Medication overuse headache associated with decreased dopamine transporter availability in the left orbitofrontal cortex: A 11CFT PET/MR study

BackgroundsThe dysfunction of dopamine in the mesocorticolimbic dopamine system in MOH is unknown. Dopamine transporter (DAT) regulates dopamine clearance and neurotransmission and is sensitive to dopamine levels. A decrease in DAT availability can reflect a decrease in dopamine. To determine DAT availability abnormalities in the mesocorticolimbic dopamine system and explore functional network changes in medication overuse headache (MOH) patients.MethodsWe examined 17 MOH patients and 16 healthy controls (HCs) using integrated positron emission tomography (PET)/magnetic resonance (MR) brain scans with 11CFT, a radioligand that binds to DAT. Standardized uptake value ratio (SUVr) images were compared voxelwise between MOH patients and HCs. Then, the significantly changed cluster (p < 0.01, GRF correction) with abnormal DAT availability was selected as a specific seed region to further evaluate altered functional connectivity (FC) in MOH. SUVr and mean FC values from significantly changed regions were extracted, and partial correlation analyses with clinical measures were conducted.ResultsMOH patients had lower SUVr levels in the left rather than right orbitofrontal cortex (OFC) than HCs. There was altered FC between the left OFC and the left superior temporal pole and bilateral calcarine gyri. SUVr levels in the left OFC and the connectivity strength linking the positive brain regions with the left OFC were not correlated with clinical measures in the MOH patients.ConclusionsMOH is characterized by decreased DAT availability in the left OFC, which might reflect compensatory downregulation due to low dopamine signalling within the mesocorticolimbic dopamine system. In addition, the OFC on both sides may have different functions in the pathogenesis of MOH. Altered intrinsic FC in the left OFC was identified in MOH patients, which may provide a new perspective to understand the pathogenesis of MOH.

Mesocorticolimbic Dopamine Pathways Across Adolescence: Diversity in Development

Mesocorticolimbic dopamine circuity undergoes a protracted maturation during adolescent life. Stable adult levels of behavioral functioning in reward, motivational, and cognitive domains are established as these pathways are refined, however, their extended developmental window also leaves them vulnerable to perturbation by environmental factors. In this review, we highlight recent advances in understanding the mechanisms underlying dopamine pathway development in the adolescent brain, and how the environment influences these processes to establish or disrupt neurocircuit diversity. We further integrate these recent studies into the larger historical framework of anatomical and neurochemical changes occurring during adolescence in the mesocorticolimbic dopamine system. While dopamine neuron heterogeneity is increasingly appreciated at molecular, physiological, and anatomical levels, we suggest that a developmental facet may play a key role in establishing vulnerability or resilience to environmental stimuli and experience in distinct dopamine circuits, shifting the balance between healthy brain development and susceptibility to psychiatric disease.

Pharmacology of Apathy

While a high prevalence of apathy across neurological disorders is well established, there remains a paucity of evidence on effective therapies. As a result, there are currently no guidelines for the treatment of apathy. This chapter reviews the current state of research on different neurotransmitter systems implicated in motivation and apathy, as well as emerging pharmacological treatments across neurological conditions. Much research in animals has focused on the role of the mesocorticolimbic dopamine system in behavioural deficits of motivation. In turn, this has inspired several dopaminergic treatments for apathy in Parkinson’s disease, while drugs targeting catecholamines (dopamine and noradrenaline) or acetylcholine in conditions such as Alzheimer’s disease show some promise. However, poorly characterized dose-dependent effects, as well as interactions between different neurotransmitter systems complicate interpretation. Future research might profitably explore these factors to provide a better understanding of effective treatment approaches.

Neurophysiological and Neurochemical Effects of the Putative Cognitive Enhancer (S)-CE-123 on Mesocorticolimbic Dopamine System

Treatments for cognitive impairments associated with neuropsychiatric disorders, such as attention deficit hyperactivity disorder or narcolepsy, aim at modulating extracellular dopamine levels in the brain. CE-123 (5-((benzhydrylsulfinyl)methyl) thiazole) is a novel modafinil analog with improved specificity and efficacy for dopamine transporter inhibition that improves cognitive and motivational processes in experimental animals. We studied the neuropharmacological and behavioral effects of the S-enantiomer of CE-123 ((S)-CE-123) and R-modafinil in cognitive- and reward-related brain areas of adult male rats. In vivo single unit recordings in anesthetized animals showed that (S)-CE-123, but not R-modafinil, dose-dependently (1.25 to 10 mg/kg i.v.) reduced firing of pyramidal neurons in the infralimbic/prelimbic (IL/PrL) cortex. Neither compound the affected firing activity of ventral tegmental area dopamine cells. In freely moving animals, (S)-CE-123 (10 mg/kg i.p.) increased extracellular dopamine levels in the IL/PrL, with different patterns when compared to R-modafinil (10 mg/kg i.p.); in the nucleus accumbens shell, a low and transitory increase of dopamine was observed only after (S)-CE-123. Neither (S)-CE-123 nor R-modafinil initiated the emission of 50-kHz ultrasonic vocalizations, a behavioral marker of positive affect and drug-mediated reward. Our data support previous reports of the procognitive effects of (S)-CE-123, and show a minor impact on reward-related dopaminergic areas.

