title: Deficits in behavioral sensitization and dopaminergic responses to methamphetamine in adenylyl cyclase 1/8-deficient mice.
abstract: The cAMP/protein kinase A pathway regulates methamphetamine (METH)-induced neuroplasticity underlying behavioral sensitization. We hypothesize that adenylyl cyclases (AC) 1/8 mediate these neuroplastic events and associated striatal dopamine regulation. Locomotor responses to METH (1 and 5 mg/kg) and striatal dopamine function were evaluated in mice lacking AC 1/8 (DKO) and wild-type (WT) mice. Only 5 mg/kg METH induced an acute locomotor response in DKO mice, which was significantly attenuated versus WT controls. DKO mice showed a marked attenuation in the development and expression of METH-induced behavioral sensitization across doses relative to WT controls. While basal and acute METH (5 mg/kg)-evoked accumbal dialysate dopamine levels were similar between genotypes, saline-treated DKO mice showed elevated tissue content of dopamine and homovanillic acid in the dorsal striatum (DS), reflecting dysregulated dopamine homeostasis and/or metabolism. Significant reductions in DS dopamine levels were observed in METH-sensitized DKO mice compared to saline-treated controls, an effect not observed in WT mice. Notably, saline-treated DKO mice had significantly increased phosphorylated Dopamine- and cAMP-regulated phosphoprotein levels, which were not further augmented following METH sensitization, as observed in WT mice. These data indicate that AC 1/8 are critical to mechanisms subserving drug-induced behavioral sensitization and mediate nigrostriatal pathway METH sensitivity. Calcium/calmodulin-stimulated adenylyl cyclase (AC) isoforms 1 and 8 were studied for their involvement in the adaptive neurobehavioral responses to methamphetamine. AC 1/8 double knockout (DKO) mice showed heightened basal locomotor activity and dorsal striatal dopamine responsivity. Conversely, methamphetamine-induced locomotor activity was attenuated in DKO mice, accompanied by reductions in dopamine and HVA content and impaired DARPP-32 activation. These findings indicate AC 1/8 signaling regulates the sensitivity of the nigrostriatal pathway subserving stimulant and neuroadaptive sensitizing effects of methamphetamine. 3-MT, 3-methoxytyramine; Ca(2+), calcium; CaM, calmodulin; cdk5; cyclin-dependent kinase 5; DA, dopamine; DARPP-32, dopamine- and cAMP-regulated phosphoprotein; D1R, dopamine D1 receptor; HVA, homovanillic acid; PKA, protein kinase A.
authors.affiliation: Research & Development, John D. Dingell VA Medical Center, Detroit, Michigan, USA.|Department of Neurosurgery, Wayne State University, Detroit, Michigan, USA.
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Bosse
authors.affiliation: Research & Development, John D. Dingell VA Medical Center, Detroit, Michigan, USA.|Department of Neurosurgery, Wayne State University, Detroit, Michigan, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Charlton
authors.affiliation: Research & Development, John D. Dingell VA Medical Center, Detroit, Michigan, USA.|Department of Neurosurgery, Wayne State University, Detroit, Michigan, USA.
authors.forename: Laura L
authors.initials: LL
authors.lastname: Susick
authors.affiliation: Department of Chemistry, Wayne State University, Detroit, Michigan, USA.
authors.forename: Brooke
authors.initials: B
authors.lastname: Newman
authors.affiliation: Department of Psychiatry and Behavioral Neurosciences, Wayne State University, Detroit, Michigan, USA.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Eagle
authors.affiliation: Department of Chemistry, Wayne State University, Detroit, Michigan, USA.
authors.forename: Tiffany A
authors.initials: TA
authors.lastname: Mathews
authors.affiliation: Department of Psychiatry and Behavioral Neurosciences, Wayne State University, Detroit, Michigan, USA.
authors.forename: Shane A
authors.initials: SA
authors.lastname: Perrine
authors.affiliation: Research & Development, John D. Dingell VA Medical Center, Detroit, Michigan, USA.|Department of Neurosurgery, Wayne State University, Detroit, Michigan, USA.
authors.forename: Alana C
authors.initials: AC
authors.lastname: Conti
mesh_terms: D000262:Adenylyl Cyclases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D000090023:Metallothionein 3; D008694:Methamphetamine / Q000494:pharmacology*; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects
chemical_list: D000697:Central Nervous System Stimulants; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D000090023:Metallothionein 3; C000715430:Mt3 protein, mouse; D008694:Methamphetamine; D000262:Adenylyl Cyclases; C106670:adenylyl cyclase 1; C118292:adenylyl cyclase 8
keywords: DARPP-32; adenylyl cyclase; dopamine; in vivo microdialysis; locomotor sensitization; methamphetamine