Effects of intrastriatal dopamine D1 or D2 antagonists on methamphetamine-induced egocentric and allocentric learning and memory deficits in Sprague–Dawley rats
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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.
We tested whether blocking dopamine receptors protects against cognitive deficits.
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.
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.
The results show for the first time that dopamine receptors are mediators of MA-induced cognitive deficits.
KeywordsMethamphetamine Dopamine D1 antagonist Dopamine D2 antagonist SCH-23390 Sulpiride Egocentric learning Spatial learning Monoamines Rat
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.
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