Reversal of neuronal and cognitive consequences of amphetamine sensitization following chronic treatment with a D1 antagonist.
Neuroplasticity is a key factor in restoration of brain function following neuropathology associated with disease or drug exposure. Here we examined the potential for chronic treatment with the selective D1 receptor antagonist SCH39166 to reverse the profound and enduring cognitive impairment associated with amphetamine (AMPH) sensitization in the nonhuman primate and to stimulate re-growth of atrophied pyramidal dendrites in the dorsolateral prefrontal cortex of these animals. Four rhesus monkeys with sustained cognitive impairment (>1year following AMPH sensitization) were treated for up to 8months with SCH39166. Cognitive testing was performed before, during, and for up to 1(1/2) year following treatment. Significant improvement in working memory performance was observed only after cessation of the D1 antagonist treatment but then was sustained for the duration of the post-treatment testing period. Postmortem quantitative assessment of Golgi-impregnated pyramidal neurons in BA9 showed that apical dendritic length and trunk spine density were increased in D1 antagonist treated monkeys relative to AMPH-sensitized and AMPH-naïve monkeys. These findings, which suggest that the deleterious consequences of AMPH sensitization can be reversed by modulation of D1 receptor signaling, have implications for treating the underlying neural basis of cognitive deficits in both schizophrenia and substance abuse.
Selemon
Lynn D
LD
Behavioral Pharmacology Group, Laboratory of Animal Morphology and Pathology, State University of North Fluminense Darcy Ribeiro, Avenida Alberto Lamego, 2000, Campos dos Goytacazes, 28013-600, RJ, Brazil.
Begović
Anita
A
Williams
Graham V
GV
Castner
Stacy A
SA
D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects*; D003712:Dendrites / Q000187:drug effects / Q000648:ultrastructure; D049229:Dendritic Spines / Q000187:drug effects / Q000648:ultrastructure; D018492:Dopamine Antagonists / Q000494:pharmacology*; D005260:Female; D008253:Macaca mulatta; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D011597:Psychomotor Performance / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects
D001552:Benzazepines; D000697:Central Nervous System Stimulants; D018492:Dopamine Antagonists; D012333:RNA, Messenger; D017447:Receptors, Dopamine D1; C534628:SCH 23390; C058081:ecopipam; D000661:Amphetamine