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.

Adenylyl Cyclase 1 Is Required for Ethanol-Induced Locomotor Sensitization and Associated Increases in NMDA Receptor Phosphorylation and Function in the Dorsal Medial Striatum

“…Furthermore, the absence of basal and acute ethanol locomotor effects in AC1KO and NB001-treated mice indicates the loss of AC1 does not impair ethanol sensitization responding through a general suppression of behavior or increased sensitivity to the sedative effects of ethanol. Greater ambulatory responses to stimulants than presently observed with acute ethanol have been reported in mice lacking calcium-stimulated ACs ( DiRocco et al, 2009 ; Bosse et al, 2015 ), further indicating that the absence of an ethanol sensitization response in AC1KO mice is not likely due to a ceiling effect on locomotor stimulation.…”

Signatures of selection in the genome of Swedish warmblood horses selected for sport performance

“…As an example, the Adenylate Cyclase 1 ( ADCY1) gene encodes adenylyl cyclase (AC) primarily expressed in the brain, influences neuroplasticity, as long-term potentiation, depression and memory formation [42]. In mice, ADCY1 and ADCY8 play an important role in the formation and maintenance of fear memory, dopaminergic responses, and behavioural sensitisation [43, 44]. Additionally, we detected the Guanylate Cyclase 2C (GUCY2C) which is associated with human attention deficiency and hyperactive behaviour [45], along with the Rho GDP Dissociation Inhibitor Beta (ARHGDIB) , and RAS Like Estrogen Regulated Growth Inhibitor (RERG) genes [46, 47].…”

Epigenetic Effects Induced by Methamphetamine and Methamphetamine‐Dependent Oxidative Stress

“…In fact, a chain of events follows DRD1 overstimulation, which involves metabolic transduction and transcriptional pathways, eventually switching gene expression and neuronal phenotype underlying addictive behavior in PD and METH [ 57 , 59 , 96 – 99 , 119 , 121 , 132 , 140 – 144 ]. Although precise signaling changes and substrates underlying this shift remain to be fully elucidated, a prominent role for AC [ 145 ] and PKA [ 146 , 147 ] is well established ( Figure 8 ). In fact, in its canonical pattern, PKA phosphorylates cellular targets, including voltage-dependent ion channels, GLUT receptors, TFs, and epigenetic enzymes involved in physiological synaptic plasticity and synaptic strength as naturally occurring in a normal striatum.…”