No abstract

Salvia divinorum, a mint plant originally used by the Mazatecs of Oaxaca, Mexico in spiritual rituals has gained popularity, in smoked form, as a legal hallucinogen in the United States and Europe. Abuse results in rapid onset and short-lasting effects that include visual hallucinations and motor-function impairment. Salvinorin A, the psychoactive component of S. divinorum, is a uniquely potent agonist at kappa-opioid receptors, targets for new therapeutic drugs. We labeled salvinorin A with C-11 by acylation of salvinorin B with [11C]-acetyl chloride to study whether its kinetic behavior in the brain parallels its uniquely fast, yet brief physiological effects. Positron emission tomography (PET) studies performed in 6 adult female baboons indicated extremely rapid brain uptake reaching a peak accounting for 3.3% of the total administered dose in 40 s and clearing with a half-life of 8 min. [11C]-salvinorin A was distributed throughout the brain with the highest concentration in the cerebellum and a notable concentration in the visual cortex, perhaps accounting for its physiological effects when smoked. Naloxone administration did not reduce the overall concentration of [11C]-salvinorin A significantly nor did it change its regional distribution. Peripheral organ kinetics suggested at least two modes of metabolism and excretion occur: through the renal and biliary systems. Our findings have revealed that the exceptionally rapid uptake and brief duration of salvinorin A in the brain match the time-course of visual hallucinations for S. divinorum when smoked. The effects of salvinorin A may occur at <10 mug in the human brain, emphasizing its remarkable potency.

The factors that determine symptom penetrance in inherited disease are poorly understood. Increasingly, magnetic resonance diffusion tensor imaging (DTI) and PET are used to separate alterations in brain structure and function that are linked to disease symptomatology from those linked to gene carrier status. One example is DYT1 dystonia, a dominantly inherited movement disorder characterized by sustained muscle contractions, postures, and/or involuntary movements. This form of dystonia is caused by a 3-bp deletion (i.e., ΔE) in the TOR1A gene that encodes torsinA. Carriers of the DYT1 dystonia mutation, even if clinically nonpenetrant, exhibit abnormalities in cerebellothalamocortical (CbTC) motor pathways. However, observations in human gene carriers may be confounded by variability in genetic background and age. To address this problem, we implemented a unique multimodal imaging strategy in a congenic line of DYT1 mutant mice that contain the ΔE mutation in the endogenous mouse torsinA allele (i.e., DYT1 knock-in). Heterozygous knock-in mice and littermate controls underwent micro-PET followed by ex vivo high-field DTI and tractographic analysis. Mutant mice, which do not display abnormal movements, exhibited significant CbTC tract changes as well as abnormalities in brainstem regions linking cerebellar and basal ganglia motor circuits highly similar to those identified in human nonmanifesting gene carriers. Moreover, metabolic activity in the sensorimotor cortex of these animals was closely correlated with individual measures of CbTC pathway integrity. These findings further link a selective brain circuit abnormality to gene carrier status and demonstrate that DYT1 mutant torsinA has similar effects in mice and humans.connectivity | regional metabolism | brain networks I n recent years, advanced imaging technologies such as PET and magnetic resonance diffusion tensor imaging (DTI) have provided unique information regarding the impact of specific genetic mutations on brain structure and function. However, to control for variability in genetic background and additional confounders such as age and sex, many more mutation carriers (and control subjects) are required than can conveniently be scanned, even in a multicenter design. Human imaging studies may also suffer from relatively low spatial resolution and sensitivity. These considerations motivated the current study in which high field magnetic resonance DTI was performed ex vivo in an experimental genetic model of a brain disorder.Primary dystonia is a childhood-onset neurological illness characterized by disabling abnormal involuntary movements without consistent brain lesions on routine structural brain imaging or at postmortem analysis (1). This disorder is associated with several genotypes (2). DYT1 dystonia, the most common inherited form of the disease, is caused by a dominantly inherited 3-bp in-frame deletion in the TOR1A gene that removes a single glutamic acid (ΔE) from the torsinA protein (3). This lowprevalence mutation (approximately 1 in 30,000...

Medically-refractory seizures cause inflammation and neurodegeneration. Seizure initiation thresholds have been linked in mice to the serine protease tissue plasminogen activator (tPA); mice lacking tPA exhibit resistance to seizure induction, and the ensuing inflammation and neurodegeneration are similarly suppressed. Seizure foci in humans can be examined using PET employing 2-deoxy-2[ 18 F]fluoro-D-glucose ( 18 FDG) as a tracer to visualize metabolic dysfunction. However, there currently exist no such methods in mice to correlate measures of brain activation with behaviour. Using a novel method for small animal PET data analysis, we examine patterns of 18 FDG uptake in wild type and tPA -/-mice and find that they correlate with the severity of druginduced seizure initiation. Furthermore, we report unexpected activations that may underlie the tPA modulation of seizure susceptibility. The methods described here should be applicable to other mouse models of human neurological disease.