Comparison of monoamine and corticosterone levels 24 h following (+)methamphetamine, (+/-)3,4-methylenedioxymethamphetamine, cocaine, (+)fenfluramine or (+/-)methylphenidate administration in the neonatal rat

Abstract

We have previously shown that neonatal administration of (+/-)3,4-methylenedioxymethamphetamine and (+)fenfluramine produce deficits in spatial and path integration learning, whereas (+)methamphetamine causes deficits in spatial learning. Conversely, cocaine and (+/-)methylphenidate have no effect on either form of learning following neonatal administration. The purpose of the present study was to determine whether corticosterone and/or monoamine levels were changed following subcutaneous administration of 10 mg/kg (+)methamphetamine, (+/-)3,4-methylenedioxymethamphetamine, (+)fenfluramine, (+/-)methylphenidate or cocaine every 2 h (total of four injections) on postnatal day 11. Twenty-four hours after the first dose, plasma, striatum and hippocampus were collected. Corticosterone levels were increased in methamphetamine-, fenfluramine-, methylenedioxymethamphetamine- and methylphenidate-treated rats relative to levels in saline-treated rats, whereas cocaine-treated rats were unaffected. In the striatum and hippocampus, serotonin and 5-hydroxyindolacetic acid were reduced in animals treated with methylenedioxymethamphetamine or fenfluramine, compared with levels in saline controls. Dopamine levels were not changed by any of the drugs, although 3,4-dihydroxyphenylacetic acid was decreased following methylenedioxymethamphetamine or methamphetamine. Minimal effects were seen in neurotransmitter levels following injection of cocaine or methylphenidate. These data suggest that drugs that affect corticosterone and hippocampal serotonin are associated with both spatial learning and path integration deficits, and those that affect corticosterone and 3,4-dihydroxyphenylacetic acid are associated with spatial learning deficits only.

Fig. 1

Corticosterone concentrations in plasma 24 h after the first of four doses (every 2 h) of FEN, MDMA, MA MPH and COC (10 mg/kg) that began on P11. Values are mean ± SEM. MA produced the greatest increase in CORT, giving significantly different levels from those in animals treated with SAL, MDMA, MPH and COC. FEN also produced an increase in these P12 animals. MDMA and MPH produced similar increases compared with SAL. *p < 0.05 versus SAL control; §p < 0.05 versus MDMA; ¶p < 0.05 versus MA; **p < 0.05 versus MPH; ††p < 0.05 versus COC. ANOVA with post-hoc step-down F-tests.

Fig. 2

Serotoninergic markers in striatum. Values are mean ± SEM (n = 8/group). Concentrations of (a) 5-HT, (b) 5-HIAA and (c) 5-HIAA/ 5-HT ratio in the striatum of animals exposed to four doses of FEN, MDMA, MA, MPH or COC on P11 and examined on P12. Decreases in 5-HT were observed in FEN-, MDMA- and MPH-treated animals, and FEN and MDMA also decreased 5-HIAA. FEN produced a significant increase in the 5-HIAA/5-HT ratio compared with the SAL group. *p < 0.05 versus SAL control; ‡p < 0.05 versus FEN; §p < 0.05 versus MDMA; ¶p < 0.05 versus MA; **p < 0.05 versus MPH; ††p < 0.05 versus COC. ANOVA with post-hoc step-down F-tests.

Fig. 3

Dopaminergic markers in striatum. Values are mean ± SEM (n = 8/group). Concentrations of (a) DA, (b) DOPAC and (c) DOPCA/ DA ratio in the striatum on P12 following administration of FEN, MDMA, MA, MPH or COC on P11. No changes were observed in DA. MA and MDMA produced a significant decrease in DOPAC. The ratio of DOPAC/DA was significantly decreased following MDMA and MA treatments, and increased in the MPH group. There was also a trend for the DOPAC/DA ratio to be decreased following FEN and increased following COC. *p < 0.05, †p < 0.10 versus SAL control; ‡p < 0.05 versus FEN; §p < 0.05 versus MDMA; ¶p < 0.05 versus MA; **p < 0.05 versus MPH; ††p < 0.05 versus COC.

Fig. 4

Serotonergic markers in the hippocampus. Values are mean ± SEM (n = 8/group). Concentrations of (a) 5-HT, (b) 5-HIAA and (c) 5-HIAA/5-HT ratio in the hippocampus of animals on P12 after four doses of FEN, MDMA, MA, MPH or COC on P11. Decreases in 5-HT were observed in FEN- and MDMA-treated animals. FEN and MDMA treatment also produced a significant decrease in 5-HIAA. There was a trend for a decrease in 5-HIAA in the MA group and an increase following MPH. Only FEN produced a significant increase in the 5-HIAA/5-HT ratio compared with the SAL group. *p < 0.05, †p < 0.10 versus SAL control; ‡p < 0.05 versus FEN; §p < 0.05 versus MDMA; ¶p < 0.05 versus MA; **p < 0.05 versus MPH; ††p < 0.05 versus COC.

Fig. 5

Comparison of FEN, MDMA, MA, COC and MPH effects on Morris water maze spatial learning from previous experiments. Each of the drugs was administered at a dose of 40 mg/kg/day from P11–20 with the exception of COC that was administered at 60 mg/kg/day. There is a clear rank order of effects (expressed as percent of SAL from each study) in the acquisition phase of the Morris water maze. FEN produced the longest latencies in finding the hidden platform (Morford et al. 2002). In the present study, FEN-treated animals showed the most dramatic decreases in both striatal (Fig. 2a) and hippocampal (Fig. 4a) 5-HT, and a significant increase in CORT (Fig. 1). MDMA produced the next greatest deficit in the Morris maze (Williams et al. 2003c), and next largest decreases in striatal (Fig. 2a) and hippocampal (Fig. 4a) 5-HT levels. MA produced significant increases in latency (Williams et al. 2002), but not to the degree of FEN or MDMA, and it did not produce any changes in 5-HT (Figs 2a and 4a), but produced the largest increase in CORT (Fig. 1). Neither MPH (Vorhees C. V., Moran M. S., Williams M. T. unpublished results) nor COC (Vorhees et al. 2000b) produced any changes in latency and only MPH slightly affected 5-HT in the striatum (Fig. 2a). *p < 0.05 versus SAL controls (100% reference line).