?CaMKII Autophosphorylation Controls the Establishment of Alcohol-Induced Conditioned Place Preference in Mice.

?CaMKII autophosphorylation controls the establishment of alcohol-induced conditioned place preference in mice.

Behav Brain Res. 2013 May 31;
Easton AC, Lucchesi W, Mizuno K, Fernandes C, Schumann G, Giese KP, Müller CP

The autophosphorylation of alpha Ca(2+)/calmodulin dependent protein kinase II (?CaMKII) is important for memory formation and is becoming increasingly implicated in the development of drug addiction. Previous work suggests that ?CaMKII acts via the monoaminergic systems to facilitate the establishment of alcohol drinking behaviour. The present study aims to investigate whether ?CaMKII autophosphorylation deficient ?CaMKII(T286A) mice show a difference in the rewarding properties of alcohol (2g/kg, i.p.), as measured by conditioned place preference (CPP). We found that alcohol-induced CPP could be established at an accelerated rate in ?CaMKII(T286A) compared to wild type (WT) mice. Hyperactivity/hyper-arousal induced by the test environment was normalized by alcohol in the ?CaMKII(T286A), but not WT mice. This effect could be conditioned to the test environment and may suggest enhanced negative reinforcing action of alcohol in ?CaMKII autophosphorylation deficient mice. HubMed – addiction


Synthesis and preclinical evaluation of [(11)C-carbonyl]PF-04457845 for neuroimaging of fatty acid amide hydrolase.

Nucl Med Biol. 2013 May 31;
Hicks JW, Parkes J, Sadovski O, Tong J, Houle S, Vasdev N, Wilson AA

INTRODUCTION: Fatty acid amide hydrolase (FAAH) has a significant role in regulating endocannabinoid signaling in the central nervous system. As such, FAAH inhibitors are being actively sought for pain, addiction, and other indications. This has led to the recent pursuit of positron emission tomography (PET) radiotracers targeting FAAH. We report herein the preparation and preclinical evaluation of [(11)C-carbonyl]PF-04457845, an isotopologue of the potent irreversible FAAH inhibitor. METHODS: PF-04457845 was radiolabeled at the carbonyl position via automated [(11)C]CO2-fixation. Ex vivo brain biodistribution of [(11)C-carbonyl]PF-04457845 was carried out in conscious rats. Specificity was determined by pre-administration of PF-04457845 or URB597 prior to [(11)C-carbonyl]PF-04457845. In a separate experiment, rats injected with the title radiotracer had whole brains excised, homogenized and extracted to examine irreversible binding to brain parenchyma. RESULTS: The title compound was prepared in 5±1% (n=4) isolated radiochemical yield based on starting [(11)C]CO2 (decay uncorrected) within 25min from end-of-bombardment in >98% radiochemical purity and a specific activity of 73.5±8.2GBq/?mol at end-of-synthesis. Uptake of [(11)C-carbonyl]PF-04457845 into the rat brain was high (range of 1.2-4.4 SUV), heterogeneous, and in accordance with reported FAAH distribution. Saturable binding was demonstrated by a dose-dependent reduction in brain radioactivity uptake following pre-treatment with PF-04457845. Pre-treatment with the prototypical FAAH inhibitor, URB597, reduced the brain radiotracer uptake in all regions by 71-81%, demonstrating specificity for FAAH. The binding of [(11)C-carbonyl]PF-04457845 to FAAH at 40min post injection was irreversible as 98% of the radioactivity in the brain could not be extracted. CONCLUSIONS: [(11)C-carbonyl]PF-04457845 was rapidly synthesized via an automated radiosynthesis. Ex vivo biodistribution studies in conscious rodents demonstrate that [11C PF-04457845 is a promising candidate radiotracer for imaging FAAH in the brain with PET. These results coupled with the known pharmacology and toxicology of PF-04457845 should facilitate clinical translation of this radiotracer. HubMed – addiction


Low dopamine transporter occupancy by methylphenidate as a possible reason for reduced treatment effectiveness in ADHD patients with cocaine dependence.

Eur Neuropsychopharmacol. 2013 May 31;
Crunelle CL, van den Brink W, Veltman DJ, van Emmerik-van Oortmerssen K, Dom G, Schoevers RA, Booij J

Methylphenidate (MPH) occupies brain striatal dopamine transporters (DATs) and is an effective treatment for attention deficit hyperactivity disorder (ADHD). However, patients with ADHD and comorbid cocaine dependence do not benefit significantly from treatment with MPH. To better understand the neurobiology of this phenomenon, we examined DAT availability and the effects of MPH treatment on DAT occupancy in ADHD patients with and without cocaine dependence. ADHD patients without a comorbid substance use disorder (N=16) and ADHD patients with comorbid cocaine dependence (N=8) were imaged at baseline and after two weeks MPH treatment using single photon emission computed tomography (SPECT) with the DAT tracer [(123)I]FP-CIT. Changes in ADHD symptoms were measured with the ADHD symptom rating scale (ASRS). At baseline, we observed lower striatal DAT availability in ADHD patients with cocaine dependence. Following fixed MPH treatment, MPH occupied significantly less striatal DATs in cocaine-dependent than in non-cocaine dependent ADHD patients. There were no significant correlations between baseline DAT availability or DAT occupancy by MPH and ADHD symptom improvement. However, we did find significant correlations between DAT occupancy by MPH and decreases in impulsivity scores and years of cocaine use. These preliminary findings suggest that low DAT occupancy is not the reason why ADHD patients with cocaine dependence do not benefit from MPH treatment. It also suggests that higher dosages of MPH in these patients are probably not the solution and that medications directed at other pharmacological targets should be considered in these comorbid ADHD patients. This trial is registered at the Dutch Trial Register, www.trialregister.nl, under Trial ID number NTR3127. HubMed – addiction