The blood-brain barrier and a bloodcerebrospinal-fluid (CSF) barrier function together to isolate the brain from circulating drugs, toxins, and xenobiotics. The blood-CSF drug-permeability barrier is localized to the epithelium of the choroid plexus (CP). However, the molecular mechanisms regulating drug permeability across the CP epithelium are defined poorly. Herein, we describe a drug-permeability barrier in human and rodent CP mediated by epithelial-specific expression of the MDR1 (multidrug resistance) P glycoprotein (Pgp) and the multidrug resistance-associated protein (MRP). Noninvasive single-photon-emission computed tomography with 99m Tcsestamibi, a membrane-permeant radiopharmaceutical whose transport is mediated by both Pgp and MRP, shows a large blood-to-CSF concentration gradient across intact CP epithelium in humans in vivo. In rats, pharmacokinetic analysis with 99m Tc-sestamibi determined the concentration gradient to be greater than 100-fold. In membrane fractions of isolated native CP from rat, mouse, and human, the 170-kDa Pgp and 190-kDa MRP are identified readily. Furthermore, the murine proteins are absent in CP isolated from their respective mdr1a͞1b(؊͞؊) and mrp(؊͞؊) gene knockout littermates. As determined by immunohistochemical and drug-transport analysis of native CP and polarized epithelial cell cultures derived from neonatal rat CP, Pgp localizes subapically, conferring an apical-to-basal transepithelial permeation barrier to radiolabeled drugs. Conversely, MRP localizes basolaterally, conferring an opposing basal-to-apical drug-permeation barrier. Together, these transporters may coordinate secretion and reabsorption of natural product substrates and therapeutic drugs, including chemotherapeutic agents, antipsychotics, and HIV protease inhibitors, into and out of the central nervous system.

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Neurturin (NTN) is a neuronal survival factor that activates the Ret tyrosine kinase in the presence of a GPI-linked coreceptor (either GFR alpha1 or GFR alpha2). Neurturin-deficient (NTN-/-) mice generated by homologous recombination are viable and fertile but have defects in the enteric nervous system, including reduced myenteric plexus innervation density and reduced gastrointestinal motility. Parasympathetic innervation of the lacrimal and submandibular salivary gland is dramatically reduced in NTN-/- mice, indicating that Neurturin is a neurotrophic factor for parasympathetic neurons. GFR alpha2-expressing cells in the trigeminal and dorsal root ganglia are also depleted in NTN-/- mice. The loss of GFR alpha2-expressing neurons, in conjunction with earlier studies, provides strong support for GFR alpha2/Ret receptor complexes as the critical mediators of NTN function in vivo.

Glucocorticoids (GCs) have a variety of effects on the brain including site-preferential, inhibitory effects on hippocampal neurons. In the case of dexamethasone (DEX), extended rather than single-dose treatment in vivo may be required for binding to brain rather than peripheral (e.g., pituitary) GC receptors and for maximizing other biologic effects in hippocampus (e.g., GC receptor downregulation, inhibition of glucose transport). Based on the contributory role of hippocampal neurons in declarative memory performance, we investigated the cognitive consequences of DEX treatment in normal adult human subjects, hypothesizing a decrease in declarative memory performance after extended but not overnight treatment. Double-blind, placebo-controlled treatment with DEX was given at 2300 hr for four consecutive days (0.5, 1, 1, 1 mg, respectively). Plasma sampling (0800 and 1600 hr) and cognitive testing (1600 hr) were performed on study days 0 (baseline), 1, and 4, and 7 d posttreatment. Repeated-measures ANOVA found a significant interaction between study day and treatment condition for correct recall during a paragraph recall task [F(3,51) = 3.52, p = 0.02]. DEX (n = 10) in comparison to placebo (n = 9) treatment decreased correct paragraph recall on study day 4 [F(1,17) = 5.01, p = 0.04] and study day 11 [F(1,17) = 5.82, p = 0.03], with the lowest level of performance occurring on day 4 followed by a return toward baseline performance level by day 11. In the placebo-treated subjects, correct paragraph recall improved over the course of treatment, consistent with practice.(ABSTRACT TRUNCATED AT 250 WORDS)

Fibroblast growth factor 14 (FGF14) belongs to a distinct subclass of FGFs that is expressed in the developing and adult CNS. We disrupted the Fgf14 gene and introduced an Fgf14(N-beta-Gal) allele that abolished Fgf14 expression and generated a fusion protein (FGF14N-beta-gal) containing the first exon of FGF14 and beta-galactosidase. Fgf14-deficient mice were viable, fertile, and anatomically normal, but developed ataxia and a paroxysmal hyperkinetic movement disorder. Neuropharmacological studies showed that Fgf14-deficient mice have reduced responses to dopamine agonists. The paroxysmal hyperkinetic movement disorder phenocopies a form of dystonia, a disease often associated with dysfunction of the putamen. Strikingly, the FGF14N-beta-gal chimeric protein was efficiently transported into neuronal processes in the basal ganglia and cerebellum. Together, these studies identify a novel function for FGF14 in neuronal signaling and implicate FGF14 in axonal trafficking and synaptosomal function.

