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. 2010 Oct;64(10):773-85.
doi: 10.1002/syn.20784.

(+)-Methamphetamine-induced monoamine reductions and impaired egocentric learning in adrenalectomized rats is independent of hyperthermia

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(+)-Methamphetamine-induced monoamine reductions and impaired egocentric learning in adrenalectomized rats is independent of hyperthermia

Nicole R Herring et al. Synapse. 2010 Oct.

Abstract

Methamphetamine (MA) is widely abused and implicated in residual cognitive deficits. In rats, increases in plasma corticosterone and egocentric learning deficits are observed after a 1-day binge regimen of MA (10 mg/kg x 4 at 2-h intervals). The purpose of this experiment was to determine if adrenal inactivation during and following MA exposure would attenuate the egocentric learning deficits in the Cincinnati water maze (CWM). In the first experiment, the effects of adrenalectomy (ADX) or sham surgery (SHAM) on MA-induced neurotoxicity at 72 h were determined. SHAM-MA animals showed typical patterns of hyperthermia, whereas ADX-MA animals were normothermic. Both SHAM-MA- and ADX-MA-treated animals showed increased neostriatal glial fibrillary acidic protein and decreased monoamines in the neostriatum, hippocampus, and entorhinal cortex. In the second experiment, SHAM-MA- and ADX-MA-treated groups showed equivalently impaired CWM performance 2 weeks post-treatment (increased latencies, errors, and start returns) compared to SHAM-saline (SAL) and ADX-SAL groups with no effects on novel object recognition, elevated zero maze, or acoustic startle/prepulse inhibition. Post-testing, monoamine levels remained decreased in both MA-treated groups in all three brain regions, but were not as large as those observed at 72-h post-treatment. The data demonstrate that MA-induced learning deficits can be dissociated from drug-induced increases in plasma corticosterone or hyperthermia, but co-occur with dopamine and serotonin reductions.

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Figures

Figure 1
Figure 1
The body temperatures of animals in Experiment 1 (A & B) and Experiment 2 (C & D). No differences in initial temperatures were observed; however, MA produced significant increases in body temperature in SHAM animals starting 30 min after the first dose (A). However, hypothermia was observed from 30–90 min in ADX-MA animals and a slight increase in temperature at 510 min (B). Exp. 2 revealed similar findings: SHAM-MA animals demonstrated hyperthermia beginning at 30 min (C) while ADX-MA did not (D). The arrows denote the times when MA was delivered. * p<0.05.
Figure 2
Figure 2
Monoamine levels in neostriatum (A–D), hippocampus (E–F), and entorhinal cortex (G–H) 3 days following MA exposure. MA-treated animals regardless of adrenalectomy demonstrated decreased levels of DA (A), DOPAC (B) in the neostriatum and 5-HT (C, E & G) and 5-HIAA (D, F, & H) in all regions. In addition, by t-test, the ADX-MA animals had higher levels of 5-HT and 5-HIAA in the neostriatum, and 5-HIAA in the hippocampus compared to SHAM-MA animals. Group sizes: SHAM SAL = 6–10; SHAM MA = 5–6; ADX-SAL = 6–8; ADX-MA = 6–9). *p≤0.05 MA vs SAL, #p<0.05 ADX-MA vs SHAM-MA.
Figure 3
Figure 3
GFAP levels 3 days following MA exposure by western blot analysis. GFAP was increased in MA-treated animals regardless of regimen at 72 h following the first dose compared to SAL-treated animals. Group sizes: SHAM–SAL = 8, SHAM–MA = 6, ADX-SAL = 8, ADX-MA = 7). *p<0.05 MA vs SAL.
Figure 4
Figure 4
Mean (± SEM) stereotypy scores 6–30 h following the first dose of MA. MA-treated groups regardless of surgical condition displayed increased stereotypy compared to SAL-treated groups from the first scoring period out to 24 h post-treatment. Differences were essentially gone by 30 h post-treatment. Group sizes: SHAM -SAL = 16, SHAM–MA = 17, ADX-SAL = 14, ADX-MA = 15). **p≤0.05 ADX-MA vs SHAM-MA; both MA groups differed significantly from both SAL groups (not marked).
Figure 5
Figure 5
CWM performance beginning 2 weeks following MA treatment. SHAM-treated animals are displayed in A, C, E and ADX-treated animals are displayed in B, D, F. MA-treated animals, regardless of ADX, demonstrated decreased latencies beginning on day 6 (A, B), increased number of errors beginning on day 5 (C, D), and increased start returns beginning on day 5 (E, F). On day 4 ADX-SAL animals committed fewer start returns than SHAM-SAL animals (E,F). Group sizes: SHAM-SAL = 15, SHAM-MA = 17, ADX-SAL = 12, ADX-MA = 13. *p≤0.05 MA vs SAL, #p≤0.05 ADX-MA vs SHAM-MA.
Figure 6
Figure 6
Monoamine levels in neostriatum (A–D), hippocampus (E–F), and entorhinal cortex (G–H) ~35 days following MA exposure. MA-treated animals regardless of ADX demonstrated decreased levels of DA (A) but no effects on DOPAC (B) in the neostriatum. There was a trend for decreased 5-HT (C) and 5-HIAA (D) in the neostriatum. MA-treated animals regardless of ADX demonstrated decreased levels of 5-HT (E, G) and 5-HIAA (F, H) in the hippocampus and entorhinal cortex, respectively. In addition, ADX animals displayed increased 5-HIAA compared to SHAM animals in the hippocampus. Analysis of just the MA-treated animals by t-test showed that in the neostriatum and hippocampus the levels of monoamines were greater in ADX-MA relative to SHAM-MA with the exception of DOPAC in the neostriatum. Group sizes: SHAM-SAL = 10–11, SHAM MA = 9–11, ADX-SAL = 9–10, ADX-MA = 10–11). *p≤0.05 MA vs SAL, #p<0.05 ADX-MA vs SHAM-MA.

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