Neurobiology of Anabolic-Androgenic Steroid Abuse

Anabolic-androgenic steroids (AAS) are both performance-enhancing substances and drugs of abuse. Although AAS are banned in competitive sports, they are widely used by both elite and rank-and-file athletes. All AAS are derived from testosterone, the principle endogenous androgen produced by the testes of adult men. While AAS increase muscular strength and athletic performance, they also have serious consequences for health and behavior. AAS are implicated in maladaptive behavioral and cognitive changes such as increased risk-taking and altered decision-making. However, effects of AAS on cognition are not well understood. Studies of human AAS users are limited by an inability to control for pre-existing psychopathology and behavioral differences. Furthermore, in order to understand AAS effects on behavior, it is important to discover how AAS impact the brain. Animal models of AAS abuse parallel human studies to uncover effects on cognition, decision-making, and underlying neurobiological mechanisms. In operant discounting tests, rats treated with chronic high-dose testosterone are less sensitive to effort, punishment, and delay but are more sensitive to uncertainty. Likewise, they demonstrate impaired cognitive flexibility when tested for set-shifting and reversal learning. It appears that AAS induce many of these cognitive changes via effects on the mesocorticolimbic dopamine system, particularly through the dopamine D1- and D2-like receptors in subnuclei of the nucleus accumbens. AAS also have rewarding effects mediated by similar neural circuits. In preclinical studies, animals will voluntarily self-administer AAS. Human users may develop dependence. These findings highlight the vulnerability of brain circuits controlling cognition and reward to androgens at high doses.

Effects of amphetamine exposure during adolescence on behavior and prelimbic cortex neuron activity in adulthood

Repeated exposure to psychostimulants during adolescence produces long-lasting changes in behavior that may be mediated by disrupted development of the mesocorticolimbic dopamine system. Here, we tested this hypothesis by assessing the effects of amphetamine (AMPH) and dopamine receptor-selective drugs on behavior and neuron activity in the prelimbic region of the medial prefrontal cortex (PFC). Adolescent male, Sprague-Dawley rats were given saline or 3 mg/kg AMPH between postnatal day (P) 27 and P45. In Experiment 1, locomotor behavior was assessed during adulthood following challenges with a dopamine D1 (SKF 82958) or D2 (quinpirole) receptor-selective agonist. In Experiment 2, pre-exposed rats were challenged during adulthood with AMPH and a D1 (SKF 83566) or D2 (eticlopride) receptor-selective antagonist. In Experiment 3, the activity of putative pyramidal cells in the prelimbic cortex was recorded as rats behaved in an open-field arena before and after challenge injections with AMPH and one of the antagonists. We found that compared to controls, adolescent pre-exposed rats were more sensitive to the stimulant effects of AMPH and the dopamine receptor agonists, as well as to the ability of the antagonists to reverse AMPH-induced stereotypy. Prelimbic neurons from AMPH pre-exposed rats were also more likely to respond to an AMPH challenge in adulthood, primarily by reducing their activity, and the antagonists reversed these effects. Our results suggest that exposure to AMPH during adolescence leads to enduring adaptations in the mesocorticolimbic dopamine system that likely mediate heightened response to the drug during adulthood.

Making the Case for ‘Power Abuse Disorder' as a Nosologic Entity

The development of societies and cultures arguably is based on the ability of human primates to form hierarchies in which some individuals acquire and wield power, that is, control resources and influence and control the behavior of their conspecifics. In the following, we focus on the type of human primate power wielding that (a) harms and (b) produces excessive negative emotions in (1) the victim(s) of the power wielder and (2) the power wielder her/himself. If such a harmful behavior of the power wielder is not accompanied by an ethically justifiable benefit for the involved human primate groups, it can be considered “power abuse.” We propose to term the associated behaviors, cognitions, and emotions of the power wielder as “power abuse disorder” (PAD). This behavior results from what we consider addictive behavior of the power abuse disordered (PADed) power wielder. PAD can be diagnosed on the basis of the World Health Organization's criteria for “dependence syndrome” as listed in the International Classification of Diseases version 10. We will demonstrate that many PADed individuals may very likely carry the Zeitgeist diagnosis “burnout.” This article reviews the current understanding of the neural correlates of PAD and suggests future research. Based on the available evidence, PAD seems to be associated with a dysfunction of the mesocorticolimbic dopamine system, rendering PADed individuals vulnerable for psychostimulant abuse/dependence, and suggesting specific pharmacotherapeutic approaches to treat PAD.