Sex differences in the behavioral response to methylphenidate in three adolescent rat strains (WKY, SHR, SD)

Chelaru, Mircea I.; Peng, Yang; Dafny, Nachum

doi:10.1016/j.bbr.2011.08.027

Cited by 32 publications

(16 citation statements)

References 76 publications

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“…The source of this discrepancy is unknown, but may have been due to the testing of multiple compounds (including nicotine), the strain tested (male Lister rats), or other procedural details including the route of administration and the temporal predictability of stimulus onset (see Bizarro et al., 2004 for discussion). Further, in our experiment, the increases in premature responses occurred in females, which is also consistent with previous findings with amphetamine in the choice reaction time task (Burton and Fletcher 2012), and in general with a greater sensitivity to psychostimulants in females (Becker et al 2001; Torres-Reveron and Dow-Edwards 2005; Roeding et al 2014; Bentley et al 2015; see Chelaru et al 2012 for strain-dependent differences).…”

Section: Discussionsupporting

confidence: 92%

Premature responding is associated with approach to a food cue in male and female heterogeneous stock rats

et al. 2016

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Rationale Disorders of behavioral regulation, including attention deficit hyperactivity disorder (ADHD) and drug addiction, are in part due to poor inhibitory control, attentional deficits, and hyper-responsivity to reward-associated cues. Objectives To determine whether these traits are related, we tested genetically variable male and female heterogeneous stock rats in the choice reaction time (CRT) task and Pavlovian conditioned approach (PavCA). Sex differences in the response to methylphenidate during the CRT were also assessed. Methods In the CRT task, rats were required to withhold responding until one of two lights indicated whether responses into a left or right port would be reinforced with water. Reaction time on correct trials and premature responses were the operational definitions of attention and response inhibition, respectively. Rats were also pre-treated with oral methylphenidate (0, 2, 4 mg/kg) during the CRT task to determine whether this drug would improve performance. Subsequently, during PavCA, presentation of an illuminated lever predicted the delivery of a food pellet into a food-cup. Lever-directed approach (sign-tracking) and food-cup approach (goal-tracking) were the primary measures, and rats were categorized as “sign-trackers” and “goal-trackers” using an index based on these measures. Results Sign-trackers made more premature responses than goal-trackers, but showed no differences in reaction time. There were sex differences in both tasks, with females having higher sign-tracking, completing more CRT trials, and making more premature responses after methylphenidate administration. Conclusions These results indicate that response inhibition is related to reward-cue responsivity, suggesting that these traits are influenced by common genetic factors.

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Section: Discussionsupporting

confidence: 92%

Premature responding is associated with approach to a food cue in male and female heterogeneous stock rats

et al. 2016

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“…The results from this study are in agreement with other studies on sex differences in response to MP and other psychostimulants that found that females showed greater levels of activity and exploration in open field than males when given oral MP (van Haaren and Meyer, 1991; Bethancourt et al, 2011). Females have generally been shown to be more sensitive to MP than their male counterparts, a finding that extends to other psychostimulants such as cocaine (Walker et al, 2001; Carrier and Kabbaj, 2012; Chelaru et al, 2012; Van Swearingen et al, 2013). …”

Section: Discussionmentioning

confidence: 96%

“…This discovery will likely increase ADHD diagnosis and subsequent treatment in females in the coming years, further supporting the need for research on possible sex differences in response to psychostimulant treatment. It has been well-documented that females are subject to different responses to drug treatments due to sex-specific pharmacological signaling differences, (i.e., growth development and hormonal distribution) (Brown et al, 2000; Zakharova et al, 2009; Tingen et al, 2010), and have been shown to be more sensitive to some of the effects of psychostimulants (Walker et al, 2001; Carrier and Kabbaj, 2012; Chelaru et al, 2012; Van Swearingen et al, 2013). …”

Section: Introductionmentioning

confidence: 99%

Sex Differences in the Physiological and Behavioral Effects of Chronic Oral Methylphenidate Treatment in Rats

Robison

Michaelos

Gandhi

et al. 2017

Front. Behav. Neurosci.

