Effects of repeated exposure to morphine in adolescent and adult male C57BL/6J mice: age-dependent differences in locomotor stimulation, sensitization, and body weight loss

Abstract

Rationale Given evidence for age-related differences in the effects of drugs of abuse, surprisingly few preclinical studies have explored effects of opioids in adolescents (versus adults). Objectives This study compared the motor stimulating and ataxic effects of repeatedly-administered morphine in adolescent, late-adolescent, and adult mice. Methods Mice were treated with saline or morphine (10–100 mg/kg, i.p.) once per day for 4 days, and morphine (3.2–56 mg/kg)-induced locomotion was assessed 3 days or 5 weeks later. Different mice were treated repeatedly with morphine and ataxia was measured. Results Acute administration of morphine increased locomotion more in adolescents than in adults. Repeated morphine enhanced morphine-induced locomotion, assessed 3 days later, to a similar extent in each age group (minimum effective dose: 17.8 mg/kg). This sensitization was still evident 5 weeks later when the adolescents had become adult, but was smaller and occurred at a higher dose (56 mg/kg). In animals treated repeatedly with morphine as adults, sensitization was no longer apparent 5 weeks later. Intermittent morphine was at least 10-fold less potent to produce body weight loss in adolescents than in adults. Repeated morphine did not alter morphine-induced ataxia at any age. Conclusions Compared with adults, adolescents were more sensitive to the acute locomotor stimulating effects of morphine and to its long-lasting locomotor sensitizing effects, consistent with overactivity of dopamine systems during adolescence. In contrast, adolescents were less sensitive than adults to body weight loss induced by intermittent morphine, an effect indicative of morphine withdrawal in adult rodents.

Morphine-induced conditioned place preference and effects of morphine pre-exposure in adolescent and adult male C57BL/6J mice

“…There were significant baseline differences in locomotion among the age groups upon initial exposure to the activity chambers (see Results), consistent with previous observations (Koek et al, 2012; Koek, 2013). Therefore, locomotion during morphine conditioning sessions was expressed for each animal as a percentage of locomotion during the saline conditioning session conducted the same day [for additional details of this approach, see results and discussion in Koek et al (2012)].…”

“…Repeated administration of morphine is known to produce locomotor sensitization in adult rodents (e.g., Kalivas and Duffy 1987; Kuribara 1996; Vanderschuren et al 1997). Consistent with previous findings in rats (White and Holtzman 2005; White et al 2008), morphine-induced locomotor sensitization during adulthood is more pronounced in mice repeatedly exposed to morphine as adolescents than as adults (Koek, 2013), conceivably involving overactivity of the mesolimbic dopamine system during adolescence.…”

“…Three days after the fourth injection, morphine-induced conditioned place preference was examined with the same procedure that was used in experiment 1 (n=8–12 per group). Previously, 17.8 mg/kg was found to be the lowest dose of morphine that produced locomotor sensitization in adult and adolescent C57BL/6J mice (Koek et al, 2013). Experiment 2 examined conditioned place preference at doses of morphine (i.e., 0.32–10 mg/kg) found to be effective in experiment 1.…”

Emergence of sex differences in the development of substance use and abuse during adolescence

“…However, similarly disparate findings are reported for nicotine, with one study reporting a sensitization that perseveres to adulthood (Faraday et al, 2003), another which reported sensitization in adults but not adolescents (Zago et al, 2012), and a third which reported comparable sensitization following adolescent or adult treatment (Adriani, Deroche-Gamonet, Le Moal, Laviola, & Piazza, 2006) Two studies reported increased cross-sensitization to cocaine (Santos, Marin, Cruz, Delucia, & Planeta, 2009) or amphetamine (McQuown et al, 2009) after adolescent nicotine. Similarly, one study reported comparable sensitization to heroin in adolescents and adults (Doherty & Frantz, 2013), while another reported more persevering sensitization in adolescents than adults (Koek, 2014). Overall, results of sensitization experiments are equivocal about whether sensitization is more, less or comparable in adolescents and adults.…”

“…For example, both enhanced and decreased locomotor responses to psychomotor stimulants, nicotine and narcotics are reported in adolescents compared to adults although reported increases outnumber decreases (Adriani & Laviola, 2000; Adriani, Macri, Pacifici, & Laviola, 2002; Cao et al, 2010; Caster, Walker, & Kuhn, 2005; Faraday, Elliott, Phillips, & Grunberg, 2003; Koek, 2014; Koek, France, & Javors, 2012; McQuown, Dao, Belluzzi, & Leslie, 2009; Zombeck, Lewicki, Patel, Gupta, & Rhodes, 2010)…”