Protein Kinase C? Is a Modulator of the Dopamine D2 Autoreceptor-Activated Trafficking of the Dopamine Transporter.

Protein kinase C? is a modulator of the dopamine D2 autoreceptor-activated trafficking of the dopamine transporter.

J Neurochem. 2013 Mar 4;
Chen R, Daining CP, Sun H, Fraser R, Stokes SL, Leitges M, Gnegy ME

The strength and duration of extracellular dopamine concentrations are regulated by the presynaptic dopamine transporter (DAT) and dopamine D2 autoreceptors (D2autoRs). There is a functional interaction between these two proteins. Activation of D2autoRs increases DAT trafficking to the surface whereas disruption of this interaction compromises activities of both proteins and alters dopaminergic transmission. Previously we reported that DAT expression and activity are subject to modulation by protein kinase C? (PKC?). Here, we further demonstrate that PKC? is integral for the interaction between DAT and D2autoR. Inhibition or absence of PKC? abolished the communication between DAT and D2autoR. In mouse striatal synaptosomes and transfected N2A cells, the D2autoR-stimulated membrane insertion of DAT was abolished by PKC? inhibition. Moreover, D2autoR-stimulated DAT trafficking is mediated by a PKC?-ERK (extracellular signal-regulated kinase) signaling cascade where PKC? is upstream of ERK. The increased surface DAT expression upon D2autoR activation resulted from enhanced DAT recycling as opposed to reduced internalization. Further, PKC? promoted accelerated DAT recycling. Our study demonstrates that PKC? critically regulates D2autoR-activated DAT trafficking and dopaminergic signaling. PKC? is a potential drug target for correcting abnormal extracellular dopamine levels in diseases such as drug addiction and schizophrenia. © 2013 The Authors Journal of Neurochemistry © 2013 International Society for Neurochemistry. HubMed – addiction


PET Studies in Nonhuman Primate Models of Cocaine Abuse: Translational Research Related to Vulnerability and Neuroadaptations.

Neuropharmacology. 2013 Feb 28;
Gould RW, Duke AN, Nader MA

The current review highlights the utility of positron emission tomography (PET) imaging to study the neurobiological substrates underlying vulnerability to cocaine addiction and subsequent adaptations following chronic cocaine self-administration in nonhuman primate models of cocaine abuse. Environmental (e.g., social rank) and sex-specific influences on dopaminergic function and sensitivity to the reinforcing effects of cocaine are discussed. Cocaine-related cognitive deficits have been hypothesized to contribute to high rates of relapse and are described in nonhuman primate models. Lastly, the long-term consequences of cocaine on neurobiology are discussed. PET imaging and longitudinal, within-subject behavioral studies in nonhuman primates have provided a strong framework for designing pharmacological and behavioral treatment strategies to aid drug-dependent treatment seekers. Non-invasive PET imaging will allow for individualized treatment strategies. Recent advances in radiochemistry of novel PET ligands and other imaging modalities can further advance our understanding of stimulant use on the brain. HubMed – addiction


Early intervention of intravenous KB220IV- neuroadaptagen amino-acid therapy (NAAT) improves behavioral outcomes in a residential addiction treatment program: a pilot study.

J Psychoactive Drugs. 2012 Nov-Dec; 44(5): 398-409
Miller M, Chen AL, Stokes SD, Silverman S, Bowirrat A, Manka M, Manka D, Miller DK, Perrine K, Chen TJ, Bailey JA, Downs W, Waite RL, Madigan MA, Braverman ER, Damle U, Kerner M, Giordano J, Morse S, Oscar-Berman M, Barh D, Blum K

Substance use disorders (SUD) are inheritable and the culprit is hypodopaminergic function regulated by reward genes. We evaluated a natural dopaminergic agonist; KB220 intravenous (IV) and oral variants, to improve dopaminergic function in SUD. Our pilot experiment found a significant reduction of chronic symptoms, measured by the Chronic Abstinence Symptom Severity (CASS) Scale. The combined group (IV and oral) did significantly better than the oral-only group over the first week and 30-day follow-up period. Next, the combination was given to 129 subjects and three factors; Emotion, Somatic, and Impaired Cognition, with eigenvalues greater than one were extracted for baseline CASS-Revised (CASS-R) variables. Paired sample t-tests for pre and post-treatment scales showed significant declines (p = .00001) from pre- to post-treatment: t = 19.1 for Emotion, t = 16.1 for Somatic, and t = 14.9 for Impaired Cognition. In a two-year follow-up of 23 subjects who underwent KB220IV therapy (at least five IV treatments over seven days) plus orals for 30+ days: 21 (91%) were sober at six months, 19 (82%) having no relapse; 19 (82%) were sober at one year, 18 (78%) having no relapse; and 21 (91%) were sober two-years post-treatment, 16(70%) having no relapse. We await additional research and advise caution in interpreting these encouraging results. HubMed – addiction


[Medical and social management of homeless individuals. A one year prospective observational study in the south part of France, Pyrénées-Orientales].

Rev Prat. 2013 Jan; 63(1): 29-34
Francès P, Daguzan P, Bismuth S

In 2007, a national survey estimated to up to 800,000 the number of homeless individuals in France. Ten percent of them live constantly in the street; often very dissocialized and in precarious conditions. Thereby it remains difficult for homeless to have access to a medical and social support. In order to identify the medical and social needs of this population, we performed a one year observational prospective study in two reception centres in Perpignan. 629 (99%) out of 635 answers were analysed. The most represented age group is 39-49 years (29,2%) with an over-representation of males (82,7%). The most frequent pathologies are psychological distress (43,9% of requests, including anxious problems 23%, and sleep disturbances 24,4%). Medical affections represented 15,7% of the cases (mainly nutritional deficiency), and skin diseases 15,%. Addictive behaviour was frequent including tobacco (84%), alcohol (17%), and drug addiction (9%). 21,7% of this population had a regular work, and 97,8% with fixed term contracts, but 45,1% did not have any health cover 17,6% of homeless did not obtain any answer to their medical request (lack of suitable medicine, or an impossibility to pull out further tests in order). To solve some aspects of that problem, family doctor can rely on a medical and social network (PASS, MAO, ANPAA). HubMed – addiction