scholarly journals Regulation of GluA1 Phosphorylation by D-amphetamine and Methylphenidate in the Cerebellum

2020 ◽  
Author(s):  
Laura Cutando ◽  
Emma Puighermanal ◽  
Laia Castell ◽  
Pauline Tarot ◽  
Federica Bertaso ◽  
...  
Keyword(s):  
Posttranslational Modification ◽  
D1 Receptor ◽  
Vesicular Monoamine Transporter ◽  
Norepinephrine Release ◽  
Prescription Stimulants ◽  
Hyperactivity Disorder ◽  
Bergmann Glial Cells ◽  
Transcriptional Alterations ◽  
Ampa Receptor Subunit ◽  
Pka Pathway

AbstractPrescription stimulants, such as d-amphetamine or methylphenidate, are potent dopamine (DA) and norepinephrine (NE) releasers used to treat children and adults diagnosed for attention-deficit/hyperactivity disorder (ADHD). Although increased phosphorylation of the AMPA receptor subunit GluA1 at Ser845 (pS845-GluA1) in the striatum has been identified as an important cellular effector for the actions of these drugs, regulation of this posttranslational modification in the cerebellum has never been recognized. Here, we demonstrate that d-amphetamine and methylphenidate increase pS845-GluA1 in the membrane fraction in both vermis and lateral hemispheres of the mouse cerebellum. This regulation occurs selectively in Bergmann Glia Cells and requires intact norepinephrine release since the effects were abolished in mice lacking the vesicular monoamine transporter-2 selectively in NE neurons. Moreover, d-amphetamine-induced pS845-GluA1 was prevented by β1-adenoreceptor antagonist, whereas the blockade of dopamine D1 receptor had no effect. Additionally, we identified transcriptional alterations of several regulators of the cAMP/PKA pathway, which might account for the absence of pS845-GluA1 desensitization in mice repeatedly exposed to d-amphetamine or methylphenidate. Together, these results point to norepinephrine transmission as a key regulator of GluA1 phosphorylation in Bergmann Glial Cells, which may represent a new target for the treatment of ADHD.

scholarly journals Investigating the modulation of methylphenidate’s effects on impulsivity by fluoxetine

2021 ◽  
Author(s):  
◽  
Rosemary Chittenden
Keyword(s):  
Nucleus Accumbens ◽  
Cognitive Process ◽  
Dopamine Release ◽  
Synergistic Effects ◽  
Norepinephrine Release ◽  
Short Term ◽  
Hyperactivity Disorder ◽  
New Variant ◽  
Stop Signal Reaction Time ◽  
Tentative Evidence

<p>The co-prescribing of methylphenidate (MPH) and a selective serotonin reuptake inhibitor for patients presenting co-morbidly with both attention deficit/hyperactivity disorder and depression or anxiety is in some cases recommended. Little research has been conducted on the specific cognitive and behavioural outcomes of this. Studies with rats have shown that SSRI’s potentiate MPH-induced dopamine release in the pre-frontal cortex, hippocampus and nucleus accumbens, as well as enhancing MPH-induced hyper-locomotion (Borycz, Zapata, Quiroz, Volkow, & Ferré, 2008; Weikop, Yoshitake, & Kehr, 2007b). Impulsivity is a behavioural construct with dissociable sub-types, of which one, ‘action restraint’, has been consistently shown to be associated with increased dopamine activity in the mesolimbic system, including the nucleus accumbens. It was hypothesised that rats would make more ‘no-go’ errors in a Go/No-Go task, indicative of an increase in ‘action restraint’ type impulsivity, when co-administered fluoxetine (FLX) and MPH compared to either drug administered alone. Although this was not shown in the current study, tentative evidence was found to suggest that the combination of these drugs may negatively impact on attention, based on a decrease in ‘go’ accuracy. A second subtype of impulsivity, “action cancellation”, was tested using a new variant of the Stop-Signal Reaction Time (SSRT) task that we have developed for rats. Studies show that this subtype of impulsivity seems to be unaffected by changes in dopamine activity, but is improved by increases in norepinephrine. In the Weikop study mentioned above, the SSRI citalopram enhanced not only MPH-induced dopamine release, but also norepinephrine release in the nucleus accumbens. Thus it was hypothesised that FLX may potentiate MPH’s impulsivity-reducing effects as measured by stopping latency in the SSRT. We were not able to show this in the current study, however the demonstration that lower doses of MPH reduced stopping latency, consistent with previous versions of the SSRT, validated the new version developed for the current study. A final experiment revealed a rapid, short-term increase in locomotor activity when rats were co-administered FLX and MPH, an effect not present when either drug was administered singly. This synergistic effect replicates previous findings, and indicates a potentiation of dopamine release in the nucleus accumbens, as was found in previous studies. Although FLX was not found to moderate MPH’s effects on impulsivity in the current study, synergistic effects of the two drugs were effects were found on motor activity and potentially on attention also. This is an indication of the value of further research into specific behavioural and cognitive process that may be affected by co-administration of MPH and an SSRI.</p>