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Methylphenidate (MP) is a psychostimulant prescribed for Attention Deficit Hyperactivity Disorder. Previously, we developed a dual bottle 8-h-limited-access-drinking-paradigm for oral MP treatment of rats that mimics the pharmacokinetic profile of treated patients. This study assessed sex differences in response to this treatment. Male and female Sprague Dawley rats were assigned to one of three treatment groups at 4 weeks of age (n = 12/group): Control (water), low dose (LD) MP, and high dose (HD) MP. Rats drank 4 mg/kg MP (LD) or 30 mg/kg MP (HD) during the first hour, and 10 mg/kg (LD) or 60 mg/kg MP (HD) for the remaining 7 h each day. Throughout 3 months of treatment, rats were monitored for body weight, food intake, and fluid intake; as well as tested for open field behavior, circadian activity, novel object recognition, and social interaction. Chronic MP treated rats exhibited reduced fluid intake during distinct treatment weeks to a greater extent in males, and reduced total fluid intake in males only. HD MP treatment decreased body weight in both sexes, while HD MP increased total food intake in females only, likely to offset energy deficits resulting from MP-induced hyperactivity. LD and HD MP increased locomotor activity in the open field, particularly in females and during later treatment weeks. MP dose-dependently increased activity during the dark cycle of circadian testing in females, while in males hyperactivity was only exhibited by HD rats. HD MP increased center activity to a greater extent in males, while MP increased rearing behavior in females only. MP had no effect on social behavior or novel object recognition in either sex. This study concludes that chronic oral MP treatment at clinically-relevant dosages has significant effects on food intake, body weight, open field behavior, and wake cycle activity. Particularly marked sex differences were apparent for locomotor activity, with females being significantly more sensitive to the hyperactivating effects of the drug. These findings suggest that chronic MP exposure beginning in adolescence can have significant behavioral effects that are both dose- and sex-dependent, and raise concerns regarding the reversibility of these effects post-discontinuation of treatment.

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“…The behavioral responses of rats to psychostimulants exhibit similar sex differences. Relative to males, female rats have enhanced responses to cocaine (COC) (Hu et al 2004; Kuhn et al 2001; van Haaren and Meyer 1991; Walker et al 2001; Walker et al 2009), MDMA (Walker et al 2007), methylphenidate (Chelaru et al 2012; Dafny and Yang 2006) and amphetamine (AMPH) (Beatty and Holzer 1978; Brass and Glick 1981; Robinson et al 1980; Stohr et al 1998). Females work harder for psychostimulants, learn to self-administer them faster, and are more sensitive to their rewarding effects than males (Anker et al 2011; Becker and Hu 2008; Davis et al 2008; Russo et al 2003b).…”

Section: Introductionmentioning

confidence: 99%

Sex differences in novelty- and psychostimulant-induced behaviors of C57BL/6 mice

2012

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Rationale Women are more sensitive than men to psychostimulants and progress from initial use to drug addiction more quickly. The mouse has been an under-utilized model to study sex differences in psychostimulant action. Mice could serve as an ideal genetically-tractable model for mechanistic studies into sex and hormone effects on psychostimulant behavior. Objectives To characterize psychostimulant effects in male and female mice with a combination of automated data collection and behavioral observation. Methods Male and female C57BL/6 mice (Charles River) were given a single dose or sequential ascending binge doses of d-amphetamine (AMPH) or cocaine (COC). Behavior was assessed in open field chambers using both automated photobeam interruptions and behavioral observations. Brain psychostimulant concentrations were determined at the time of maximum behavioral stimulation. Results Psychostimulants induced behavioral activation in mice including both increased locomotion as detected with an automated system and a sequence of behaviors progressing from stereotyped sniffing at low doses to patterned locomotion and rearing at high doses. Females exhibited more patterned locomotion and a shift towards higher behavior scores after either psychostimulant despite having lower AMPH and equivalent COC brain levels as males. Conclusions Female C57BL/6 mice exhibit enhanced psychostimulant-induced behavior compared to males, similar to reports in rats. The combination of automated behavioral measures and behavioral observation was essential for verifying the existence of these differences. These results indicate the importance of testing both sexes when characterizing genetically manipulated mice to control for potential sex-specific effects.

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Sex differences in the behavioral response to methylphenidate in three adolescent rat strains (WKY, SHR, SD)

Cited by 32 publications

References 76 publications

Premature responding is associated with approach to a food cue in male and female heterogeneous stock rats

Premature responding is associated with approach to a food cue in male and female heterogeneous stock rats

Sex Differences in the Physiological and Behavioral Effects of Chronic Oral Methylphenidate Treatment in Rats

Sex differences in novelty- and psychostimulant-induced behaviors of C57BL/6 mice

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