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

Abstract

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 x 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.

Figure 1

Diagrams for annuli swimming and direct swim analysis. (A) The target annulus for analysis of target annuli swims was drawn by drawing a 20 cm ring that encompassed the distal and proximal corners of the platform. (B) The corridor for direct swims was a 36 cm channel directly from the start location to the platform.

Figure 2

Neonatal CORT following MA exposure. (A) Levels of CORT in plasma (mean ± SEM) show a slight decrease on P15 following MA exposure from P11–15 (N = 10 per treatment). (B) CORT levels are increased following MA exposure on P11 (N = 10 per treatment). (C) On P20, CORT levels are increased following MA exposure in males only (N = 10 per treatment). ***p<0.001, †p<0.07.

Figure 3

Adult CORT interactions. (A) Adult CORT levels are decreased as a result of P11–20 MA treatment. (B) Female animals had higher levels of CORT compared to males. (C) CORT levels are increased immediately following MWM training and decline over time. (D) Females generally have higher CORT following MWM training. **p<0.01, *p<0.05; N = 12 per treatment.

Figure 4

Neonatal BDNF following MA exposure. MA treatment increases hippocampal BDNF protein levels in P15 animals. Animals were exposed to MA from P11–15 and sacrificed after final exposure on P15, *<0.05; N = 10 per age group.

Figure 5

Neonatal sex effects in BDNF following MA exposure on P11, female rats had lower levels of hippocampal (A) and hypothalamic (B) BDNF compared to males. MA treatment increased BDNF in P20 animals regardless of sex following P11–20 exposure (C). ***p<0.001, *p<0.05. N = 10 per age group.

Figure 6

BDNF levels following MWM training. BDNF levels remain relatively stable following MWM testing with MA treated animals having a slight increase in BDNF that approached significance (N = 12 per treatment).

Figure 7

NGF changes due to sex and training. (A) Females have higher levels of hippocampal NGF compared to males (N = 10 per treatment). (B) MA treatment increases NGF levels in the hippocampus on P20 (N = 10 per treatment). (C) Trained female MA-treated animals (N = 12 per treatment) have lower hypothalamic NGF levels than SAL-treated females. (D) NGF(N = 12 per treatment) levels are lower in untrained females treated with MA compared to untrained females. **p<0.01.

Figure 8

Neonatal MA treatment induces MWM deficits. P11–20 MA treatment caused increases in latency (A), path length (B), cumulative distance (C) and first bearing (D) to the platform. ***p<0.001, **p<0.01 (N = 12 per treatment).

Figure 9

MA treatment alters strategies in the MWM. (A) P11–20 MA treatment increases time spent in the periphery of the MWM. (B) MA treatment decreases the percent of direct swims to the platform from the start. (C) MA treatment decreases total direct swims by day. ***p<0.001, **p<0.01 (N = 12 per treatment).