Amphetamine Elicits Opposing Actions on Readily Releasable and Reserve Pools for Dopamine.

Amphetamine elicits opposing actions on readily releasable and reserve pools for dopamine.

PLoS One. 2013; 8(5): e60763
Covey DP, Juliano SA, Garris PA

Amphetamine, a highly addictive drug with therapeutic efficacy, exerts paradoxical effects on the fundamental communication modes employed by dopamine neurons in modulating behavior. While amphetamine elevates tonic dopamine signaling by depleting vesicular stores and driving non-exocytotic release through reverse transport, this psychostimulant also activates phasic dopamine signaling by up-regulating vesicular dopamine release. We hypothesized that these seemingly incongruent effects arise from amphetamine depleting the reserve pool and enhancing the readily releasable pool. This novel hypothesis was tested using in vivo voltammetry and stimulus trains of varying duration to access different vesicular stores. We show that amphetamine actions are stimulus dependent in the dorsal striatum. Specifically, amphetamine up-regulated vesicular dopamine release elicited by a short-duration train, which interrogates the readily releasable pool, but depleted release elicited by a long-duration train, which interrogates the reserve pool. These opposing actions of vesicular dopamine release were associated with concurrent increases in tonic and phasic dopamine responses. A link between vesicular depletion and tonic signaling was supported by results obtained for amphetamine in the ventral striatum and cocaine in both striatal sub-regions, which demonstrated augmented vesicular release and phasic signals only. We submit that amphetamine differentially targeting dopamine stores reconciles the paradoxical activation of tonic and phasic dopamine signaling. Overall, these results further highlight the unique and region-distinct cellular mechanisms of amphetamine and may have important implications for its addictive and therapeutic properties. HubMed – addiction


Leptin influence in craving and relapse of alcoholics and smokers.

J Clin Med Res. 2013 Jun; 5(3): 164-7
Aguiar-Nemer AS, Toffolo MC, da Silva CJ, Laranjeira R, Silva-Fonseca VA

Leptin inhibits signaling of dopamine in the nucleus accumbens, suggesting its role in regulating stress and its possible involvement in the neurobiology of reward system. The aim of this study was to review of the literature on the influence of leptin in the craving for alcohol and tobacco and whether there is already evidence that leptin may be a biomarker to indicate risk for craving and relapse. The review used as data bases Medline, LILACS and SciElo in the period between 2000 and 2012. Keywords were leptin, substance use disorders, craving and withdrawal, in Portuguese and English. Only 12 articles were met the inclusion criteria, relating leptin with craving in alcoholics (n = 10) and smokers (n = 2). No studies were found in the LILACS database. Leptin levels increase during abstinence and this may be related to a reduction of dopaminergic action in mesolimbic system, resulting in a greater intensity of craving and maintenance of addictive behavior. Although there are few studies, the most recent results indicate the usefulness of leptin as a marker of risk for relapse among smokers and alcoholics in abstinence. HubMed – addiction


The diagnosis and treatment of generalized anxiety disorder.

Dtsch Arztebl Int. 2013 Apr; 110(17): 300-10
Bandelow B, Boerner J R, Kasper S, Linden M, Wittchen HU, Möller HJ

Generalized anxiety disorder (GAD) is a common and serious disease with a lifetime prevalence of 4.3% to 5.9%. It is underdiagnosed in primary care.Recommendations on the treatment of GAD are given on the basis of all available findings from pertinent randomized trials, retrieved by a selective search of the literature.Among psychotherapeutic techniques, various kinds of cognitive behavioral therapy (CBT) have been found useful in controlled trials. The drugs of first choice include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephine reuptake inhibitors (SNRIs), and the calcium-channel modulator pregabalin. Tricyclic antidepressants are also effective but have more adverse effects than SSRIs. Although benzodiazepines are effective anxiolytic agents for short-term use, they should not be given over the long term because of the danger of addiction. Buspirone, an azapirone, was found to be effective in a small number of trials, but the findings across trials are inconsistent. The response rate of GAD to CBT in published studies lies between 47% and 75%, while its response rate to drug treatment lies between 44% and 81%.The treatment of GAD with CBT and drugs is evidence-based and has a good chance of improving the manifestations of the disorder. HubMed – addiction


Reinstatement of nicotine seeking is mediated by glutamatergic plasticity.

Proc Natl Acad Sci U S A. 2013 May 13;
Gipson CD, Reissner KJ, Kupchik YM, Smith AC, Stankeviciute N, Hensley-Simon ME, Kalivas PW

Nicotine abuse and addiction is a major health liability. Nicotine, an active alkaloid in tobacco, is self-administered by animals and produces cellular adaptations in brain regions associated with drug reward, such as the nucleus accumbens. However, it is unknown whether, akin to illicit drugs of abuse such as cocaine or heroin, the adaptations endure and contribute to the propensity to relapse after discontinuing nicotine use. Using a rat model of cue-induced relapse, we made morphological and electrophysiological measures of synaptic plasticity, as well as quantified glutamate overflow, in the accumbens after 2 wk of withdrawal with extinction training. We found an enduring basal increase in dendritic spine head diameter and in the ratio of AMPA to NMDA currents in accumbens spiny neurons compared with yoked saline animals at 2 wk after the last nicotine self-administration session. This synaptic potentiation was associated with an increase in both AMPA (GluA1) and NMDA (GluN2A and GluN2B) receptor subunits, and a reduction in the glutamate transporter-1 (GLT-1). When nicotine seeking was reinstated by presentation of conditioned cues, there were parallel increases in behavioral responding, extracellular glutamate, and further increases in dendritic spine head diameter and ratio of AMPA to NMDA currents within 15 min. These findings suggest that targeting glutamate transmission might inhibit cue-induced nicotine seeking. In support of this hypothesis, we found that pharmacological inhibition of GluN2A with 3-Chloro-4-fluoro-N-[4-[[2-(phenylcarbonyl)hydrazino]carbonyl]benzyl]benzenesulfonamide (TCN-201) or GluN2B with ifenprodil abolished reinstated nicotine seeking. These results indicate that up-regulated GluN2A, GluN2B, and rapid synaptic potentiation in the accumbens contribute to cue-induced relapse to nicotine use. HubMed – addiction



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