Deep Brain Stimulation Reveals a Dissociation of Consummatory and Motivated Behaviour in the Medial and Lateral Nucleus Accumbens Shell of the Rat

Following the successful application of deep brain stimulation (DBS) in the treatment of Parkinson's disease and promising results in clinical trials for obsessive compulsive disorder and major depression, DBS is currently being tested in small patient-populations with eating disorders and addiction. However, in spite of its potential use in a broad spectrum of disorders, the mechanisms of action of DBS remain largely unclear and optimal neural targets for stimulation in several disorders have yet to be established. Thus, there is a great need to examine site-specific effects of DBS on a behavioural level and to understand how DBS may modulate pathological behaviour. In view of the possible application of DBS in the treatment of disorders characterized by impaired processing of reward and motivation, like addiction and eating disorders, we examined the effect of DBS of the nucleus accumbens (NAcc) on food-directed behavior. Rats were implanted with bilateral stimulation electrodes in one of three anatomically and functionally distinct sub-areas of the NAcc: the core, lateral shell (lShell) and medial shell (mShell). Subsequently, we studied the effects of DBS on food consumption, and the motivational and appetitive properties of food. The data revealed a functional dissociation between the lShell and mShell. DBS of the lShell reduced motivation to respond for sucrose under a progressive ratio schedule of reinforcement, mShell DBS, however, profoundly and selectively increased the intake of chow. DBS of the NAcc core did not alter any form of food-directed behavior studied. DBS of neither structure affected sucrose preference. These data indicate that the intake of chow and the motivation to work for palatable food can independently be modulated by DBS of subregions of the NAcc shell. As such, these findings provide important leads for the possible future application of DBS as a treatment for eating disorders such as anorexia nervosa

Season of Sampling and Season of Birth Influence Serotonin Metabolite Levels in Human Cerebrospinal Fluid

BACKGROUND: Animal studies have revealed seasonal patterns in cerebrospinal fluid (CSF) monoamine (MA) turnover. In humans, no study had systematically assessed seasonal patterns in CSF MA turnover in a large set of healthy adults. METHODOLOGY/PRINCIPAL FINDINGS: Standardized amounts of CSF were prospectively collected from 223 healthy individuals undergoing spinal anesthesia for minor surgical procedures. The metabolites of serotonin (5-hydroxyindoleacetic acid, 5-HIAA), dopamine (homovanillic acid, HVA) and norepinephrine (3-methoxy-4-hydroxyphenylglycol, MPHG) were measured using high performance liquid chromatography (HPLC). Concentration measurements by sampling and birth dates were modeled using a non-linear quantile cosine function and locally weighted scatterplot smoothing (LOESS, span = 0.75). The cosine model showed a unimodal season of sampling 5-HIAA zenith in April and a nadir in October (p-value of the amplitude of the cosine = 0.00050), with predicted maximum (PC(max)) and minimum (PC(min)) concentrations of 173 and 108 nmol/L, respectively, implying a 60% increase from trough to peak. Season of birth showed a unimodal 5-HIAA zenith in May and a nadir in November (p = 0.00339; PC(max) = 172 and PC(min) = 126). The non-parametric LOESS showed a similar pattern to the cosine in both season of sampling and season of birth models, validating the cosine model. A final model including both sampling and birth months demonstrated that both sampling and birth seasons were independent predictors of 5-HIAA concentrations. CONCLUSION: In subjects without mental illness, 5-HT turnover shows circannual variation by season of sampling as well as season of birth, with peaks in spring and troughs in fall

Partitioning the Heritability of Tourette Syndrome and Obsessive Compulsive Disorder Reveals Differences in Genetic Architecture

The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained

The role of dopamine in obsessive-compulsive disorder: preclinical and clinical evidence

Obsessive-compulsive disorder (OCD) is a frequent and chronic psychiatric disorder that has been linked closely to the serotonin system mainly because of the antiobsessional efficacy of selective serotonin reuptake inhibitors (SSRIs). A limitation of the serotonin hypothesis of OCD is that a substantial number of the patients with OCD show no significant improvement after an adequate trial with SSRIs. There is substantial evidence that these patients may benefit from addition of antipsychotics to their ongoing SSRI treatment, suggesting that dopamine also might play a role in the pathophysiology of OCD. In this review, the preclinical and clinical evidence on the role of dopamine in OCD is summarize

Effects of quetiapine on cognitive functioning in obsessive-compulsive disorder

In recent years, growing evidence supports the efficacy of antipsychotic addition to serotonin reuptake inhibitors in patients with treatment-refractory obsessive-compulsive disorder. This study is the first to investigate the effects of antipsychotic addition on cognitive functioning in obsessive-compulsive disorder patients. Cognitive functioning was evaluated at baseline and at endpoint of an 8-week double-blind, placebo-controlled quetiapine addition trial. Neurocognitive performance was compared between the placebo and quetiapine group and between responders and nonresponders. The neuropsychological test battery consisted of the national adult reading test, the Wisconsin Card Sorting Test, the Trail Making Test, verbal fluency, the Stroop Color Word Test, the California Verbal Learning Test, the Rey Complex Figure Task, the Continuous Performance Test, and the Digit Symbol Substitution. The results of this study suggest that quetiapine addition to serotonin reuptake inhibitors has no major effects on cognitive functioning in obsessive-compulsive disorder patients, apart from some evidence for a failure to maintain set on the Wisconsin Card Sorting Test. It is proposed that this failure may be caused by attention difficulties owing to somnolenc

