Juvenile Methylphenidate Exposure and Factors That Influence Incentive Processing

Brenhouse, Heather C.; Napierata, Lee; Kussmaul, Lucinda; Leussis, Melanie P.; Andersen, Susan

doi:10.1159/000207498

Cited by 21 publications

(21 citation statements)

References 136 publications

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“…An interaction was evident in the days to extinction. Developing females are equally sensitive as males to the locomotor effects of cocaine pre-pubertally (Kuhn et al, 2001), and more sensitive to low doses of cocaine than males during adolescent place conditioning (Brenhouse et al, 2009; Zakharova et al, 2009). This increased sensitivity to cocaine in females, we believe, played a role in noticing cocaine’s absence, and extinguished faster.…”

Section: Discussionmentioning

confidence: 99%

“…Female rats show stronger place preferences for cocaine-associated environments than male rats in adulthood and adolescence (Brenhouse et al, 2009; Kuhn et al, 2001; Russo et al, 2003; Zakharova et al, 2009). Extinction of these cocaine place preferences is protracted in adult female mice compared with males (Hilderbrand and Lasek, 2014), whereas no sex difference in the degree of extinction is observed between male and female adult rats (Bobzean et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Extinction and reinstatement to cocaine-associated cues in male and female juvenile rats and the role of D1 dopamine receptor

et al. 2015

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Extinction of behaviors in response to drug-associated cues and prevention of reinstatement are integral for addiction treatment, and can reverse or ameliorate the harmful consequences of drug use. The mechanisms controlling extinction and reinstatement involve prefrontal cortical dopamine receptors, which change in expression and activity during the juvenile and adolescent transitions until they mature in adulthood. Little is known about the role that PFC D1 dopamine receptors play in extinction of drug-paired associations early in life. We used extinction of place preferences for cocaine in juvenile male and female rats following genetic, cell-specific overexpression of D1 on glutamatergic cells in the PFC. All subjects needed to demonstrate cocaine preferences for inclusion in the extinction studies. Here, male juveniles with a preference to 10 mg/kg cocaine took longer to extinguish preferences compared to both male adults and female juveniles. Female juveniles extinguished more rapidly than male juveniles at 20 mg/kg cocaine. Overexpression of D1 in juvenile males significantly facilitated extinction relative to juvenile male controls, whereas D1 prolonged expression of extinction in adults overexpressing D1 and adolescents who naturally have elevated D1 expression. These data suggest that an immature D1 profile in juveniles prevented the learning of new associations, and D1 overexpression may provide sufficient activity to facilitate extinction learning. D1 overexpression reduced reinstatement to a priming dose of cocaine in juvenile males. Together, these data show D1 expression may re-program motivational circuitry to facilitate extinction learning during juvenility that is normally unavailable to juveniles and that sex differences exist.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Extinction and reinstatement to cocaine-associated cues in male and female juvenile rats and the role of D1 dopamine receptor

et al. 2015

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“…Females ingested MPH (2 mg/kg) or Veh via Frootloop (General Mills) twice daily between P20–35 (Brenhouse et al, 2009). This MPH dose was based on previous preclinical studies and represents a clinically relevant dose for humans (Andersen et al, 2002b; Brenhouse et al, 2009).…”

Section: Methodsmentioning

confidence: 99%

“…This MPH dose was based on previous preclinical studies and represents a clinically relevant dose for humans (Andersen et al, 2002b; Brenhouse et al, 2009). …”

Section: Methodsmentioning

confidence: 99%

“…The ADHD-like risk behaviors of impulsivity and increased sensitivity to cocaine-associated environments found following PFC 6-OHDA depletions (Freund et al, 2014) can aid in determining whether early MPH treatment increases (e.g., as we found in typically developing females (Brenhouse et al, 2009)) or decreases risk behaviors in older females. Ovarian hormones may also influence the expression of lasting treatment effects on behavior and on underlying mechanisms.…”

Section: Introductionmentioning

confidence: 99%

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Preventative treatment in an animal model of ADHD: Behavioral and biochemical effects of methylphenidate and its interactions with ovarian hormones in female rats

