The bed nucleus of the stria terminalis (BNST) is involved in the mediation of fear behavior in rats. A previous study of our laboratory demonstrated that temporary inactivation of the BNST blocks fear behavior induced by exposure to trimethylthiazoline (TMT), a component of fox odor. The present study investigates whether noradrenaline release within the BNST is critical for TMT-induced fear behavior. First, we confirmed previous studies showing that the ventral BNST is the part of the BNST that receives the densest noradrenaline innervation. Second, using in vivo microdialysis, we showed that noradrenaline release within the BNST is strongly increased during TMT exposure, and that this increase can be blocked by local infusions of the ␣ 2 -receptor blocker clonidine. Third, using intracerebral injections, we showed that clonidine injections into the ventral BNST, but not into neighboring brain sites, completely blocked TMTinduced potentiation of freezing behavior. The present data clearly show that the noradrenergic innervation of the ventral BNST is important for the full expression of behavioral signs of fear to the predator odor TMT.

Phosphodiesterase 10A (PDE10A) plays a key role in the regulation of brain striatal signaling, and several pharmaceutical companies currently investigate PDE10A inhibitors in clinical trials for various central nervous system diseases. A PDE10A PET ligand may provide evidence that a clinical drug candidate reaches and binds to the target. Here we describe the successful discovery and initial validation of the novel radiolabeled PDE10A ligand 5,8-dimethyl-2-[2-((1-11 C-methyl)-4-phenyl-1H-imidazol-2-yl)-ethyl]-[1,2,4]triazolo [1,5-a]pyridine ( 11 C-Lu AE92686) and its tritiated analog 3 H-Lu AE92686. Methods: Initial in vitro experiments suggested Lu AE92686 as a promising radioligand, and the corresponding tritiated and 11 C-labeled compounds were synthesized. 3 H-Lu AE92686 was evaluated as a ligand for in vivo occupancy studies in mice and rats, and 11 C-Lu AE92686 was evaluated as a PET tracer candidate in cynomolgus monkeys and in humans. Results: 11 C-Lu AE92686 displayed high specificity and selectivity for PDE10A-expressing regions in the brain of cynomolgus monkeys and humans. Similar results were found in rodents using 3 H-Lu AE92686. The binding of 11 C-Lu AE92686 and 3 H-Lu AE92686 to striatum was completely and dose-dependently blocked by the structurally different PDE10A inhibitor 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (MP-10) in rodents and in monkeys. In all species, specific binding of the radioligand was seen in the striatum but not in the cerebellum, supporting the use of the cerebellum as a reference region. The binding potentials (BP ND ) of 11 C-Lu AE92686 in the striatum of both cynomolgus monkeys and humans were evaluated by the simplified reference tissue model with the cerebellum as the reference tissue, and BP ND was found to be high and reproducible-that is, BP ND s were 6.5 ± 0.3 (n 5 3) and 7.5 ± 1.0 (n 5 12) in monkeys and humans, respectively. Conclusion: Rodent, monkey, and human tests of labeled Lu AE92686 suggest that 11 C-Lu AE92686 has great potential as a human PET tracer for the PDE10A enzyme.Key Words: 11 C; 3 H; PET; PDE10A; brain imaging; Lu AE92686 J Nucl Med 2014; 55:1513 55: -1518 55: DOI: 10.2967 Phosphodi esterase 10A (PDE10A) is predominantly expressed in medium spiny neurons and plays a key role in striatal signaling. During the past 10 y, large efforts have been made to develop PDE10A inhibitors for the treatment of schizophrenia (1-3). Preclinical evidence in several animal models suggests that PDE10A inhibitors can improve positive, negative, and cognitive symptoms of schizophrenia, and current clinical trials evaluate PDE10A inhibitors for the treatment of schizophrenia (4). Noninvasive imaging techniques such as PET may be useful for the clinical development of PDE10A inhibitors, because they may provide comparative data on the expression of the enzyme in healthy individuals and in individuals with brain disorders. Furthermore, a PDE10A PET ligand can be used to provide evidence that a clinical drug candidate reaches and bind...

ObjectiveTo evaluate efficacy and safety of lacosamide (up to 12 mg/kg/day or 400 mg/day) as adjunctive treatment for uncontrolled primary generalised tonic-clonic seizures (PGTCS) in patients (≥4 years) with idiopathic generalised epilepsy (IGE).MethodsPhase 3, double-blind, randomised, placebo-controlled trial (SP0982; NCT02408523) in patients with IGE and PGTCS taking 1–3 concomitant antiepileptic drugs. Primary outcome was time to second PGTCS during 24-week treatment.Results242 patients were randomised and received ≥1 dose of trial medication (lacosamide/placebo: n=121/n=121). Patients (mean age: 27.7 years; 58.7% female) had a history of generalised-onset seizures (tonic-clonic 99.6%; myoclonic 38.8%; absence 37.2%). Median treatment duration with lacosamide/placebo was 143/65 days. Risk of developing a second PGTCS during 24-week treatment was significantly lower with lacosamide than placebo (Kaplan-Meier survival estimates 55.27%/33.37%; HR 0.540, 95% CI 0.377 to 0.774; p<0.001; n=118/n=121). Median time to second PGTCS could not be estimated for lacosamide (>50% of patients did not experience a second PGTCS) and was 77.0 days for placebo. Kaplan-Meier estimated freedom from PGTCS at end of the 24-week treatment period (day 166) for lacosamide/placebo was 31.3%/17.2% (difference 14.1%; p=0.011). More patients on lacosamide than placebo had ≥50% (68.1%/46.3%) or ≥75% (57.1%/36.4%) reduction from baseline in PGTCS frequency/28 days, or observed freedom from PGTCS during treatment (27.5%/13.2%) (n=119/n=121). 96/121 (79.3%) patients on lacosamide had treatment-emergent adverse events (placebo 79/121 (65.3%)), most commonly dizziness (23.1%), somnolence (16.5%), headache (14.0%). No patients died during the trial.ConclusionsLacosamide was efficacious and generally safe as adjunctive treatment for uncontrolled PGTCS in patients with IGE.

No abstract

Nalmefene blunts BOLD response in the mesolimbic system during anticipation of monetary reward and an alcohol infusion. This is consistent with nalmefene's actions on opioid receptors, which modulate the mesolimbic dopaminergic system, and provides a neurobiological basis for its efficacy.