Background-There has been a dramatic rise in the consumption of alcohol mixed with energy drinks (AmED) in young people. AmEDs have been implicated in risky drinking practices and greater accidents and injuries have been associated with their consumption. Despite the increased popularity of these beverages (e.g., Red Bull and vodka), there is little laboratory research examining how the effects of AmED differ from alcohol alone. This experiment was designed to investigate if the consumption of AmED alters neurocognitive and subjective measures of intoxication compared with the consumption of alcohol alone.

Previous research has implicated dopamine as a modulating factor in choice behavior based on effort. The purpose of the present study was to determine the individual contribution of different dopamine receptors to effort-based decision-making in rats. Rats were trained in a T-maze to choose a large-reward arm that contained eight pellets of food over a small-reward arm that contained two pellets of food. The rats then were trained to climb progressively higher barriers in order to obtain the food from the large-reward arm. Using a discounting procedure on each test day, it was found that rats were more likely to choose the small-reward arm after treatment with the D 1 antagonist, SCH-23390, or the D 2 antagonist, haloperidol. The dopamine agonist, Damphetamine, biased the rats towards choosing the large-reward arm and blunted the effects of SCH-23390 or haloperidol. Treatment with the D 3 receptor antagonist, U99194, or the D 3 receptor agonist, 7-OH-DPAT, did not alter choice behavior. These data indicate that D 1 and D 2 receptors are required for decisions based on effort. KeywordsDopamine receptor; choice behavior; T-maze; amphetamine; haloperidol; SCH-23390 Decision-making is influenced by many factors. A multitude of empirical work has characterized developmental, cultural, and environmental factors that modify decisionmaking. Moreover, research has started to reveal the neurobiological determinants of decision-making. To date, most of the neurobiological work has focused on how the probability of a particular outcome or the delay between a given response and outcome can influence choice behavior (see Cardinal, 2006, for review). The amount of effort required to achieve a particular outcome also constrains choice behavior, and the biological basis of such effort-based decision-making has begun to receive attention over the last several years.In most studies of effort-based decision-making, animals are provided with a choice between a large food reward and a small food reward, but the animals are required to exert greater Correspondence concerning this article should be addressed to Mark E. Bardgett, Department of Psychology, Northern Kentucky University, 1 Nunn Drive, Highland Heights, KY 41076. bardgettm@nku.edu. NIH Public Access Author ManuscriptBehav Neurosci. Author manuscript; available in PMC 2009 December 10. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscripteffort to obtain the large reward. Research over the past several years has endeavored to identify the brain regions responsible for such decision-making. Initial work by Salamone and colleagues (Cousins, Atherton, Turner, & Salamone, 1996;Salamone, Cousins, & Bucher, 1994) found that dopamine depletion in the nucleus accumbens biased rats towards making less effortful choices in a T-maze cost-benefit procedure. Walton, Bannerman, and Rushworth (2002) later showed that relatively large lesions of the medial prefrontal cortex in rats also reduced the likelihood of effortful choices. This same group (Walton, Ban...

Mutations in ATP13A2 (PARK9), encoding a lysosomal P-type ATPase, are associated with both Kufor-Rakeb syndrome (KRS) and neuronal ceroid lipofuscinosis (NCL). KRS has recently been classified as a rare genetic form of Parkinson's disease (PD), whereas NCL is a lysosomal storage disorder. Although the transport activity of ATP13A2 has not been defined, in vitro studies show that its loss compromises lysosomal function, which in turn is thought to cause neuronal degeneration. To understand the role of ATP13A2 dysfunction in disease, we disrupted its gene in mice. Atp13a2(-/-) and Atp13a2(+/+) mice were tested behaviorally to assess sensorimotor and cognitive function at multiple ages. In the brain, lipofuscin accumulation, α-synuclein aggregation and dopaminergic pathology were measured. Behaviorally, Atp13a2(-/-) mice displayed late-onset sensorimotor deficits. Accelerated deposition of autofluorescent storage material (lipofuscin) was observed in the cerebellum and in neurons of the hippocampus and the cortex of Atp13a2(-/-) mice. Immunoblot analysis showed increased insoluble α-synuclein in the hippocampus, but not in the cortex or cerebellum. There was no change in the number of dopaminergic neurons in the substantia nigra or in striatal dopamine levels in aged Atp13a2(-/-) mice. These results show that the loss of Atp13a2 causes sensorimotor impairments, α-synuclein accumulation as occurs in PD and related synucleinopathies, and accumulation of lipofuscin deposits characteristic of NCL, thus providing the first direct demonstration that null mutations in Atp13a2 can cause pathological features of both diseases in the same organism.