Neonatal (+)-methamphetamine increases brain derived neurotrophic factor, but not nerve growth factor, during treatment and results in long-term spatial learning deficits

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Summary

In this study, brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) were examined at five time points [postnatal day (P)11, 15, 20, 21, and 68 (the latter with or without behavioral testing)] during and after P11–20 (+)-methamphetamine (MA) (10 mg/kg 4×day) treatment. BDNF in MA-treated animals was elevated on P15 and P20 in the hippocampus but not in the hypothalamus and was unchanged on P11 and P21. On P68 (1 h after Morris water maze testing) MA-treated offspring showed a trend toward higher levels of BDNF in the hippocampus than saline-treated animals. MA treatment increased NGF levels in the hippocampus but only on P20. No effect of MA treatment was observed in the elevated zero maze. MA-treated offspring had increased latencies, cumulative distances, path lengths, and first bearings in the Morris water maze. The findings indicate that early MA exposure induces hippocampal BDNF increases that precede the later emergence of spatial learning deficits.

Introduction

With the recent increase in use of methamphetamine (MA) by young adults (Johnston et al., 2005a, Johnston et al., 2005b) there is concern regarding fetal exposure to the drug since female users may become pregnant. MA is a powerful psychostimulant that upon administration blocks monoamine transporters for dopamine, serotonin, and norepinephrine and causes release of these neurotransmitters into the synaptic cleft, therefore resulting in a sustained presence of these neurotransmitters in the cleft (Kucaenski and Segal, 1994). While the literature on prenatal MA exposure is limited, there is an association between MA and low birth weight and length, decreased head circumference, and increased fetal distress (Chomchai et al., 2004; Little et al., 1988; Smith et al., 2006). Reductions in the volume of the caudate, putamen, globus pallidus, and hippocampus were observed in children who were prenatally exposed to MA (Chang et al., 2004). Prenatal MA exposure has also been suggested to alter brain ultrasonography (Dixon and Bejar, 1989) and increase the concentration of glutamine/glutamate and creatine (Smith et al., 2001). Children exposed to MA in utero have lower scores on visual motor tests as well as delayed verbal development and deficits in long-term spatial memory compared to age matched controls (Chang et al., 2004).

In rats, exposure to MA from postnatal days (P)11–20 causes long-term spatial learning and memory deficits (Vorhees et al., 1994a, Vorhees et al., 1994b, Vorhees et al., 2000; Williams et al., 2002, Williams et al., 2003a, Williams et al., 2003b). This period is approximately analogous to mid-second through third trimester human hippocampal development (Bayer et al., 1993). According to data from Clancy et al.(2007), P11 in a developing rat is equivalent to 182 d of human gestation in cortical development and 134 d in limbic development. Our model may represent a sensitive period to exogenous influences, such as drug exposure, that interfere with neurogenesis and/or synaptogenesis.

In addition, the beginning of the above exposure period is near the end of the stress hyporesponsive period (SHRP), a time when stress-induced increases in corticosterone (CORT) release are attenuated (Sapolsky and Meaney, 1986). The SHRP is presumed to protect the brain from possible neurotoxic effects of high glucocorticoid exposure when neurons that express glucocorticoid receptors are developing, such as in the hippocampus. Increased CORT levels were observed following MA exposure in neonatal rats on P11 or on P15 and P20 following daily dosing beginning on P11 (Williams et al., 2000). In addition, CORT levels were shown to be increased following a single MA dose to separate groups dosed on one of the following days: P1, 3, 5, 7, 9, 11, 13, 15, 17 or 19, or following five consecutive days of MA dosing on P1–5, 3–7, 5–9, 7–11, 9–13, 11–15, 13–17, or 15–19 (Williams et al., 2006). We have also shown that MA administration from P11–15, but not P16–20, causes spatial learning and memory deficits (Williams et al., 2003a). These effects are not limited to MA. For example, MDMA also induces increases in CORT on P11 (Williams et al., 2005) and spatial learning deficits when administered from P11–20 (Broening et al., 2001).

