Kappa opioid-mediated behavioral sensitization in the preweanling rat: relationship to Fos immunoreactivity

Abstract

When given acutely, drugs that stimulate kappa opioid receptors (e.g., U-50,488) enhance the locomotor activity of preweanling rats and induce regional increases in Fos immunoreactivity (IR). In contrast, the effects of chronic treatment with kappa opioid agonists are unknown. The purpose of the present study was two-fold: first, to determine whether repeated treatment with a kappa opioid agonist would sensitize the locomotor activity of preweanling rats and, second, to determine whether changes in Fos IR correspond with the occurrence of locomotor sensitization. To test these hypotheses, rats were injected with U-50,488 (5 mg/kg, s.c.) or saline on either postnatal days (PD) 5-9 or PD 11-15. For rats pretreated on PD 5-9, a test day injection of U-50,488 or saline was given after either 1 or 7 abstinence days (i.e., at PD 11 or PD 17). For rats pretreated on PD 11-15, a test day injection of U-50,488 or saline was given after 1 abstinence day (i.e., at PD 17). In two additional experiments, the acute and chronic effects of U-50,488 treatment were assessed in adult rats. As expected, repeated treatment with U-50,488 produced locomotor sensitization at both PD 11 and PD 17, but only when the test day occurred 1, and not 7, days after cessation of drug pretreatment. Thus, the persistence of the sensitized response was very brief. Test day treatment with U-50,488 stimulated Fos IR in various brain regions of the preweanling rat, including the medial striatum, nucleus accumbens, lateral habenula, and septal area. Chronic treatment with U-50,488 depressed Fos expression in a number of brain regions (relative to acutely treated rats); however, these changes in Fos IR did not necessarily coincide with the occurrence of behavioral sensitization. Repeated treatment with U-50,488 did not produce locomotor sensitization in adult rats, so Fos IR was not assessed in this age group. Therefore, while acute treatment with U-50,488 both increased locomotor activity and stimulated Fos IR in preweanling rats, chronic U-50,488 treatment produced behavioral changes that did not correspond with Fos expression.

Long-term contextual memory in infant rats as evidenced by an ethanol conditioned tolerance procedure

“…Moreover, we observed that this effect lasts for at least eight days in the infant rat (Castello et al, 2016), which also contrasts with the literature employing different psychostimulants, showing that sensitization acquired during the second postnatal week of life does not last for more than three days (McDougall et al, 1994, Collins et al, 1998, McDougall et al, 1999. Considering the long-term persistence of tolerance and sensitization, the present results also have relevance for the ethanol literature.…”

κ-Opioid System Regulates the Long-Lasting Behavioral Adaptations Induced by Early-Life Exposure to Methylphenidate

“…It is speculated that different KOR populations, located in different brain regions, may mediate U-50,488 effects (Charntikov et al, 2008; Kuzmin et al, 2000). This notion is intriguing because U-50,488 induces hyperactivity in developing rats, while inducing hypoactivity in adult rats (Collins et al, 1998; McDougall et al, 1997), yet it attenuates drug reward in developing and adult rats in a similar manner (Bolaños et al, 1996; Crawford et al, 1995). …”

One-trial cocaine-induced behavioral sensitization in preweanling rats: Role of contextual stimuli.

“…The purpose of Experiment 2 was to determine whether pretreating rats with a compound other than cocaine would differentially affect the expression of context-specific and context-independent behavioral sensitization. MK-801 (an NMDA antagonist), U50,488 (a kappa opioid agonist), and methylphenidate (a psychostimulant) were used because all three drugs typically induce substantial locomotor activity in preweanling rats (Duke, Meier, et al, 1997; Frantz & Van Hartesveldt, 1999; Jackson & Kitchen, 1989; McDougall, Collins, Karper, Watson, & Crawford, 1999) and are capable of inducing a sensitized locomotor response (Collins, Zavala, Ingersoll, Duke, Crawford, & McDougall, 1998; Duke, O'Neal, & McDougall, 1997; McDougall et al, 1999). On PD 19, rats were pretreated with MK-801, U50,488, methylphenidate, or cocaine before placement in activity chambers or small, enclosed anesthesia chambers.…”