Amphetamine modulation of long-term potentiation in the prefrontal cortex: dose dependency, monoaminergic contributions, and paradoxical rescue in hyperdopaminergic mutant.
Amphetamine can improve cognition in healthy subjects and patients with schizophrenia, attention-deficit hyperactivity disorder, and other neuropsychiatric diseases; higher doses, however, can impair cognitive function, especially those mediated by the prefrontal cortex. We investigated how amphetamine affects prefrontal cortex long-term potentiation (LTP), a cellular correlate of learning and memory, in normal and hyperdopaminergic mice lacking the dopamine transporter. Acute amphetamine treatment in wild-type mice produced a biphasic dose-response modulation of LTP, with a low dose enhancing LTP and a high dose impairing it. Amphetamine-induced LTP enhancement was prevented by pharmacological blockade of D(1) - (but not D(2)-) class dopamine receptors, by blockade of β-adrenergic receptors, or by inhibition of cAMP-PKA signaling. In contrast, amphetamine-induced LTP impairment was prevented by inhibition of post-synaptic protein phosphatase-1, a downstream target of PKA signaling, or by blockade of either D(1) - or D(2)-class dopamine, but not noradrenergic, receptors. Thus, amphetamine biphasically modulates LTP via cAMP-PKA signaling orchestrated mainly through dopamine receptors. Unexpectedly, amphetamine restored the loss of LTP in dopamine transporter-knockout mice primarily by activation of the noradrenergic system. Our results mirror the biphasic effectiveness of amphetamine in humans and provide new mechanistic insights into its effects on cognition under normal and hyperdopaminergic conditions.
Division of Neurosciences, New England Primate Research Center, Harvard Medical School, Southborough, Massachusetts, USA.
Tai-Xiang
TX
Xu
Qi
Q
Ma
Roger D
RD
Spealman
Wei-Dong
WD
Yao
D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D065127:Dopamine D2 Receptor Antagonists; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005473:Fluoxetine / Q000031:analogs & derivatives / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics*; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000502:physiology; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000502:physiology; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000502:physiology; D017448:Receptors, Dopamine D2 / Q000502:physiology
D065127:Dopamine D2 Receptor Antagonists; D050483:Dopamine Plasma Membrane Transport Proteins; D011943:Receptors, Adrenergic, beta; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D005473:Fluoxetine; C011386:nisoxetine; D000661:Amphetamine; D009638:Norepinephrine