65 research outputs found
Extending the Family: Roles for Uptake\u3csub\u3e2\u3c/sub\u3e Transporters in Regulation of Monoaminergic Signaling
Targeting Serotonin Transporters in the Treatment of Juvenile and Adolescent Depression
Depression is a serious public health concern. Many patients are not effectively treated, but in children and adolescents this problem is compounded by limited pharmaceutical options. Currently, the Food and Drug Administration approves only two antidepressants for use in these young populations. Both are selective serotonin reuptake inhibitors (SSRIs). Compounding matters further, they are therapeutically less efficacious in children and adolescents than in adults. Here, we review clinical and preclinical literature describing the antidepressant efficacy of SSRIs in juveniles and adolescents. Since the high-affinity serotonin transporter (SERT) is the primary target of SSRIs, we then synthesize these reports with studies of SERT expression/function during juvenile and adolescent periods. Preclinical literature reveals some striking parallels with clinical studies, primary among them is that, like humans, juvenile and adolescent rodents show reduced antidepressant-like responses to SSRIs. These findings underscore the utility of preclinical assays designed to screen drugs for antidepressant efficacy across ages. There is general agreement that SERT expression/function is lower in juveniles and adolescents than in adults. It is well established that chronic SSRI treatment decreases SERT expression/function in adults, but strikingly, SERT expression/function in adolescents is increased following chronic treatment with SSRIs. Finally, we discuss a putative role for organic cation transporters and/or plasma membrane monoamine transporter in serotonergic homeostasis in juveniles and adolescents. Taken together, fundamental differences in SERT, and putatively in other transporters capable of serotonin clearance, may provide a mechanistic basis for the relative inefficiency of SSRIs to treat pediatric depression, relative to adults
Ontogeny of NET expression and antidepressant-like response to desipramine in wild-type and SERT mutant mice
Abstract word count: 250 Introduction word count: 74
PICK1-Deficient Mice Exhibit Impaired Response to Cocaine and Dysregulated Dopamine Homeostasis
Impaired Striatal Akt Signaling Disrupts Dopamine Homeostasis and Increases Feeding
DOI is broken and has been reportedThe prevalence of obesity has increased dramatically worldwide. The obesity epidemic begs for novel concepts and therapeutic targets that cohesively address “food-abuse” disorders. We demonstrate a molecular link between impairment of a central kinase (Akt) involved in insulin signaling induced by exposure to a high-fat (HF) diet and dysregulation of higher order circuitry involved in feeding. Dopamine (DA) rich brain structures, such as striatum, provide motivation stimuli for feeding. In these central circuitries, DA dysfunction is posited to contribute to obesity pathogenesis. We identified a mechanistic link between metabolic dysregulation and the maladaptive behaviors that potentiate weight gain. Insulin, a hormone in the periphery, also acts centrally to regulate both homeostatic and reward-based HF feeding. It regulates DA homeostasis, in part, by controlling a key element in DA clearance, the DA transporter (DAT). Upon HF feeding, nigro-striatal neurons rapidly develop insulin signaling deficiencies, causing increased HF calorie intake.
Methodology/Principal Findings
We show that consumption of fat-rich food impairs striatal activation of the insulin-activated signaling kinase, Akt. HF-induced Akt impairment, in turn, reduces DAT cell surface expression and function, thereby decreasing DA homeostasis and amphetamine (AMPH)-induced DA efflux. In addition, HF-mediated dysregulation of Akt signaling impairs DA-related behaviors such as (AMPH)-induced locomotion and increased caloric intake. We restored nigro-striatal Akt phosphorylation using recombinant viral vector expression technology. We observed a rescue of DAT expression in HF fed rats, which was associated with a return of locomotor responses to AMPH and normalization of HF diet-induced hyperphagia.
Conclusions/Significance
Acquired disruption of brain insulin action may confer risk for and/or underlie “food-abuse” disorders and the recalcitrance of obesity. This molecular model, thus, explains how even short-term exposure to “the fast food lifestyle” creates a cycle of disordered eating that cements pathological changes in DA signaling leading to weight gain and obesity.National Institutes of Health (U.S.) (grant DA14684)National Institutes of Health (U.S.) (grant DK085712
Hypoinsulinemia Regulates Amphetamine-Induced Reverse Transport of Dopamine
The behavioral effects of psychomotor stimulants such as amphetamine (AMPH) arise from their ability to elicit increases in extracellular dopamine (DA). These AMPH-induced increases are achieved by DA transporter (DAT)-mediated transmitter efflux. Recently, we have shown that AMPH self-administration is reduced in rats that have been depleted of insulin with the diabetogenic agent streptozotocin (STZ). In vitro studies suggest that hypoinsulinemia may regulate the actions of AMPH by inhibiting the insulin downstream effectors phosphotidylinositol 3-kinase (PI3K) and protein kinase B (PKB, or Akt), which we have previously shown are able to fine-tune DAT cell-surface expression. Here, we demonstrate that striatal Akt function, as well as DAT cell-surface expression, are significantly reduced by STZ. In addition, our data show that the release of DA, determined by high-speed chronoamperometry (HSCA) in the striatum, in response to AMPH, is severely impaired in these insulin-deficient rats. Importantly, selective inhibition of PI3K with LY294002 within the striatum results in a profound reduction in the subsequent potential for AMPH to evoke DA efflux. Consistent with our biochemical and in vivo electrochemical data, findings from functional magnetic resonance imaging experiments reveal that the ability of AMPH to elicit positive blood oxygen level–dependent signal changes in the striatum is significantly blunted in STZ-treated rats. Finally, local infusion of insulin into the striatum of STZ-treated animals significantly recovers the ability of AMPH to stimulate DA release as measured by high-speed chronoamperometry. The present studies establish that PI3K signaling regulates the neurochemical actions of AMPH-like psychomotor stimulants. These data suggest that insulin signaling pathways may represent a novel mechanism for regulating DA transmission, one which may be targeted for the treatment of AMPH abuse and potentially other dopaminergic disorders
Dysregulation of the Norepinephrine Transporter Sustains Cortical Hypodopaminergia and Schizophrenia-Like Behaviors in Neuronal Rictor Null Mice
A novel animal model highlights the link between Akt dysfunction, reduced cortical dopamine function, norepinephrine transporters, and schizophrenia-like behaviors
Health informatics and modernisation: bridging the gap
This pilot initiative uses an approach that focuses on improving the whole business of primary care, its processes and its people. The Health Informatics Programme for Coronary Heart Disease (HIP for CHD) addresses the two faces of clinical governance but has a prime focus on the development of learning organisations. The project has developed a methodology and an associated set of tools that it has tested and evaluated in a small number of pilot sites. The work of HIP for CHD is focused on coronary heart disease but the methodology is equally applicable to other clinical areas. In particular, HIP for CHD provides an approach that allows the diverse strands of all of the National Service Frameworks to be handled in a joined-up way in primary care
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