scholarly journals Attention-Deficit and Hyperactivity Disorder: A Disorder or a Fraud?

2019 ◽  
Vol 11 (5) ◽  
pp. 100
Author(s):  
Rony Chaaya ◽  
Diala El Khoury
Keyword(s):  
Prefrontal Cortex ◽  
Attention Deficit ◽  
Health Professionals ◽  
Biological Pathways ◽  
Behavioral Disorder ◽  
Norepinephrine Release ◽  
Tobacco Exposure ◽  
Hyperactivity Disorder ◽  
Cellular Pathways ◽  
The Brain

Attention Deficit Hyperactivity Disorder is a psychiatric and behavioral disorder marked by chronic inattention and/or hyperactivity-impulsivity that interferes with functioning or development. This disorder is caused by many dysfunctions in the brain especially in the prefrontal cortex. To date, numerous studies have attempted to unravel the biological pathways behind ADHD. Many environmental risk factors have been identified including lead exposure and prenatal alcohol and tobacco exposure. Specific mutations in genes affecting dopamine and norepinephrine release are also under investigation. Moreover, around three thousand papers have been published showing that ADHD is due to an abnormal dopamine and norepinephrine neurotransmitters secretion in the prefrontal cortex (PFC). This paper aims to provide an updated review of the biological causes of ADHD with an unprecedented focus on different cellular pathways involving catecholamine secretion in the prefrontal cortex. A well rounded and comprehensive review of the etiology of ADHD would prevent its misdiagnosis by health professionals and consequently restrict its malpractice by the use of unnecessary treatments and medications. The ADHD controversy still remains: a disorder or a fraud?

scholarly journals Investigating the modulation of methylphenidate’s effects on impulsivity by fluoxetine

2021 ◽  
Author(s):  
◽  
Rosemary Chittenden
Keyword(s):  
Nucleus Accumbens ◽  
Cognitive Process ◽  
Dopamine Release ◽  
Synergistic Effects ◽  
Norepinephrine Release ◽  
Short Term ◽  
Hyperactivity Disorder ◽  
New Variant ◽  
Stop Signal Reaction Time ◽  
Tentative Evidence

