Dataset Information

Repeated dexamphetamine treatment alters the dopaminergic system and increases the phMRI response to methylphenidate.

ABSTRACT: Dexamphetamine (AMPH) is a psychostimulant drug that is used both recreationally and as medication for attention deficit hyperactivity disorder. Preclinical studies have demonstrated that repeated exposure to AMPH can induce damage to nerve terminals of dopamine (DA) neurons. We here assessed the underlying neurobiological changes in the DA system following repeated AMPH exposure and pre-treated rats with AMPH or saline (4 times 5 mg/kg s.c., 2 hours apart), followed by a 1-week washout period. We then used pharmacological MRI (phMRI) with a methylphenidate (MPH) challenge, as a sensitive and non-invasive in-vivo measure of DAergic function. We subsequently validated the DA-ergic changes post-mortem, using a.o. high-performance liquid chromatography (HPLC) and autoradiography. In the AMPH pre-treated group, we observed a significantly larger BOLD response to the MPH challenge, particularly in DA-ergic brain areas and their downstream projections. Subsequent autoradiography studies showed that AMPH pre-treatment significantly reduced DA transporter (DAT) density in the caudate-putamen (CPu) and nucleus accumbens, whereas HPLC analysis revealed increases in the DA metabolite homovanillic acid in the CPu. Our results suggest that AMPH pre-treatment alters DAergic responsivity, a change that can be detected with phMRI in rats. These phMRI changes likely reflect increased DA release together with reduced DAT binding. The ability to assess subtle synaptic changes using phMRI is promising for both preclinical studies of drug discovery, and for clinical studies where phMRI can be a useful tool to non-invasively investigate DA abnormalities, e.g. in neuropsychiatric disorders.

SUBMITTER: Schrantee A

PROVIDER: S-EPMC5328278 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Repeated dexamphetamine treatment alters the dopaminergic system and increases the phMRI response to methylphenidate.

Schrantee Anouk A Tremoleda Jordi L JL Wylezinska-Arridge Marzena M Bouet Valentine V Hesseling Peter P Meerhoff Gideon F GF de Bruin Kora M KM Koeleman Jan J Freret Thomas T Boulouard Michel M Desfosses Emilie E Galineau Laurent L Gozzi Alessandro A Dauphin François F Gsell Willy W Booij Jan J Lucassen Paul J PJ Reneman Liesbeth L

PloS one 20170227 2

Dexamphetamine (AMPH) is a psychostimulant drug that is used both recreationally and as medication for attention deficit hyperactivity disorder. Preclinical studies have demonstrated that repeated exposure to AMPH can induce damage to nerve terminals of dopamine (DA) neurons. We here assessed the underlying neurobiological changes in the DA system following repeated AMPH exposure and pre-treated rats with AMPH or saline (4 times 5 mg/kg s.c., 2 hours apart), followed by a 1-week washout period. ...[more]

PMID: 28241065

Similar Datasets

Project description:Methylphenidate (MPD) is one of the most prescribed drugs for alleviating the symptoms of Attention Deficit/Hyperactivity Disorder (ADHD). However, changes in the molecular mechanisms related to MPD withdrawal and susceptibility to consumption of other psychostimulants in normal individuals or individuals with ADHD phenotype are not completely understood. The aims of the present study were: (i) to characterize the molecular differences in the prefrontal dopaminergic system of SHR and Wistar strains, (ii) to establish the neurochemical consequences of short- (24 hours) and long-term (10 days) MPD withdrawal after a subchronic treatment (30 days) with Ritalin® (Methylphenidate Hydrochloride; 2.5 mg/kg orally), (iii) to investigate the dopaminergic synaptic functionality after a cocaine challenge in adult MPD-withdrawn SHR and Wistar rats. Our results indicate that SHR rats present reduced [3H]-Dopamine uptake and cAMP accumulation in the prefrontal cortex (PFC) and are not responsive to dopaminergic stimuli in when compared to Wistar rats. After a 24-hour withdrawal of MPD, SHR did not present any alterations in [3H]-Dopamine Uptake, [3H]-SCH 23390 binding and cAMP production; nonetheless, after a 10-day MPD withdrawal, the results showed a significant increase of [3H]-Dopamine uptake, of the quantity of [3H]-SCH 23390 binding sites and of cAMP levels in these animals. Finally, SHR that underwent a 10-day MPD withdrawal and were challenged with cocaine (10 mg/kg i.p.) presented reduced [3H]-Dopamine uptake and increased cAMP production. Wistar rats were affected by the 10-day withdrawal of MPD in [3H]-dopamine uptake but not in cAMP accumulation; in addition, cocaine was unable to induce significant modifications in [3H]-dopamine uptake and in cAMP levels after the 10-day withdrawal of MPD. These results indicate a mechanism that could explain the high comorbidity between ADHD adolescent patients under methylphenidate treatment and substance abuse in adult life.

Project description:This trial was designed to prospectively explore the relationship among personality disorder (PD) symptoms, attention-deficit/hyperactivity disorder (ADHD), and treatment response in a randomized, double-blind, crossover clinical trial of methylphenidate transdermal system (MTS) and to confirm results of a prior exploratory study. 67 adults who met the Utah and/or DSM-IV-TR criteria for ADHD were recruited with no attempt to include or exclude patients with PD. Responders were defined by a 50% improvement on the Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS), the primary outcome measure. Personality disorder was diagnosed by the clinicians using the Structured Clinical Interview for DSM-IV-TR Axis II Personality Disorders Questionnaire, several self-report scales, and clinical observations. Subjects were categorized as: no PD (PD-negative), 1 PD (PD-positive), and 2 or more PDs (PD-plus). The study was conducted from February 2007 to December 2009 at the Mood Disorders Clinic at the University of Utah School of Medicine, Salt Lake City. 37% (n = 25) were PD-positive, and another 27% (n = 18) were PD-plus. In those with a PD, 65% (n = 28) had a cluster C diagnosis, 44% (n = 19) cluster B, and 5% (n = 12) cluster A. PD-plus subjects had significantly higher levels of oppositional defiant disorder (ODD) symptoms (P = .007) and emotional dysregulation (P = .004). 71% (15/21) of the PD-positive and PD-negative subjects were responders in the MTS arm (P < .001) as opposed to 38% (6/16) of the PD-plus subjects (P = .24). Conversely, the interaction between treatment (placebo versus MTS) and the 3 PD groups was not statistically significant (P = .46) when the total WRAADDS was used as the outcome measure. Personality disorder status was associated with more complex ADHD, especially high levels of emotional dysregulation and ODD symptoms. There was a significant treatment effect for PD-positive and PD-negative, but not PD-plus subjects. ClinicalTrials.gov identifier: NCT00506285.

Dataset Information

Repeated dexamphetamine treatment alters the dopaminergic system and increases the phMRI response to methylphenidate.

Publications

Repeated dexamphetamine treatment alters the dopaminergic system and increases the phMRI response to methylphenidate.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets