Requirement for the POZ/BTB protein NAC1 in acute but not chronic psychomotor stimulant response.
NAC1 is a novel member of the POZ/BTB (Pox virus and Zinc finger/Bric-a-bracTramtrack Broad complex) but varies from other proteins of this class in that it lacks the characteristic DNA-binding motif, suggesting a novel role. We have employed constitutive gene deletion to elucidate the role of NAC1 in vivo. Nac1 mutant mice are viable with no obvious developmental or physiological impairments. Previous studies suggest a role for NAC1 in cocaine-mediated behaviors. Therefore, we evaluated a variety of behaviors associated with psychomotor stimulant effects in Nac1 mutant mice. Acute locomotor activating effects of cocaine or amphetamine are absent in Nac1 mutant mice, however longer exposure to these psychomotor stimulants result in the development of behavioral sensitization. Acute rewarding properties of cocaine and amphetamine are also blunted in mutant mice, yet repeated exposure resulted in conditioned place preference similar to that observed in wild-type mice. Lastly, increases in extracellular dopamine in the nucleus accumbens, which accompany acute cocaine administration, are blunted in mutant mice, but following chronic cocaine extracellular dopamine levels are increased to the same extent as in wild-type mice. Together these data indicate involvement of NAC1 in the acute behavioral and neurochemical responses to psychomotor stimulants.
Mackler
Scott
S
Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, United States.
Pacchioni
Alejandra
A
Degnan
Ryan
R
Homan
Ying
Y
Conti
Alana C
AC
Kalivas
Peter
P
Blendy
Julie A
JA
D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D001923:Brain Chemistry / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D003042:Cocaine / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D018076:DNA, Complementary / Q000096:biosynthesis / Q000302:isolation & purification; D004298:Dopamine / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology*; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D012097:Repressor Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000697:Central Nervous System Stimulants; D018076:DNA, Complementary; C484605:Nacc1 protein, mouse; D009419:Nerve Tissue Proteins; D012097:Repressor Proteins; D012313:RNA; D000661:Amphetamine; D003042:Cocaine; D004298:Dopamine