The Size, Burden and Cost of Disorders of the Brain in the UK.

The size, burden and cost of disorders of the brain in the UK.

J Psychopharmacol. 2013 Jul 24;
Fineberg NA, Haddad PM, Carpenter L, Gannon B, Sharpe R, Young AH, Joyce E, Rowe J, Wellsted D, Nutt D, Sahakian BJ

Aim:The aim of this paper is to increase awareness of the prevalence and cost of psychiatric and neurological disorders (brain disorders) in the UK.Method:UK data for 18 brain disorders were extracted from a systematic review of European epidemiological data and prevalence rates and the costs of each disorder were summarized (2010 values).Results:There were approximately 45 million cases of brain disorders in the UK, with a cost of €134 billion per annum. The most prevalent were headache, anxiety disorders, sleep disorders, mood disorders and somatoform disorders. However, the five most costly disorders (€ million) were: dementia: €22,164; psychotic disorders: €16,717; mood disorders: €19,238; addiction: €11,719; anxiety disorders: €11,687. Apart from psychosis, these five disorders ranked amongst those with the lowest direct medical expenditure per subject (<€3000). The approximate breakdown of costs was: 50% indirect costs, 25% direct non-medical and 25% direct healthcare costs.Discussion:The prevalence and cost of UK brain disorders is likely to increase given the ageing population. Translational neurosciences research has the potential to develop more effective treatments but is underfunded. Addressing the clinical and economic challenges posed by brain disorders requires a coordinated effort at an EU and national level to transform the current scientific, healthcare and educational agenda. HubMed – addiction

Membrane permeable C-terminal dopamine transporter peptides attenuate amphetamine-evoked dopamine release.

J Biol Chem. 2013 Jul 24;
Rickhag M, Owens WA, Winkler MT, Strandfelt KN, Rathje M, Sørensen G, Andresen B, Madsen KL, Jørgensen TN, Wörthwein G, Woldbye DP, Sitte H, Daws LC, Gether U

The dopamine transporter (DAT) is responsible for sequestration of extracellular dopamine (DA). The psychostimulant amphetamine (AMPH) is a DAT substrate, which is actively transported into the nerve terminus, eliciting vesicular depletion and reversal of DA transport via DAT. Here, we investigate the role of the DAT C-terminus in AMPH-evoked DA efflux using cell-permeant dominant-negative peptides. A peptide, which corresponded to the last 24 C-terminal residues of DAT (TAT-C24 DAT) and thereby contained the CaMKII? (Ca(2+)-calmodulin dependent protein kinase II?) binding domain and the PDZ (PSD-95/Discs-large/ZO-1) binding sequence of DAT, was made membrane-permeable by fusing it to the cell-membrane transduction domain of the HIV-1 Tat protein (TAT-C24WT). The ability of TAT-C24WT but not a scrambled peptide (TAT-C24Scr) to block the CaMKII?-DAT interaction was supported by co-immunoprecipitation experiments in heterologous cells. In heterologous cells, we also found that TAT-C24WT, but not TAT-C24Scr, decreased AMPH-evoked (3)H-MPP+ efflux. Moreover, chronoamperometric recordings in striatum revealed diminished AMPH-evoked DA efflux in mice preinjected with TAT-C24WT. Both in heterologous cells and in striatum, the peptide did not further inhibit efflux upon KN-93-mediated inhibition of CaMKII? activity, consistent with a dominant-negative action preventing binding of CaMKII? to the DAT C-terminus. This was further supported by the ability of a peptide with perturbed PDZ-binding sequence, but preserved CaMKII? binding (TAT-C24AAA), to diminish AMPH-evoked DA efflux in vivo to the same extent as TAT-C24WT. Finally, AMPH-induced locomotor hyperactivity was attenuated following systemic administration of TAT-C24WT but not TAT-C24Scr. Summarized, our findings substantiate that DAT C-terminal protein-protein interactions are critical for AMPH-evoked DA efflux and suggest that it may be possible to target protein-protein interactions to modulate transporter function and interfere with psychostimulant effects. HubMed – addiction