Neurotrophic factors are important for neuronal proliferation, survival, and differentiation during development, and remain expressed during adulthood where they regulate neuronal survival and maintenance. Two neurotrophic factors are brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF). BDNF and NGF expression are highest during the perinatal period, with BDNF protein levels reaching peak concentrations in the hippocampus by P14, while NGF levels peak at P7 (Das et al., 2001). In addition to their neurotrophic properties, BDNF and NGF have been implicated in learning and memory. Infusion of NGF for four weeks partially restores age-induced cholinergic atrophy in the nucleus basalis magnocellularis and improves Morris water maze (MWM) performance (Fischer et al., 1987). Mice that carry a heterozygous disruption of NGF have deficits in MWM performance that are alleviated when NGF is infused (Chen et al., 1997). BDNF mRNA has been shown to be increased following three or six days of spatial (Kesslak et al., 1998) or inhibitory avoidance learning (Bekinschtein et al., 2007), as is trkB mRNA (Gomez-Pinilla et al., 2001), which is the primary receptor for BDNF. Blocking BDNF using neutralizing antibodies or antisense nucleotides prior to or following inhibitory avoidance learning eliminates memory retention in rats (Bekinschtein et al., 2007; Mu et al., 1999). Furthermore, heterozygous BDNF knockout mice show learning deficits in the MWM (Linnarsson et al., 1997). In adult animals increased BDNF levels in the hippocampus enhance long-term potentiation and facilitate the phosphorylation of the NMDA-NR1 (Suen et al., 1997) and NMDA-NR2 receptor subunits (Lin et al., 1998). While these data come from experiments on BDNF effects in adult brain, they demonstrate its involvement in learning and memory.

There are also interactions between neurotrophins and CORT. BDNF and NGF are altered by increases in CORT. High levels of CORT from P1–7 increase mRNA for NGF in the hippocampus (Roskoden et al., 2004). Adult adrenalectomized (ADX) rats have higher levels of BDNF mRNA in the dentate gyrus than ADX animals that received CORT replacement (Chao and McEwen, 1994; Schaaf et al., 1997, Schaaf et al., 1998). Immobilization stress also decreases BDNF mRNA in the dentate in adult animals (Smith et al., 1995). Application of CORT to cultured neurons increases NGF mRNA which is blocked using a glucocorticoid antagonist (Scully and Otten, 1995), while dexamethasone (a synthetic glucocorticoid) treatment increases NGF mRNA in the cerebral cortex and hippocampus (Mocchetti et al., 1996).

The present experiments were designed to explore the effects of neonatal MA treatment on BDNF and NGF concentrations at five different developmental ages: (1) following five days of MA treatment (P11–15; P15 being the age with the highest levels of BDNF expression as demonstrated by Das et al., 2001); (2) after an acute treatment of MA on P11 (the first day of the sensitive period for MA-induced spatial learning deficits); (3) after P11–20 treatment of MA and examined after the last dose on P20; (4) on P21, 24 h after the end of MA treatment; and (5) on P68 either following MWM testing or on P68 with no testing, after P11–20 MA administration. While it is known that adult animals have a sexually dimorphic response to stressors (Beiko et al., 2004), it is not known if sexually dimorphic differences occur throughout development in neurotrophin levels, especially after MA. Therefore, in this study we examined males and females at all ages to be tested.

Section snippets

Subjects and conditions

Male and nulliparous female Sprague-Dawley CD (IGS) rats were obtained from Charles Rivers Laboratories (Raleigh, NC). Animals were allowed to acclimate to the lighting (14/10 h light/dark cycle; lights on at 0600 h) and ambient temperature (20±1 °C) of the vivarium (50±10% humidity) for a minimum of 2 weeks prior to breeding. One male and one female were placed together in hanging wire cages for two weeks, after which females were moved to polycarbonate cages and left undisturbed until

Corticosterone

Experiment 1: Rats were treated four times/day with MA or SAL from P11–14, treated twice on P15 and examined 1 h after the second dose. MA-treated animals showed a trend toward decreased CORT in plasma 1 h following the last injection of MA compared to SAL-treated animals (F(1,9)=4.13, p<0.07; Fig. 2A).

Experiment 2: Rats were administered MA three times on P11 and sacrificed 1 h after the last dose. There was a main effect of treatment (F(1,8)=48.74, p<0.0001; Fig. 2B) showing significantly higher

Discussion

We have previously shown that MA exposure from P11–20 causes deficits in MWM learning and memory (Vorhees et al., 1994a, Vorhees et al., 1994b, Vorhees et al., 1996, Vorhees et al., 1999, Vorhees et al., 2000; Williams et al., 2002, Williams et al., 2003a, Williams et al., 2003b). Consistent with these findings, we showed that MA exposure caused learning deficits when the animals were tested here. The results of this study also confirmed our previous work that showed CORT was increased on P11,

Role of the funding source

Grants funds from the US National Institutes of Health provided all financial support for the research reported in this manuscript in its entirety.

Conflict of interest

The authors certify that they have no conflict of interest pertaining to any aspect of the research reported in this manuscript.

Acknowledgment

This research was supported by NIH Grants DA006733 (CVV), DA014269 (MTW), and training grant ES07051 (MRS and TLS). We acknowledge Carrie Brown-Strittholt's participation in this research.

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