Methamphetamine potentiates behavioral and electrochemical responses after mild traumatic brain injury in mice

Abstract

We previously demonstrated that high doses of methamphetamine (MA) exacerbate damage induced by severe brain trauma. The purpose of the present study was to examine if MA, at low dosage, affected abnormalities in locomotor activity and dopamine turnover in a mouse model of mild traumatic brain injury (mTBI). Adult male CD1 mice were treated with MA (5 mg/kgi.p.) or vehicle 30-min prior to mTBI, conducted by dropping a 30 g metal weight onto the temporal skull, anterior the right ear. At 15 min after mTBI, animals were put into locomotor activity chambers for up to 72 h. During the first 3 h, mTBI alone, compared with vehicle control, did not alter total distance travelled. Treatment with MA significantly increased locomotor activity in the control animals during the first 3 h; mTBI reduced MA-induced hyperactivity. In contrast, at 2 and 3 days after injury, mTBI or MA alone reduced locomotor activity. Co-treatment with MA and mTBI further reduced this activity, suggesting a differential and temporal behavioral interaction between MA and mTBI during acute and subacute phases after injury. Dopamine and DOPAC levels in striatal tissue were analyzed using HPLC-ECD. At 1h after mTBI or injection, DA was not altered but DOPAC level and DOPAC/DA turnover ratios were significantly reduced. Co-treatment with MA further reduced the DOPAC/DA ratio. At 36 h after injury, mTBI increased tissue DA levels, but reduced DOPAC levels and DOPAC/DA ratios. Co-treatment with MA further reduced DOPAC/DA ratios in striatum. In conclusion, our data suggest that low dosage of MA worsens the suppression of locomotor responses and striatal dopamine turnover after mTBI.

Fig. 1

Locomotor activity in the acute phase (initial 3 hours) after treatment with MA and/or mTBI. Behavioral data were analyzed every 30min. Treatment with MA (5mg/kg) enhanced (A) total distance travelled, (B) horizontal activity, (C) movement time, and (D) movement number. mTBI did not alter locomotor activity, but significantly reduced MA -mediated hyperactivity. (p<0.05, two way ANOVA+Newman-Keuls test).

Fig. 2

Locomotor activity in the sub-acute phase (2 and 3 days) after treatment with MA and/or mTBI. Behavioral data were analyzed every 4 hours. Animals demonstrated increased activity in dark phase with reduced activity in light phase. Locomotor activity returned to the same basal level at 24, 48 and 72 hours after injury in the light cycle. mTBI or MA alone reduced activity. Co-treatment with MA and mTBI further significantly attenuated locomotor activity, as compared to treatment with MA or mTBI only (p<0.05, two way ANOVA+Newman-Keuls test).

Fig. 3

Striatal DA, DOPAC and DOPAC/DA ratios in mice treated with MA and/or mTBI. At one hour after injection or injury (A, C, E), mTBI, compared to vehicle treatment, significantly reduced DOPAC levels and DOPAC/DA turnover ratios. MA alone significantly reduced tissue DA and DOPAC levels as well as DOPAC/DA ratios. There was a further reduction of DOPAC levels and DOPAC/DA ratios in animals treated with MA +mTBI, compared to mTBI only. At 36 hours after injection or injury (B, D.F), treatment with mTBI or MA significantly increased tissue DA level (p<0.001). Striatal DA levels were further enhanced in mice treated with mTBI and MA. mTBI and/or MA significantly reduced DOPAC levels and DOPAC/DA turnover. Co-treatment with mTBI and MA further suppressed DOPAC/DA ratios in striatum. (#p=0.030, Student's t test; *p<0.05, one way ANOVA+Newman-Keuls test)