Adenylyl cylases 1 and 8 mediate select striatal-dependent behaviors and sensitivity to ethanol stimulation in the adolescent period following acute neonatal ethanol exposure.
Neonatal alcohol exposure in rodents causes dramatic neurodegenerative effects throughout the developing nervous system, particularly in the striatum, acutely after exposure. These acute neurodegenerative effects are augmented in mice lacking adenylyl cyclases 1 and 8 (AC1/8) as neonatal mice with a genetic deletion of both AC isoforms (DKO) have increased vulnerability to ethanol-induced striatal neurotoxicity compared to wild type (WT) controls. While neonatal ethanol exposure is known to negatively impact cognitive behaviors, such as executive functioning and working memory in adolescent and adult animals, the threshold of ethanol exposure required to impinge upon developmental behaviors in mice has not been extensively examined. Therefore, the purpose of this study was to determine the behavioral effects of neonatal ethanol exposure using various striatal-dependent developmental benchmarks and to assess the impact of AC1/8 deletion on this developmental progression. WT and DKO mice were treated with 2.5 g/kg ethanol or saline on postnatal day (P)6 and later subjected to the wire suspension, negative geotaxis, postural reflex, grid hang, tail suspension and accelerating rotarod tests at various time points. At P30, mice were evaluated for their hypnotic responses to 4.0 g/kg ethanol by using the loss of righting reflex assay and ethanol-induced stimulation of locomotor activity after 2.0 g/kg ethanol. Ethanol exposure significantly impaired DKO performance in the negative geotaxis test while genetic deletion of AC1/8 alone increased grid hang time and decreased immobility time in the tail suspension test with a concomitant increase in hindlimb clasping behavior. Locomotor stimulation was significantly increased in animals that received ethanol as neonates, peaking significantly in ethanol-treated DKO mice compared to ethanol-treated WT controls, while sedation duration following high-dose ethanol challenge was unaffected. These data indicate that the maturational parameters examined in the current study may not be sensitive enough to detect effects of a single ethanol exposure during the brain growth spurt period. Genetic deletion of AC1/8 reveals a role for these cylases in attenuating ethanol-induced behavioral effects in the neonatally-exposed adolescent.
John D. Dingell VA Medical Center and Department of Neurosurgery, Wayne State University, School of Medicine, Detroit, MI 48201, USA. Electronic address: LSusick@med.wayne.edu.
Laura L
LL
Susick
John D. Dingell VA Medical Center and Department of Neurosurgery, Wayne State University, School of Medicine, Detroit, MI 48201, USA. Electronic address: JLowing@med.wayne.edu.
Jennifer L
JL
Lowing
John D. Dingell VA Medical Center and Department of Neurosurgery, Wayne State University, School of Medicine, Detroit, MI 48201, USA. Electronic address: KBosse@med.wayne.edu.
Kelly E
KE
Bosse
John D. Dingell VA Medical Center and Department of Neurosurgery, Wayne State University, School of Medicine, Detroit, MI 48201, USA. Electronic address: CHildebr@med.wayne.edu.
Clara C
CC
Hildebrandt
John D. Dingell VA Medical Center and Department of Neurosurgery, Wayne State University, School of Medicine, Detroit, MI 48201, USA. Electronic address: Alexandria.Chrumka@yahoo.com.
Alexandria C
AC
Chrumka
John D. Dingell VA Medical Center and Department of Neurosurgery, Wayne State University, School of Medicine, Detroit, MI 48201, USA. Electronic address: AConti@med.wayne.edu.
Alana C
AC
Conti
D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism*; D019973:Alcohol-Related Disorders / Q000503:physiopathology* / Q000523:psychology; D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D002492:Central Nervous System Depressants / Q000009:adverse effects*; D003342:Corpus Striatum / Q000187:drug effects / Q000254:growth & development / Q000503:physiopathology; D000431:Ethanol / Q000009:adverse effects*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D009483:Neuropsychological Tests; D012018:Reflex / Q000187:drug effects / Q000502:physiology; D045442:Rotarod Performance Test
D002492:Central Nervous System Depressants; D000431:Ethanol; D000262:Adenylyl Cyclases; C106670:adenylyl cyclase 1; C118292:adenylyl cyclase 8
Adenylyl cyclase; Behavior; Ethanol; Fetal Alcohol Spectrum Disorders (FASD); Striatum