Research reportMaternal separation affects cocaine-induced locomotion and response to novelty in adolescent, but not in adult rats
Introduction
Behavioral sensitization is a progressive and enduring enhancement of the motor stimulant effects of psychostimulants and other drugs of abuse, elicited by repeated administration of these drugs [28]. This phenomenon has been extensively studied in experimental animals and has been implicated as a key component of drug addiction [6], [29].
Stressful experiences appear to have a strong influence on susceptibility to drug-taking behavior [8], [19]. Cross-sensitization can occur between stress and drug-induced locomotor response. For example, adult rats repeatedly exposed to stress develop an increased behavioral response to challenge doses of amphetamine [27], cocaine [3], [31] and morphine [37].
Stress activates the hypothalamus–pituitary–adrenal (HPA) axis and releases adrenocorticotrophic (ACTH) and glucocorticoid hormones [18], [32]. Most evidence available until now points to a critical role for the hypothalamus–pituitary–adrenal (HPA) axis in drug- and stress-induced behavioral sensitization. For example, sensitization after repeated use of cocaine or amphetamine was not observed in adrenalectomized rats [7], [25]. However, Badiani et al. [4] found that both sham-treated and adrenalectomized rats develop locomotor sensitization to amphetamine, suggesting that circulating adrenal hormones are not essential for the development of amphetamine-induced sensitization.
Developmental studies in animals have confirmed clinical evidence that both prenatal and early postnatal perturbations can have a long-lasting impact on HPA axis function, and on subsequent neurochemical and behavioral responses to stress [9], [10], [23]. Acute or repeated separation from the dam during early postnatal life is an environmental manipulation that is called maternal separation. Maternal separation is considered one of the most powerful stress to which rat pups can be exposed [30], [38]. The most robust outcomes evident in adulthood following maternal separation are changes in HPA axis activity [13], [24], [38] and in behavioral responses to stress [17], [20], [38].
Maternal separation has been shown to affect behavioral responses to amphetamine and cocaine in adulthood in some studies, but not in others. For example, adult rats separated from their dams during 5 h, 10 times from postnatal day 5 (P5) to P20, had a reduction in amphetamine-induced locomotion when compared to handled controls [17]. Li et al. [15] found no alterations in the acute response, and a less robust sensitization to cocaine in female adult rats exposed to 3 h daily of maternal separation during the first 21 days of life when compared to non-handled animals. These results suggest that the impact of maternal separation on the effects of psychostimulant drugs depend on the duration of the separation as well as the control group used.
Investigations addressing the interplay between early postnatal manipulations and the effects of drugs of abuse have generally used adult subjects. Drug abuse among humans often begins during adolescence, a period of ontogeny in which individuals exhibit age-specific behavioral characteristics, such as risk taking and novelty seeking, which could predispose them to initiate drug use [35]. Many adolescent-specific neurobehavioral alterations seen in humans are also seen in rats of comparable age. Spear and Brake [36] defined periadolescence as the age period around the time of sexual maturation, when age-specific behavioral and psychopharmacological discontinuities are evident. Based on this criterion, the age period of approximately P30 to P42 was designated as periadolescence in rats.
Recently, we found that adolescent rats exposed daily to 3 h of maternal separation from P6 to P20 did not have altered behavioral responses to acute or chronic cocaine exposure when compared to non-handled controls [22].
Given that the response to psychostimulant drugs in animals exposed to maternal separation seems to depend on the duration and period of separation, and considering the differences between adolescence and adulthood, further investigations on the impact of maternal separation on the effect of cocaine are warranted. Exploring different protocols might lead to the identification of critical periods, during which exposure to stress could increase the vulnerability to drug abuse. Our approach was to examine whether maternal separation during 5 h daily from P2 to P6 affects the locomotor response to forced novelty or to cocaine during adolescence and adulthood. As corticosterone seems to be involved in mediating stress-induced changes in psychostimulant responses, we also measured the plasma levels of this hormone in these maternally separated animals exposed to forced novelty.
Section snippets
Subjects
We tested Wistar rats obtained from Institute of Biomedical Science, University of São Paulo, SP. Virgin adult females were mated with sexually experienced males in the animal facility of the School of Pharmaceutical Sciences-UNESP-Araraquara and transferred to the animal facility of our laboratory on gestational day 14; they were housed for a week before giving birth. The housing conditions (described below) were the same in both facilities. The date of birth was designated as P0. At P2, all
Locomotor response to novelty
In adolescent rats, there was a major effect of time on locomotion in response to a novel environment [F(1,17)=138.55; P<0.001], but not to postnatal condition [F(1,17)=2.23; P=0.154] (Fig. 1A). In addition, an interaction between factors was detected [F(1, 17)=7.11; P=0.016]. The finding of a significant postnatal condition by time interaction indicated a mixed profile. Separate analyses were then performed within each time interval with the F-test for contrasts. A main effect of group emerged
Discussion
We investigated the consequences of MS for 5 h daily, from P2 to P6, for adolescent and adult rats by measuring (a) locomotor and corticosterone responses to forced novelty and (b) acute locomotor response to cocaine. We found distinct effects of MS on these responses in adolescence and adulthood.
MS adolescent rats had an increased locomotor response to novelty, while no changes were observed in adult animals. Following forced novelty, both adolescent and adult rats displayed an increase in
Acknowledgements
The authors appreciate the excellent technical assistance by Elisabete Zocal Paro Lepera and Rosana Finoti Pupim Silva. We also thank Celso Luı́s Borsato for animal care. This work was supported by Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP-97/11010-2 and 00/09319-0).
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