Synergistic dopamine increase in the rat prefrontal cortex with the combination of quetiapine and fluvoxamine

RATIONALE: The combination of atypical antipsychotic drugs in addition to serotonin reuptake inhibitors has recently proven to be beneficial in a number of neuropsychiatric disorders, such as major depression, schizophrenia, and obsessive-compulsive disorder. OBJECTIVES: To investigate the effects of an atypical antipsychotic drug in combination with a serotonin reuptake inhibitor on extracellular serotonin [5-HT]ex, and dopamine levels [DA]ex in different brain areas. METHODS: The effects of quetiapine (10 mg/kg) with fluvoxamine (10 mg/kg) on [5-HT]ex and [DA]ex were compared in the rat dorsal striatum, prefrontal cortex, nucleus accumbens (core and shell), and thalamus by means of microdialysis coupled to HPLC with electrochemical detection. RESULTS: Quetiapine had no significant effect on [DA]ex and [5-HT]ex levels in the prefrontal cortex and thalamus, but increased [DA]ex and [5-HT]ex levels in the dorsal striatum. In the accumbens, quetiapine increased [DA]ex levels and decreased [5-HT]ex levels. Fluvoxamine increased [5-HT]ex levels in all brain areas, and also increased [DA]ex levels in the striatum. The combination of quetiapine with fluvoxamine increased [DA]ex and [5-HT]ex levels in all brain areas compared with baseline. Although neither quetiapine nor fluvoxamine in monotherapy affected [DA]ex levels in the prefrontal cortex and thalamus, the combination produced a significant increase of [DA]ex levels in these two brain areas. CONCLUSIONS: The combination of quetiapine with fluvoxamine causes a synergistic dopamine increase in the prefrontal cortex and the thalamu

Neurobiology of obsessive-compulsive disorder: serotonin and beyond

The evidence for the involvement of the serotonergic system in the pathogenesis of obsessive-compulsive disorder (OCD) is circumstantial at best, despite being the focus for most pathophysiological research over the last 2 decades. This hypothesis was initially motivated by the observed differential efficacy of selective serotonin reuptake inhibitors (SSRIs) in alleviating OCD symptoms. Direct evidence that serotonergic perturbations are implicated in the pathophysiology of OCD is still sparse. There is growing evidence, from both preclinical and clinical studies, that the dopamine system may also be involved in the pathogenesis of OCD, and that dopaminergic and serotonergic pathways play a role in the genesis and maintenance of obsessive-compulsive symptoms. The complex interactions between both systems, the phenotypic heterogeneity of the disorder, and the limitations of the available tests to probe both systems, make it as yet impossible to draw firm conclusions as to how these systems are implicated. Further studies with more selective pharmacologic agents and neurocognitive probes in humans, studies using deep brain stimulation in combination with neuroimaging, and the development of better animal models for OCD may further our understanding of this disabling conditio

Emerging skin-picking behaviour after serotonin reuptake inhibitor-treatment in patients with obsessive-compulsive disorder: possible mechanisms and implications for clinical care

Pathological skin-picking is a self-injurious, impulsive behaviour with repetitive, and ritualistic characteristics. A number of studies show that selective serotonin reuptake inhibitors (SSRIs) may be efficacious in reducing skin-picking behaviour. Two case reports are presented demonstrating that SSRI-treatment may induce or aggravate pathological skin-picking behaviour. Possible mechanisms of SSRI-induced pathological skin-picking and implications for clinical care are discusse

Bupropion for patients with obsessive-compulsive disorder: an open-label, fixed-dose study

OBJECTIVE: In the present study, we examined the efficacy of bupropion for patients with obsessive-compulsive disorder (OCD). METHOD: Twelve patients with OCD according to DSM-IV criteria were included in an open trial with bupropion, maximum dosage 300 mg per day, during 8 weeks. The primary efficacy parameter was the Yale-Brown Obsessive Compulsive Scale (YBOCS). A responder was defined by a reduction in score on the YBOCS of > or = 25%. Data were collected from February 2003 to July 2003. RESULTS: An intent-to-treat analysis using the last observation carried forward demonstrated that bupropion had no mean effect on OCD symptoms (mean YBOCS decrease was 1.1 +/- 9.6). Four patients improved, with a mean decrease on the YBOCS of 31%, and 2 of them met responder rate criteria. Eight patients experienced an exacerbation of OCD symptoms, with a mean increase on the YBOCS of 21%. CONCLUSION: Bupropion is not an effective treatment for OCD, but the bimodal distribution of the effect supports the notion that dopamine might be involved in the pathophysiology of OC