Lukkes

Freund

Thompson

et al. 2016

European Neuropsychopharmacology

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Clinical and preclinical studies on attention deficit hyperactivity disorder (ADHD) show that juvenile males that are exposed to methylphenidate (MPH) show reduced risk for substance use later in life. In contrast, little is known about whether females have the same enduring treatment response to stimulants and how gonadal hormones influence their behavior later in life. Females received either a sham or 6-hydroxydopamine (6-OHDA) microinjection in the prefrontal cortex (PFC) at postnatal day (P)10. Subjects were then treated with Vehicle or MPH (2 mg/kg, p.o.) between P20–35 and tested during late adolescence/young adulthood (P60); half of these subjects underwent ovariectomy at P55 to determine hormonal influences. Females with 6-OHDA were depleted of PFC dopamine by 61% and demonstrated increased impulsive choice (delayed discounting) and preferences for cocaine-associated environments relative to control females. Both MPH and ovariectomy reduced impulsive choice and cocaine preferences in 6-OHDA females, but had no enduring effect in Sham females. Ovariectomy itself did not significantly affect impulsivity. Juvenile MPH interacted strongly with 6-OHDA to increase D4, D5, Alpha-1A, Alpha-2A, and 5-HT-1A mRNA receptor expression in the PFC. MPH alone effected D1 mRNA, while 6-OHDA increased BDNF; all markers were decreased by ovariectomy. Together, these data suggest that 6-OHDA changes in dopamine are not only relevant for ADHD-like behaviors, but their long-term modulation by treatment and the influence of cyclical differences in menstrual cycle.

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Effects of psychotropic drugs on second messenger signaling and preference for nicotine in juvenile male mice

et al. 2014

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Rationale A common treatment strategy for pediatric attention deficit/hyperactivity disorder (ADHD) and major depressive disorder (MDD) is combined methylphenidate (MPH) and fluoxetine (FLX). This has raised concerns because MPH+FLX treatment may have pharmacodynamic properties similar to cocaine, potentially increasing drug abuse liability. Objectives To examine the short- and long-term consequences of repeated vehicle, MPH, FLX, MPH+FLX, and cocaine treatment on gene expression in juvenile (postnatal days [PD] 20–34) and adult (PD 70–84) male mice. We further assessed whether juvenile drug treatment influenced subsequent sensitivity for nicotine in adulthood. Methods Juvenile and adult C57BL/6J mice received vehicle, MPH, FLX, MPH+FLX, or cocaine twice-daily for 15 consecutive days. Mice were sacrificed 24 h or 2 months after the last drug injection to assess drug-induced effects on the extracellular signal-regulated protein kinase-1/2 (ERK) pathway within the ventral tegmental area. Subsequent sensitivity for nicotine (0.05, 0.07, and 0.09 mg/kg) was measured using the place-conditioning paradigm (CPP) 24 h and 2 months after juvenile drug exposure. Results MPH+FLX, or cocaine exposure in juvenile mice increased mRNA expression of ERK2 and its downstream targets (CREB, cFos, and Zif268), and increased protein phosphorylation of ERK2 and CREB 2 months after drug exposure. Similar mRNA findings were observed in the adult-treated mice. Findings on gene expression 24 h following drug treatment were variable. Juvenile drug exposure increased preference for nicotine when tested in adulthood. Conclusions Early-life MPH+FLX, or cocaine exposure similarly disrupts the ERK pathway, a signaling cascade implicated in motivation and mood regulation, and increases sensitivity for nicotine in adulthood.

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Juvenile Methylphenidate Exposure and Factors That Influence Incentive Processing

Cited by 21 publications

References 136 publications

Extinction and reinstatement to cocaine-associated cues in male and female juvenile rats and the role of D1 dopamine receptor

Extinction and reinstatement to cocaine-associated cues in male and female juvenile rats and the role of D1 dopamine receptor

Preventative treatment in an animal model of ADHD: Behavioral and biochemical effects of methylphenidate and its interactions with ovarian hormones in female rats

Effects of psychotropic drugs on second messenger signaling and preference for nicotine in juvenile male mice

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