<p>The co-prescribing of methylphenidate (MPH) and a selective serotonin reuptake inhibitor for patients presenting co-morbidly with both attention deficit/hyperactivity disorder and depression or anxiety is in some cases recommended. Little research has been conducted on the specific cognitive and behavioural outcomes of this. Studies with rats have shown that SSRI’s potentiate MPH-induced dopamine release in the pre-frontal cortex, hippocampus and nucleus accumbens, as well as enhancing MPH-induced hyper-locomotion (Borycz, Zapata, Quiroz, Volkow, & Ferré, 2008; Weikop, Yoshitake, & Kehr, 2007b). Impulsivity is a behavioural construct with dissociable sub-types, of which one, ‘action restraint’, has been consistently shown to be associated with increased dopamine activity in the mesolimbic system, including the nucleus accumbens. It was hypothesised that rats would make more ‘no-go’ errors in a Go/No-Go task, indicative of an increase in ‘action restraint’ type impulsivity, when co-administered fluoxetine (FLX) and MPH compared to either drug administered alone. Although this was not shown in the current study, tentative evidence was found to suggest that the combination of these drugs may negatively impact on attention, based on a decrease in ‘go’ accuracy. A second subtype of impulsivity, “action cancellation”, was tested using a new variant of the Stop-Signal Reaction Time (SSRT) task that we have developed for rats. Studies show that this subtype of impulsivity seems to be unaffected by changes in dopamine activity, but is improved by increases in norepinephrine. In the Weikop study mentioned above, the SSRI citalopram enhanced not only MPH-induced dopamine release, but also norepinephrine release in the nucleus accumbens. Thus it was hypothesised that FLX may potentiate MPH’s impulsivity-reducing effects as measured by stopping latency in the SSRT. We were not able to show this in the current study, however the demonstration that lower doses of MPH reduced stopping latency, consistent with previous versions of the SSRT, validated the new version developed for the current study. A final experiment revealed a rapid, short-term increase in locomotor activity when rats were co-administered FLX and MPH, an effect not present when either drug was administered singly. This synergistic effect replicates previous findings, and indicates a potentiation of dopamine release in the nucleus accumbens, as was found in previous studies. Although FLX was not found to moderate MPH’s effects on impulsivity in the current study, synergistic effects of the two drugs were effects were found on motor activity and potentially on attention also. This is an indication of the value of further research into specific behavioural and cognitive process that may be affected by co-administration of MPH and an SSRI.</p>

scholarly journals Rise, and pronounced regional variation, in methylphenidate, amphetamine, and lisdexamfetamine distribution in the United States

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e12619
Author(s):  
Sneha M. Vaddadi ◽  
Nicholas J. Czelatka ◽  
Belsy D. Gutierrez ◽  
Bhumika C. Maddineni ◽  
Kenneth L. McCall ◽  
...  
Keyword(s):  
United States ◽  
Adult Adhd ◽  
Regional Analysis ◽  
The United States ◽  
The West ◽  
Prescription Stimulants ◽  
Drug Enforcement ◽  
Hyperactivity Disorder ◽  
Sympathomimetic Drugs ◽  
Usage Patterns

Background The prescription stimulants methylphenidate, amphetamine, and lisdexamfetamine are sympathomimetic drugs with therapeutic use. They are designated in the United States as Schedule II substances, defined by the 1970 Controlled Substances Act as having a “high potential for abuse”. Changing criteria for the diagnosis of Attention Deficit Hyperactivity Disorder in 2013 and the approval of lisdexamfetamine for binge eating disorder in 2015 may have impacted usage patterns. This report compared the pharmacoepidemiology of these stimulants in the United States from 2010–2017. Methods Distribution of amphetamine, methylphenidate, lisdexamfetamine were examined via weights extracted from the Drug Enforcement Administration’s (DEA) Automated Reports and Consolidated Ordering System (ARCOS). Median stimulant Daily Dosage per patient was determined for a regional analysis. The percent of cost and prescriptions attributable to each stimulant and atomoxetine in Medicaid from the “Drug Utilization 2018 - National Total” from the Centers for Medicare and Medicaid was determined. Results There was a rise in amphetamine (+67.5%) and lisdexamfetamine (+76.7%) from 2010–2017. The change in methylphenidate (−3.0%) was modest. Persons/day stimulant usage was lower in the West than in other US regions from 2014-2017. There was a negative correlation (r(48) = −0.43 to −0.65, p < .05) between the percent Hispanic population per state and the Daily Dosage/population per stimulant. Methylphenidate formulations accounted for over half (51.7%) of the $3.8 billion reimbursed by Medicaid and the plurality (45.4%) of the 22.0 million prescriptions. Amphetamine was responsible for less than one-fifth (18.4%) of cost but one-third of prescriptions (33.6%). Lisdexamfetamine’s cost (26.0%) exceeded prescriptions (16.3%). Conclusion The rising amphetamine and lisdexamfetamine distribution may correspond with a rise in adult ADHD diagnoses. Regional analysis indicates that stimulant distribution in the West may be distinct from that in other regions. The lower stimulant distribution in areas with greater Hispanic populations may warrant further study.

