Estrogen-Dependent Upregulation of Adcyap1r1 Expression in Nucleus Accumbens Is Associated With Genetic Predisposition of Sex-Specific QTL for Alcohol Consumption on Rat Chromosome 4

Spence, John P.; Reiter, Jill L.; Qiu, Bin; Gu, Hao; Garcia, Dawn; Zhang, Lingling; Graves, Tamara; Williams, Kent E.; Bice, Paula J.; Zou, Yi; Lai, Zhao; Yong, Weidong; Liang, Tiebing

doi:10.3389/fgene.2018.00513

Cited by 15 publications

(10 citation statements)

References 68 publications

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“…Our present study also demonstrates that this postsynaptic effect of PACAP in POMC neurons is sexually differentiated; with females being more sensitive than males in the presence of E 2 . This is consistent with the findings of Spence et al [57], in which expression of the Adcy-ap1r1 gene, encoding the PAC1 receptor, is upregulated in the nucleus accumbens of females compared to males, and enhanced by ERα-mediated transcription of the gene. Earlier studies showed that brain ADCYAP1 transcript levels vary across the rat estrous cycle; with the greatest change occurring during proestrus [58], a period characterized by peak E 2 levels.…”

Section: Discussionsupporting

confidence: 93%

Pituitary Adenylate Cyclase-Activating Polypeptide Excites Proopiomelanocortin Neurons: Implications for the Regulation of Energy Homeostasis

et al. 2020

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Objective: We examined whether pituitary adenylate cyclase-activating polypeptide (PACAP) excites proopiomelanocortin (POMC) neurons via PAC1 receptor mediation and transient receptor potential cation (TRPC) channel activation. Methods: Electrophysiological recordings were done in slices from both intact male and ovariectomized (OVX) female PACAP-Cre mice and eGFP-POMC mice. Results: In recordings from POMC neurons in eGFP-POMC mice, PACAP induced a robust inward current and increase in conductance in voltage clamp, and a depolarization and increase in firing in current clamp. These postsynaptic actions were abolished by inhibitors of the PAC1 receptor, TRPC channels, phospholipase C, phosphatidylinositol-3-kinase, and protein kinase C. Estradiol augmented the PACAP-induced inward current, depolarization, and increased firing, which was abrogated by estrogen receptor (ER) antagonists. In optogenetic recordings from POMC neurons in PACAP-Cre mice, high-frequency photostimulation induced inward currents, depolarizations, and increased firing that were significantly enhanced by G_q-coupled membrane ER signaling in an ER antagonist-sensitive manner. Importantly, the PACAP-induced excitation of POMC neurons was notably reduced in obese, high-fat (HFD)-fed males. In vivo experiments revealed that intra-arcuate nucleus (ARC) PACAP as well as chemogenetic and optogenetic stimulation of ventromedial nucleus (VMN) PACAP neurons produced a significant decrease in energy intake accompanied by an increase in energy expenditure, effects blunted by HFD in males and partially potentiated by estradiol in OVX females. Conclusions: These findings reveal that the PACAP-induced activation of PAC1 receptor and TRPC5 channels at VMN PACAP/ARC POMC synapses is potentiated by estradiol and attenuated under conditions of diet-induced obesity/insulin resistance. As such, they advance our understanding of how PACAP regulates the homeostatic energy balance circuitry under normal and pathophysiological circumstances.

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Section: Discussionsupporting

confidence: 93%

Pituitary Adenylate Cyclase-Activating Polypeptide Excites Proopiomelanocortin Neurons: Implications for the Regulation of Energy Homeostasis

et al. 2020

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“…In the females, ACE was associated with upregulation of the GABA A Receptor Epsilon Subunit, Gabre . In the context of substance use disorders, rats with a genetic predisposition to alcohol consumption showed a Gabre upregulation ( Spence et al, 2018 ). The hormone activity gene ontology was enriched in the female subset of DEGs, and, noteworthy, the neuropeptides included in this subset may be determining the dopaminergic activity in the NAcc shell of THC-treated females.…”

Section: Discussionmentioning

confidence: 99%

Δ 9-Tetrahydrocannabinol During Adolescence Reprograms the Nucleus Accumbens Transcriptome, Affecting Reward Processing, Impulsivity, and Specific Aspects of Cocaine Addiction-Like Behavior in a Sex-Dependent Manner

