Brain Exposure (brain + exposure)

Distribution by Scientific Domains
Medical Sciences100%

Selected Abstracts

Approaches to the development of medications for the treatment of methamphetamine dependence

ADDICTION, Issue 2007
Frank J. Vocci
ABSTRACT Background Methamphetamine abuse has become an increasing problem in both the United States and globally with concomitant increases in adverse medical, social and environmental sequelae. Behavioral therapies have been used with some success to treat methamphetamine abusers and dependent individuals, but are not universally efficacious. Methamphetamine has a rich pharmacology that theoretically provides many opportunities for potential pharmacotherapeutic intervention. Nevertheless, there are no approved medications with an indication for treating methamphetamine abusers or addicts at this time. Aim To describe briefly how methamphetamine functions and affects function in brain and report how basic researchers and clinicians are attempting to exploit and exploiting this knowledge to discover and develop effective pharmacotherapies. Results Scientifically based approaches to medications development by evaluating medications that limit brain exposure to methamphetamine; modulate methamphetamine effects at vesicular monoamine transporter-2 (VMAT-2); or affect dopaminergic, serotonergic, GABAergic, and/or glutamatergic brain pathways that participate in methamphetamine's reinforcing effects are presented. Conclusion The evidence supports the rationale that pharmacotherapies to decrease methamphetamine use, or reduce craving during abstinence may be developed from altering the pharmacokinetics and pharmacodynamics of methamphetamine or its effects on appetitive systems in the brain. [source]

Effect of pulsatile administration of levodopa on dyskinesia induction in drug-naïve MPTP-treated common marmosets: Effect of dose, frequency of administration, and brain exposure

MOVEMENT DISORDERS, Issue 5 2003
Lance A. Smith MSc
Abstract Levodopa (L -dopa) consistently primes basal ganglia for the appearance of dyskinesia in parkinsonian patients and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) -treated primates. This finding may reflect its relatively short duration of effects resulting in pulsatile stimulation of postsynaptic dopamine receptors in the striatum. We have compared the relationship between L -dopa dose and frequency of administration on dyskinesia initiation in drug-naïve, MPTP-treated common marmosets. We have also studied the effect of increased brain exposure to pulsatile administration by combining a low-dose of L -dopa with the peripheral catechol- O -methyltransferase inhibitor (COMT-I), entacapone. Pulsatile administration of a low (dose range, 5.0,7.5 mg/kg p.o.) or a high (12.5 mg/kg) dose of L -dopa plus carbidopa b.i.d. produced a dose-related reversal of motor deficits. Repeated administration of low and high doses of L -dopa for 26 days to drug-naïve, MPTP-treated animals also caused a dose-related induction of peak-dose dyskinesia. Repeated administration of high-dose L -dopa b.i.d. compared to once daily caused a frequency-related improvement of motor symptoms, resulting in a more rapid and initially more intense appearance of peak-dose dyskinesia. Administration of low-dose L -dopa b.i.d. for 26 days in combination with entacapone enhanced the increase in locomotor activity and reversal of disability produced by L -dopa alone, but with no obvious change in duration of L -dopa's effect. However, combining entacapone with L -dopa resulted in the more rapid appearance of dyskinesia, which was initially more severe than occurred with L -dopa alone. Importantly, increasing pulsatile exposure of brain to L -dopa by preventing its peripheral breakdown also increases dyskinesia induction. © 2003 Movement Disorder Society [source]

Differential effects of cannabinoid receptor agonists on regional brain activity using pharmacological MRI

BRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2008
C-L Chin
Background and purpose: Activation of cannabinoid CB1 and/or CB2 receptors mediates analgesic effects across a broad spectrum of preclinical pain models. Selective activation of CB2 receptors may produce analgesia without the undesirable psychotropic side effects associated with modulation of CB1 receptors. To address selectivity in vivo, we describe non-invasive, non-ionizing, functional data that distinguish CB1 from CB2 receptor neural activity using pharmacological MRI (phMRI) in awake rats. Experimental approach: Using a high field (7 T) MRI scanner, we examined and quantified the effects of non-selective CB1/CB2 (A-834735) and selective CB2 (AM1241) agonists on neural activity in awake rats. Pharmacological specificity was determined using selective CB1 (rimonabant) or CB2 (AM630) antagonists. Behavioural studies, plasma and brain exposures were used as benchmarks for activity in vivo. Key results: The non-selective CB1/CB2 agonist produced a dose-related, region-specific activation of brain structures that agrees well with published autoradiographic CB1 receptor density binding maps. Pretreatment with a CB1 antagonist but not with a CB2 antagonist, abolished these activation patterns, suggesting an effect mediated by CB1 receptors alone. In contrast, no significant changes in brain activity were found with relevant doses of the CB2 selective agonist. Conclusion and implications: These results provide the first clear evidence for quantifying in vivo functional selectivity between CB1 and CB2 receptors using phMRI. Further, as the presence of CB2 receptors in the brain remains controversial, our data suggest that if CB2 receptors are expressed, they are not functional under normal physiological conditions. British Journal of Pharmacology (2008) 153, 367,379; doi:10.1038/sj.bjp.0707506; published online 29 October 2007 [source]