Neonatal methamphetamine-induced corticosterone release in rats is inhibited by adrenal autotransplantation without altering the effect of the drug on hippocampal serotonin
Introduction
Methamphetamine (MA) is one of the most widespread drugs of abuse [20], [21]. Recent data show that 24% of pregnant women entering drug treatment programs report MA as their primary drug of abuse [42]. Prospectively ascertained data in humans suggest that ∼ 40% of pregnant MA users continue to use throughout pregnancy [7], [37], and since MA readily crosses the placenta [4], [15] there is passive exposure of the fetus. Infants born to women who used MA during pregnancy are reported to have reduced birth weight, length, and head circumference and increased rates of anemia and hemorrhage [7], [12], [13], [26], [32], [38]. Children exposed to MA in utero also show deficits in visual motor integration, attention, psychomotor speed, spatial and verbal memory [5], [6], novel object recognition memory on the Fagan Test of Infant Intelligence [41], as well as reduced arousal and quality of movement in newborns [38]. Magnetic resonance imaging (MRI) studies of in utero MA-exposed children reveal decreased volume of the hippocampus, putamen, and globus pallidus [6], and changes in white matter diffusivity using diffusion tensor imaging (DTI-MRI) with no changes in fractional anisotropy [10]. Magnetic resonance spectroscopy (MRS) data show higher total creatine, N-acetyl aspartate, and glutamate/glutamine in frontal white matter [5].
Algorithms that compare brain development across species reveal that P11 brain development in rats is comparable to humans at 26 weeks of gestation for cortex and 19 weeks of gestation for limbic structures [8], [9]. Rats treated with MA neonatally exhibit later deficits in spatial learning and memory, egocentric learning, have augmented acoustic startle reactivity, and other effects [45], [46], [47], [48], [49], [52], [55], [56], [58] as well as decreased spine density in the dentate gyrus and nucleus accumbens and increases in apical dendritic branching in the parietal cortex [53]. These animals also show reductions in 5-HT levels in the hippocampus and neostriatum during and immediately following drug exposure and at P90, however dopamine (DA) levels are unaffected during dosing, but depletions emerge by P90 [11], [35]. Neonatal MA treatment also causes increased release of ACTH and corticosterone [1], [36], [54], [57] lasting for at least 24 h [34], [35]. This effect of MA is more potent than corticosterone released in response to stressors such as forced swim or isolation at the same age [16]. The increase in neonatal MA-induced corticosterone release occurs during a period of normal adrenal quiescence referred to as the stress hyporesponsive period (SHRP) (approximately P4–14) [33] when despite dampened responsiveness, exposure to stressors can have long-lasting effects, an observation that may be important in understanding how neonatal MA leads to long-term effects. For example, prolonged stress that triggers increases in corticosterone during the SHRP sometimes leads to long-term alterations in hypothalamic-pituitary-adrenal (HPA) axis reactivity, increased startle reactivity, and spatial learning deficits in the Morris water maze [2], [14], [18], [22], [23], [52]; effects similar to those caused by neonatal MA treatment as described above.
Previous experiments using bilateral adrenalectomy (ADX) effectively prevented P11 MA-induced corticosterone release but caused secondary effects on 5-HT in which hippocampal 5-HT levels in ADX-MA treated animals were reduced more than those in SHAM-MA treated animals (unpublished observations). This is a potential confound since hippocampal 5-HT changes may be involved in the MA-induced learning deficits [27]. In order to avoid this we sought an alternative to ADX.
Here we describe a method of attenuating MA-induced neonatal corticosterone release that may be useful for testing hypotheses concerning the role of adrenal responses to neonatal MA treatment or other drugs/stressors. We chose adrenal autotransplantation (ADXA) because experiments using corticosterone synthesis inhibitors (ketoconazole or metyrapone), while initially blocking MA-induced corticosterone release, exhibited later corticosterone rebound 24 h later (unpublished observations). Partial restoration of the adrenal cortex function following ADXA has the advantage of attenuating MA-induced corticosterone release while still allowing sufficient corticosterone for normal growth and development and reducing the compensatory mechanisms (increased release of CRF and ACTH) known to accompany ADX [50], [51].
Section snippets
Subjects and conditions
Male (251–275 g) and nulliparous female (151–175 g) Sprague–Dawley CD IGS rats (Charles River Laboratories, Raleigh, NC) were acclimated to the vivarium for at least one week prior to breeding. The offspring were the subjects of this experiment and a total of 34 litters were used. Environmentally-enriching stimuli (stainless steel enclosures) [46] were placed in cages of the animals throughout the experiment. Food and water were provided ad libitum and the housing room was maintained on a 14:10 h
Body weight
In the P11 group, there was an effect of surgery, F(1,363) = 10.5, p < 0.001; the ADXA groups had reduced weight compared to the SHAM groups. This effect was also significant for the P12 through P19 groups (p-values from p < 0.001 to p < 0.03). No effect of surgery was observed on P20. There were also effects of drug and these began on P12, F(1,335) = 24.8, p < 0.0001, and were significant on all days through P20, e.g., on P20 the treatment main effect was F(1,41) = 89.8, p < 0.0001. Regardless of surgery,
Discussion
MA significantly increases corticosterone from P12–20 (Fig. 2B). ADXA effectively attenuated this effect, reducing the increases in corticosterone to ∼ 51% of SHAM–MA levels averaged across the 10 days of treatment (Fig. 3A). However, the degree of corticosterone release inhibition varied. Corticosterone levels in ADXA–MA animals were ∼ 30% of SHAM–MA levels on P11 and rose to ∼ 75% by P20. These data suggest that neonatal adrenal engraftment occurs more rapidly than in adults. In adult rats,
Conclusions
Adrenal autotransplantation provides an effective method of attenuating corticosterone release in neonatal rats. This model could be utilized for examining the effects of early exposure to stress or other drugs on brain development and function. Of particular interest in the present context is determining whether the MA-induced corticosterone release in neonates contributes to later learning and other behavioral effects.
Conflict of interest statement
The authors declare no conflict of interest concerning the research reported herein.
Acknowledgments
The authors express their appreciation to Mary Moran for assistance with the statistical analyses of the data. This research was supported by the NIH project grant RO1 DA006733 and the training grant T32 ES007031 (CEG; TLS). There are no conflicts of interest for this work.
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