Orihuel

Capellán

Roura-Martínez

et al. 2021

International Journal of Neuropsychopharmacology

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Background Cannabis exposure during adolescence is associated with emotional and motivational alterations that may entail an enhanced risk of developing psychiatric disorders. In rodent models, exposure to cannabinoids during adolescence leads to increased self-administration of opiates and cocaine, however, the psychological and neural mechanisms and the sex-specificity of this phenomenon are largely unknown. Methods We exposed male and female adolescent rats to Δ9-tetrahydrocannabinol (THC) and studied at adulthood the effects of such treatment on psychological processes related to reward, such as Pavlovian conditioned approach, Pavlovian to instrumental transfer, habit formation and waiting impulsivity. In the light of these data and given the involvement of the nucleus accumbens in the processes examined, we performed an RNASeq transcriptomic study and assessed cocaine addiction-like behavior. Results THC exposure increased goal-tracking (in males and females) and enhanced Pavlovian to instrumental transfer (especially in males) but did not affect habit formation. THC-exposed rats exhibited subtle, state-dependent changes in premature responding in the 2-CSRTT task. RNASeq data showed gene expression alterations in a marked sex-specific manner. While no effects were found on the acquisition of cocaine self-administration or punished drug-seeking, rats exposed to THC self-administered more cocaine under a progressive ratio schedule (males), had a higher rebound upon returning to continuous access to the drug (females) and showed reduced drug-seeking after 30 days of withdrawal (females). Conclusions Adolescent THC affects specific aspects of reward- (and cocaine-) guided behavior and the function of a key brain region mediating these effects, in a remarkable sex-specific manner.

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“…In the clinical literature, polymorphisms of the gene encoding the PACAP receptor, ADCYAP1R1 , have been associated with a diagnosis of posttraumatic stress disorder in women but not men, 37 and this association is particularly strong in women with low serum estradiol 38 . In preclinical studies, selectively bred alcohol‐preferring compared with nonpreferring female rats show upregulated expression in the NAc of Adcyap1r1 , and sequence variants in the promoter region for this gene are differentially responsive to stimulation by estrogen 39 . With this research suggesting that females overall may be more sensitive to the effects of PACAP, future work should fully characterize the effect of PACAP‐27 on ethanol consumption in this population, as females may show even greater benefit from PACAP treatment.…”

Section: Discussionmentioning

confidence: 99%

Effects of pituitary adenylate cyclase‐activating polypeptide isoforms in nucleus accumbens subregions on ethanol drinking

et al. 2020

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While limited research has implicated the neuropeptide, pituitary adenylate cyclase‐activating polypeptide (PACAP), in problematic alcohol use, the brain regions and isoforms involved in this effect remain to be determined. One region that has been found both to exhibit PACAP binding and, separately, to be involved in ethanol drinking is the nucleus accumbens (NAc). Thus, this study sought to characterize the effect of the PACAP isoforms in the NAc on ethanol drinking under the intermittent‐access two‐bottle‐choice paradigm, in male and female Long–Evans rats. With microinjection into the medial NAc shell, PACAP‐27 but not PACAP‐38 was found to dose‐dependently reduce binge‐like ethanol drinking. In contrast, the PACAP receptor antagonist, PACAP (6‐27), but not PACAP (6‐38), enhanced ethanol drinking. This effect of PACAP was substance specific, as neither isoform in the NAc shell affected binge‐like sucrose drinking. It was also anatomically specific, as PACAP‐38 rather than PACAP‐27 suppressed ethanol drinking when injected into the NAc core, and PACAP‐27 instead enhanced drinking when injected into the caudal third of the medial NAc shell. Finally, while PACAP‐38 in the NAc shell affected stress‐related exploratory behavior, reducing time spent in the light chamber of a light–dark box, PACAP‐27 did not significantly affect behavior in a light–dark box or open field. Together, these results, showing that PACAP‐27 in the NAc shell attenuates binge‐like ethanol drinking without affecting select stress‐related behaviors, suggest that compounds related to this PACAP isoform should be investigated as potential novel therapeutics for the treatment of alcohol use disorder.

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Estrogen-Dependent Upregulation of Adcyap1r1 Expression in Nucleus Accumbens Is Associated With Genetic Predisposition of Sex-Specific QTL for Alcohol Consumption on Rat Chromosome 4

Cited by 15 publications

References 68 publications

Pituitary Adenylate Cyclase-Activating Polypeptide Excites Proopiomelanocortin Neurons: Implications for the Regulation of Energy Homeostasis

Pituitary Adenylate Cyclase-Activating Polypeptide Excites Proopiomelanocortin Neurons: Implications for the Regulation of Energy Homeostasis

Δ 9-Tetrahydrocannabinol During Adolescence Reprograms the Nucleus Accumbens Transcriptome, Affecting Reward Processing, Impulsivity, and Specific Aspects of Cocaine Addiction-Like Behavior in a Sex-Dependent Manner

Effects of pituitary adenylate cyclase‐activating polypeptide isoforms in nucleus accumbens subregions on ethanol drinking

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