scholarly journals Prescription Stimulant-Induced Neurotoxicity: Mechanisms, outcomes, and relevance to ADHD

2021 ◽  
Vol 5 (0) ◽  
Author(s):  
Joshua Ellis Tucker
Keyword(s):  
Primary Care Physicians ◽  
Adult Population ◽  
Clinical Manifestations ◽  
Prescription Stimulants ◽  
University Campuses ◽  
College And University ◽  
Hyperactivity Disorder ◽  
Diagnostic And Statistical Manual ◽  
Current State ◽  
Young Adult Population

Attention-deficit/hyperactivity disorder (ADHD) is a relatively prevalent neuropsychiatric and neurodevelopmental condition characterized in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ( DSM-5 ) as difficulty sustaining attention and maintaining tasks at hand, heightened distractibility, and other deficits in executive functioning. Prescription stimulants—amphetamine (AMP) and methylphenidate (MPH)—are the first-line treatment(s) for ADHD in both pediatric and adult populations and exist in many formulations. Troublingly, the non-medical use (NMU) of amphetamine and methylphenidate is more prevalent in the American population, especially on college and university campuses, than the condition of interest. The neurotoxicological profile and NMU epidemiology of prescription stimulants is of direct relevance to primary care physicians and psychiatrists as they are the providers most frequently tasked with the treatment of ADHD and the surveillance of substance misuse behaviors in the young adult population. As comprehensive literature reviews of the mechanisms and potential adverse sequelae of prescription stimulant-induced neurotoxicity intended for medical clinicians have been quite sparse in the last decade—especially given the gravity of the issue—this article includes a brief primer on ADHD etiology and pathophysiology; considers the current state of NMU epidemiology; reviews the mechanisms of action of AMP and MPH; and, finally, summarizes known molecular and clinical manifestations of AMP and MPH neurotoxicity.

Development of the Subtle ADHD Malingering Screener

Assessment ◽  
2018 ◽  
Vol 26 (3) ◽  
pp. 524-534 ◽  
Author(s):  
Sujith Ramachandran ◽  
Erin R. Holmes ◽  
Meagen Rosenthal ◽  
Benjamin F. Banahan ◽  
John Young ◽  
...  
Keyword(s):  
Psychometric Testing ◽  
Self Report ◽  
Control Group ◽  
Clinical Settings ◽  
Adhd Group ◽  
Factor Solution ◽  
Cross Sectional ◽  
Prescription Stimulants ◽  
Hyperactivity Disorder ◽  
Group A

The objective of this study was to develop a subtle self-report scale—the Subtle ADHD Malingering Screener (SAMS)—to screen for malingering among individuals reporting symptoms of attention deficit/hyperactivity disorder (ADHD). This study employed a cross-sectional experimental design with an ADHD group, a control group—comprising individuals without ADHD—and a malingering group—comprising individuals without ADHD who were instructed to feign ADHD in their responses. Factor analysis and psychometric testing were conducted to develop a final scale that could distinguish the malingering from the other groups. A 10-item, two-factor solution was obtained for the SAMS, with a sensitivity of 90.3% and specificity of 80.1%. The SAMS presents an innovative approach to help reduce overdiagnosis of ADHD and misuse of prescription stimulants. The efficient, straightforward form of the measure particularly enhances its potential application in both medical and psychosocial clinical settings.

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