 4-h period mid light cycle using a mechanical barrier. Mc3r(-/-) mice adapted poorly to the food restriction schedule. Anticipatory activity and the initial bout of intense feeding activity associated with granting food access were attenuated in Mc3r(-/-) mice, resulting in increased weight loss relative to controls. To investigate whether activity in specific hypothalamic nuclei contribute to the Mc3r(-/-) phenotype observed, we assessed hypothalamic FOS-immunoreactivity (FOS-IR) associated with food restriction. Food access markedly increased FOS-IR in the dorsomedial hypothalamus (DMH), but not in the suprachiasmatic or ventromedial hypothalamic nuclei (SCN and VMN, respectively) compared to ad libitum fed mice. Mc3r(-/-) mice displayed a significant reduction in FOS-IR in the DMH during feeding. Analysis of MC3R signaling in vitro indicated dose-dependent stimulation of the extracellular signal-regulated kinase (ERK) pathway by the MC3R agonist d-Trp(8)-γMSH. Treatment of WT mice with d-Trp(8)-γMSH administered intracerebroventricularly increased the number of pERK neurons 1.7-fold in the DMH. These observations provide further support for the involvement of the MC3Rs in regulating adaptation to food restriction. Moreover, MC3Rs may modulate the activity of neurons in the DMH, a region previously linked to the expression of the anticipatory response to RF.

Serotonin 5-HT(2C) receptors regulate anxiety-like behavior.

Central serotonin (5-hydroxytryptamine, 5-HT) systems have been implicated in the pathophysiology and treatment of anxiety disorders, which are among the world's most prevalent psychiatric conditions. Here, we report that the 5-HT(2C) receptor (5-HT(2C)R) subtype is critically involved in regulating behaviors characteristic of anxiety using male 5-HT(2C)R knockout (KO) mice. Specific neural substrates underlying the 5-HT(2C)R KO anxiolytic phenotype were investigated, and we report that 5-HT(2C)R KO mice display a selective blunting of extended amygdala corticotropin-releasing hormone neuronal activation in response to anxiety stimuli. These findings illustrate a mechanism through which 5-HT(2C)Rs affect anxiety-related behavior and provide insight into the neural circuitry mediating the complex psychological process of anxiety.

A paradoxical locomotor response in serotonin 5-HT(2C) receptor mutant mice.

Paradoxical behavioral responses to nonselective neuropsychiatric drugs are frequently encountered and poorly understood. We report that a single receptor gene mutation produces a paradoxical response to the nonspecific serotonin receptor agonist m-chlorophenylpiperazine (mCPP). Although this compound normally suppresses locomotion, it produces hyperactivity in mice bearing a targeted mutation of the 5-HT(2C) receptor gene. This effect was blocked by pretreatment with a 5-HT(1B) receptor antagonist, indicating that the behavioral consequences of mCPP-induced 5-HT(1B) receptor stimulation are unmasked in animals devoid of 5-HT(2C) receptor function. Furthermore, this paradoxical response to mCPP was reproduced in wild-type C57BL/6 mice by previous pharmacological blockade of 5-HT(2C) receptors, indicating that the mutant phenotype does not result from perturbations of brain development. These effects of 5-HT1B and 5-HT(2C) receptor antagonists likely reflected blockade of pharmacological actions of mCPP, because these compounds did not alter locomotor activity levels when administered alone. Thus, mCPP interacts with distinct 5-HT receptor targets that produce opposing effects on locomotor activity levels. A paradoxical behavioral response is produced by the genetic inactivation of the target that produces the prevailing effect of the drug in the wild-type animal. This genetically based paradoxical drug effect provides a model for considering the effects of genetic load on neurobehavioral responses to drugs.

Self-defeating personality disorder reconsidered.

The objective of this study was to assess the distinctiveness, incremental validity, and gender bias of self-defeating personality disorder (SDPD) symptoms. A total of 441 nonclinical subjects completed personality disorder questionnaires. Structural equation modeling and regression analyses indicated that SDPD symptoms were distinctive, predicted impairment/distress beyond other personality disorder symptoms, and showed no gender bias. SDPD warrants reconsideration as a valid nosological category.

Reduction of fat and protein intakes but not carbohydrate intake following acute and chronic fluoxetine in female rats.

Fluoxetine hydrochloride, a selective serotonin reuptake inhibitor, leads to reductions in food intake and body weight and is under investigation as a possible treatment for obesity. Additionally, it has been suggested that fluoxetine administration could lead to a selective suppression in carbohydrate consumption. Because women more often than men seek weight reduction treatment, the present study examined the acute and chronic effects of fluoxetine on food intake, macronutrient selection, body weight, estrous cycle, and motor activity in female rats. Female Long-Evans rats were provided with separate sources of protein, fat and carbohydrate, and nutrient intakes were recorded following single (5.0, 10.0, and 20.0 mg/kg, IP) and chronic daily (10 mg/kg for 28 days) injections of fluoxetine. Acute and chronic administration of fluoxetine significantly reduced total caloric intake when compared to vehicle treatment. Moreover, fluoxetine significantly suppressed fat and protein intakes, but not carbohydrate intake following both acute and chronic drug administration. Animals chronically treated with fluoxetine gained significantly less weight than animals treated with vehicle. Chronic fluoxetine treatment did not significantly alter estrous cycle. However, in both fluoxetine- and vehicle-treated animals, total caloric intake, and carbohydrate and protein intakes were reduced and fat intake was increased when estrogen levels were high. Fluoxetine significantly reduced motor activity up to 4 h postinjection, and increased motor activity 24 h postinjection.

Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice.

The brain serotonin (5-hydroxytryptamine; 5-HT) system is a powerful modulator of emotional processes and a target of medications used in the treatment of psychiatric disorders. To evaluate the contribution of serotonin 5-HT1A receptors to the regulation of these processes, we have used gene-targeting technology to generate 5-HT1A receptor-mutant mice. These animals lack functional 5-HT1A receptors as indicated by receptor autoradiography and by resistance to the hypothermic effects of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Homozygous mutants display a consistent pattern of responses indicative of elevated anxiety levels in open-field, elevated-zero maze, and novel-object assays. Moreover, they exhibit antidepressant-like responses in a tail-suspension assay. These results indicate that the targeted disruption of the 5-HT1A receptor gene leads to heritable perturbations in the serotonergic regulation of emotional state. 5-HT1A receptor-null mutant mice have potential as a model for investigating mechanisms through which serotonergic systems modulate affective state and mediate the actions of psychiatric drugs.

Epilepsy and obesity in serotonin 5-HT2C receptor mutant mice.

Serotonin 5-HT2C receptor null mutant mice were generated to assess the contribution of this receptor to the actions of serotonin. Mutant mice displayed both an epilepsy and obesity phenotype. The epilepsy syndrome was characterized by spontaneous seizures, lowered seizure threshold, enhanced seizure propagation and sound-induced seizure susceptibility. These findings implicate 5-HT2C receptors in the regulation of neuronal network excitability. It was also observed that body weight and adipose tissue deposition were elevated in adult mutant mice relative to their wild type littermates. Paired-feeding studies suggest that the obesity syndrome is a result of increased food intake. In addition, mutants displayed reduced sensitivity to the appetite suppressant actions of non-specific serotonergic agonists. These studies establish a role for 5-HT2C receptors in the serotonergic regulation of body weight and food intake.

Fluoxetine decreases fat and protein intakes but not carbohydrate intake in male rats.

Administration of fluoxetine, a selective serotonin reuptake inhibitor, results in decreases in food intake and body weight. The present study investigated whether the anorectic actions of fluoxetine were due to a general decrease in caloric intake or macronutrient specific. Male Long-Evans rats were maintained on a dietary self-selection regime with separate sources of protein, fat, and carbohydrate. During the acute phase of the experiment, nutrient intakes were measured 2, 4, 6, and 24 h after injections of 0, 5.0, and 10.0 mg/kg fluoxetine hydrochloride. Fluoxetine significantly decreased protein and fat intakes in a dose-related manner at all measurement times. In comparison, fluoxetine had a less pronounced effect on carbohydrate intake. During the chronic phase, rats were divided into two groups, one receiving daily injections of 10.0 mg/kg fluoxetine, and the other, vehicle injections. Drug injections continued for 28 days, and were followed by a 28-day withdrawal period. Rats given fluoxetine on a chronic basis consumed significantly less calories and gained significantly less weight than rats injected with the vehicle. Both caloric intake and body weight returned to control values during the withdrawal period. Fat and protein intakes also were significantly reduced throughout the drug injection period, and were restored to baseline levels during the withdrawal period. In contrast, carbohydrate intake was not reduced on an absolute basis, and actually was increased as percent of total caloric intake during the drug period. The results of this experiment call into question the idea that increased serotoninergic activity is related to selective reductions in carbohydrate intake.

Prior exposure to palatable solutions enhances the effects of naltrexone on food intake in rats.

Previous research has suggested that chronic intake of palatable foods and fluids enhances the activity of the endogenous opioid system. To examine this suggestion, the effect of naltrexone on food intake was examined in male Long-Evans rats with or without prior exposure to palatable solutions. In Experiment 1, rats were fed laboratory chow alone or laboratory chow and a 32% sucrose solution, and in Experiment 2, were fed chow alone, chow and a 32% Polycose solution, or chow and a 0.15% saccharin solution for three weeks. The sucrose, Polycose, and saccharin solutions were removed 18 h prior to drug administration. Rats then received injections of naltrexone hydrochloride (0.0, 0.3 or 3.0 mg/kg. sc) and chow intakes were measured during the subsequent 1, 2, 4, 6 and 24 h. Naltrexone injections had minimal effects on intakes of animals which previously had consumed only chow. In contrast, naltrexone led to significant dose-related decreases in chow intakes in rats which had previously consumed the sucrose, Polycose, or saccharin solutions. These results provide confirmation for the suggestion that chronic intake of palatable solutions alters the activity of the endogenous opioid system.

Self-defeating personality disorder. A cross-national study of clinical utility.

The clinical utility of the DSM-II-R-proposed diagnostic category self-defeating personality disorder (SDPD) was assessed through the presentation of prototypic case histories to American and British psychiatrists and clinical psychologists. The most frequent diagnoses assigned were SDPD and personality disorder not otherwise specified; no alternative diagnoses were consistently provided. More than one in two professionals reported treating patients with a condition similar to the SDPD cases, and approximately 65% of these patients were reported to be female. American and British nonpatients were also assessed through the administration of an SDPD self-report questionnaire. The results suggest that the reported high prevalence of SDPD in the practitioners' patients is not a result of the expression of a general personality trait, and the reported greater incidence of SDPD in women is not a reflection of a normal, culturally learned, female behavior pattern.