Dependence, withdrawal and rebound of CNS drugs: an update and regulatory considerations for new drugs development.

The purpose of this article is to describe dependence and withdrawal phenomena related to CNS drugs discontinuation and to clarify issues related to the evaluation of clinical drug withdrawal and rebound as they relate to safety in new drug development. The article presents current understanding and definitions of drug dependence and withdrawal which are also relevant and important features of addiction, though not the same. Addiction, called substance use disorder in DSM-5, affects an individual's brain and behaviour, represents uncontrollable drug abuse and inability to stop taking a drug regardless of the harm it causes.

Altered cerebral benzodiazepine receptor binding in post-traumatic stress disorder.

Agonists of the γ-aminobutyric acid (GABA) type A benzodiazepine (BZD) receptor exert anxiolytic effects in anxiety disorders, raising the possibility that altered GABA-ergic function may play a role in the pathophysiology of anxiety disorders, such as post-traumatic stress disorder (PTSD). However, few neuroimaging studies have assessed the function or binding potential of the central GABA BZD receptor system in PTSD. Therefore, our aim was to compare the BZD receptor binding potential between PTSD patients and healthy controls.

Remission of Gilles de la Tourette Syndrome after Heat-Induced Dehydration.

Heat has been reported to exert variable effects on people with Gilles de la Tourette syndrome (TS). At age 24 years, a 32-year-old right-handed man with TS experienced a marked reduction in tics for two years after undergoing dehydration by entering a hot tub at 103°F (39.4°C) to 104°F (40.

Loss of inhibition in sensorimotor networks in focal hand dystonia.

Objective: To investigate GABA-ergic receptor density and associated brain functional and grey matter changes in focal hand dystonia (FHD).

Methods: 18 patients with FHD of the right hand and 18 age and gender matched healthy volunteers (HV) participated in this study. We measured the density of GABA-A receptors using [C] Flumazenil and perfusion using [O] HO.

Widespread abnormality of the γ-aminobutyric acid-ergic system in Tourette syndrome.

Dysfunction of the γ-aminobutyric acid-ergic system in Tourette syndrome may conceivably underlie the symptoms of motor disinhibition presenting as tics and psychiatric manifestations, such as attention deficit hyperactivity disorder and obsessive-compulsive disorder. The purpose of this study was to identify a possible dysfunction of the γ-aminobutyric acid-ergic system in Tourette patients, especially involving the basal ganglia-thalamo-cortical circuits and the cerebellum. We studied 11 patients with Tourette syndrome and 11 healthy controls.

Quantitation of cannabinoid CB1 receptors in healthy human brain using positron emission tomography and an inverse agonist radioligand.

[11C]MePPEP is a high affinity, CB1 receptor-selective, inverse agonist that has been studied in rodents and monkeys. We examined the ability of [11C]MePPEP to quantify CB1 receptors in human brain as distribution volume calculated with the "gold standard" method of compartmental modeling and compared results with the simple measure of brain uptake. A total of 17 healthy subjects participated in 26 positron emission tomography (PET) scans, with 8 having two PET scans to assess retest variability.

Decreased neurokinin-1 (substance P) receptor binding in patients with panic disorder: positron emission tomographic study with [18F]SPA-RQ.

Background: Positron emission tomography (PET) can localize and quantify neurokinin-1 (NK(1)) receptors in brain using the nonpeptide antagonist radioligand, [(18)F]SPA-RQ. We sought to determine if patients with panic disorder have altered density of NK(1) receptors in brain because of their history of recurrent panic attacks. We also sought to determine if a drug-induced panic attack releases substance P in brain, as measured by decreased binding of [(18)F]SPA-RQ.

Involvement of insula and cingulate cortices in control and suppression of natural urges.

The physiology of control and suppression of natural urges is not well understood. We used [(15)O]H(2)O positron-emission tomography imaging to identify neural circuits involved in suppression of spontaneous blinking as a model of normal urges. Suppression of blinking was associated with prominent activation of bilateral insular-claustrum regions, right more than left; activation was also found in bilateral anterior cingulate cortex (ACC), supplementary motor areas, and the face area of the primary motor cortex bilaterally.

Olfactory pathogenesis of idiopathic Parkinson disease revisited.

Idiopathic Parkinson disease (PD) is traditionally considered a movement disorder with hallmark lesions located in the substantia nigra pars compacta (SNpc). However, recent histopathological studies of some PD cases suggest the possibility of a multisystem disorder which progresses in a predictable sequence as described in Braak's staging criteria. The disease process starts in the dorsal motor nucleus of the vagus (dmX) and anterior olfactory nucleus and bulb, and from there, spreads through the brainstem nuclei to ultimately reach the SNpc, which then presents as symptomatic PD.

Small effect of dopamine release and no effect of dopamine depletion on [18F]fallypride binding in healthy humans.

Molecular imaging has been used to estimate both drug-induced and tonic dopamine release in the striatum and most recently extrastriatal areas of healthy humans. However, to date, studies of drug-induced and tonic dopamine release have not been performed in the same subjects. This study performed positron emission tomography (PET) with [18F]fallypride in healthy subjects to assess (1) the reproducibility of [18F]fallypride and (2) both D-amphetamine-induced and alpha-methyl-p-tyrosine (AMPT)-induced changes in dopamin release on [(18)F]fallypride binding in striatal and extrastriatal areas.

Increased midbrain gray matter in Tourette's syndrome.

Objective: To investigate cerebral structure in Tourette's syndrome (TS).

Methods: Voxel-based morphometry study of high-resolution MRIs in 31 TS patients compared with 31 controls.

Results: Increased gray matter mainly in the left mesencephalon in 31 TS patients.

Brain incorporation of 11C-arachidonic acid, blood volume, and blood flow in healthy aging: a study with partial-volume correction.

Unlabelled: PET with 11C-arachidonic acid (AA) can be used to quantify neural signaling related to phospholipase A2 (PLA2). Animal studies suggest reduction in the activity of this signaling system with age. The aim of this study was to evaluate the effect of healthy aging on brain incorporation of 11C-AA, before and after partial-volume correction (PVC).

Serotonin transporter: gene, genetic disorders, and pharmacogenetics.

The highly evolutionarily conserved serotonin transporter (SERT) regulates the entire serotoninergic system and its receptors via modulation of extracellular fluid serotonin concentrations. Differences in SERT expression and function produced by three SERT genes and their variants show associations with multiple human disorders. Screens of DNA from patients with autism, ADHD, bipolar disorder, and Tourette's syndrome have detected signals in the chromosome 17q region where SERT is located.

Regional cerebral blood flow correlates of the severity of writer's cramp symptoms.

Unlabelled: Writer's cramp is a type of idiopathic focal dystonia with incompletely understood pathophysiology. Recent studies provide evidence that one element might be a sensory processing defect. We performed a PET study with O(15) H(2)O to find out in which brain areas activity correlates with the severity of writer's cramp symptoms.