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Psychopharmacology

, Volume 236, Issue 7, pp 2243–2258 | Cite as

Effects of intrastriatal dopamine D1 or D2 antagonists on methamphetamine-induced egocentric and allocentric learning and memory deficits in Sprague–Dawley rats

  • Arnold Gutierrez
  • Samantha L. Regan
  • Christopher S. Hoover
  • Michael T. Williams
  • Charles V. VorheesEmail author
Original Investigation
  • 185 Downloads

Abstract

Rationale

Methamphetamine (MA) is an abused psychostimulant that causes cognitive deficits after chronic use. Neostriatal dopamine receptors play a role in MA monoamine neurotoxicity. Blocking dopamine receptors prior to MA exposure in adult rats attenuates monoamine reductions and reactive gliosis.

Objectives

We tested whether blocking dopamine receptors protects against cognitive deficits.

Methods

First, we determined the effects of MA alone versus MA in combination with the dopamine receptor D1 antagonist SCH-23390 or the dopamine receptor D2 antagonist sulpiride on cFos expression and monoamines at the age when rats in the cognitive experiment were to begin testing and monoamines in rats after cognitive testing.

Results

SCH-23390 infused into the neostriatum prior to systemic administration of MA attenuated MA-induced cFos activation while sulpiride induced cFos activation. Two weeks after MA, rats had dopamine and serotonin reductions that were attenuated by each antagonist. Other rats treated the same way, were tested for egocentric learning and memory in the Cincinnati water maze, for navigational strategy in a star water maze, and spatial learning and memory in a Morris water maze. Pre-treatment with SCH-23390 or sulpiride attenuated the effects of MA on egocentric and spatial learning and memory. MA-treated rats showed a shift from an egocentric to a disorganized strategy in the star maze that was less disorganized in groups receiving MA and an antagonist. Post-behavior monoamine reductions remained but were attenuated by the antagonists but not identically to what was seen in rats not behaviorally tested.

Conclusions

The results show for the first time that dopamine receptors are mediators of MA-induced cognitive deficits.

Keywords

Methamphetamine Dopamine D1 antagonist Dopamine D2 antagonist SCH-23390 Sulpiride Egocentric learning Spatial learning Monoamines Rat 

Notes

Acknowledgments

This research was supported by National Institutes of Health grant T32 ES007051 (AG), a doctoral dissertation award from the University of Cincinnati Graduate School (AG), and a grant from the University of Cincinnati University Research Council (AG).

Conflict of interest

The authors declare that they have no conflicts of interest.

Compliance with ethical standards

The protocol was approved by the Institutional Animal Care and Use Committee of Cincinnati Children’s Research Foundation and adhered to guidelines on animal use from the National Institutes of Health.

Supplementary material

213_2019_5221_Fig6_ESM.png (309 kb)
Figure S1

Schematic of cannula placement and c-fos expression of coronal section:Right: Illustration of cannula placement in center of caudate with anterior-posterior position +0.26 mm anterior to bregma, mediolateral position ±3.0 mm relative to the midline, and dorsal-ventral position -5.2 mm deep from dorsal surface (Paxinos and Watson 1998). Left: Striatal c-fos expression after DRD2 antagonist infusion. Image was compiled using binary superimposed sections (n=6) from DRD2 antagonist infusions to illustrate how the drug spread as reflected by c-fos activation and where the greatest concentration of expression occurred. (PNG 309 kb)

213_2019_5221_MOESM1_ESM.tif (436 kb)
High Resolution Image (TIF 435 kb)
213_2019_5221_Fig7_ESM.png (619 kb)
Figure S2

DRD1 Experiment: Star water maze (maze schematic shown in lower-left pane). (A) Number of successful trials. (B) Latency and (C) Errors across blocks. (D) Percent of rats using each strategy on the day-5 probe trial. (E) Day-10 probe trial. (F) Day 15 probe trial. (G) Day 20 probe trial. Strategies (from probe trial start position): A = allocentric, E = egocentric, G = guidance, and U = undetermined. Most rats showed no consistent strategy and were classified as U. Data are Mean ± SEM. Group sizes: S/S=14, SCH/S=15, SCH/MA=13, S/MA=14. *P ≤ 0.05 vs. S/S panel A; *P ≤ 0.05; **P < 0.01 for strategies within each group (panels D-G). (PNG 619 kb)

213_2019_5221_MOESM2_ESM.tif (1.3 mb)
High Resolution Image (TIF 1339 kb)
213_2019_5221_Fig8_ESM.png (323 kb)
Figure S3

DRD2 Experiment: Star water maze.A: Successful trials by block. B: Latency to escape. C, Errors. Probe trials: D: Day 5, E: Day 10, F: Day 15, G: Day 20. Most groups showed undeterminable patterns that did not fit one of the defined strategies. Group sizes: S/S=14, SUL/S=15, SUL/MA=16, S/MA=15. *P < 0.05; **P < 0.01; ***P < 0.001 for navigation type within each group. (PNG 322 kb)

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High Resolution Image (TIF 1032 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pediatrics, Div. of NeurologyUniversity of Cincinnati College of Medicine and Cincinnati Children’s Research FoundationCincinnatiUSA

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