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1.
Neuropsychopharmacology ; 46(9): 1574-1583, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34007042

RESUMO

Drugs of abuse regulate the activity of the mesolimbic dopamine (DA) system, and drug-induced changes in ventral tegmental area (VTA) cellular activity and gene regulation are linked to behavioral outputs associated with addiction. Previous work from our lab determined that VTA serum- and glucocorticoid-inducible kinase 1 (SGK1) transcription and catalytic activity were increased by repeated cocaine administration; however, it was unknown if these biochemical changes contributed to cocaine-elicited behaviors. Using transgenic and viral-mediated manipulations, we investigated the role of VTA SGK1 catalytic activity in regulating cocaine conditioned place preference and self-administration. We showed intra-VTA infusion of a catalytically inactive SGK1 mutant (K127Q) significantly decreased cocaine conditioned place preference (CPP). Further, we found that K127Q expression in VTA DA neurons significantly decreased cocaine CPP, while this same manipulation in VTA GABA neurons had no effect. However, blunted VTA DA SGK1 catalytic activity did not alter cocaine self-administration. Altogether, these studies identify the specific VTA cells critical for SGK1-mediated effects on cocaine CPP but not self-administration.


Assuntos
Cocaína , Área Tegmentar Ventral , Cocaína/farmacologia , Condicionamento Clássico , Neurônios Dopaminérgicos , Glucocorticoides
2.
Neuroscience ; 461: 11-22, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33689861

RESUMO

Despite the high prevalence of major depressive disorder (MDD), understanding of the biological underpinnings remains limited. Rodent models suggest that changes in activity and output of dopamine (DA) neurons in the ventral tegmental area (VTA) are important for depressive-like phenotypes. Additionally, brain inflammatory processes are thought to contribute to MDD pathology and inflammation in the VTA has been linked to changes in VTA DA neuronal activity. Thus, we sought to determine whether there is increased inflammatory signaling in the VTA following forms of chronic stress that induce depressive-like symptoms. First, we subjected male mice to either physical or vicarious chronic social defeat stress (CSDS), paradigms known to induce long-term depressive-like behavior and changes in VTA signaling. Second, we subjected male and female mice to subchronic variable stress (SCVS), a paradigm that induces depressive-like behavior only in female mice. We then isolated mRNA from the VTA and assessed proinflammatory gene regulation via RT-PCR. Our results show that physical, but not vicarious, CSDS increases interleukin 1ß (IL-1ß) mRNA expression and this inversely correlates with social interaction score. In contrast, IL-1ß expression was unchanged in male or female mice following SCVS. No significant increases in VTA ionized calcium binding adapter molecule 1 (Iba1) and glial fibrillary acidic protein (GFAP) immunochemistry were detected following CSDS that would be indicative of a robust inflammatory response. In conclusion, we show that chronic stressors distinctively alter expression of proinflammatory genes in the VTA and changes may depend on the severity and time-course of the stress exposure.


Assuntos
Transtorno Depressivo Maior , Área Tegmentar Ventral , Animais , Modelos Animais de Doenças , Neurônios Dopaminérgicos , Feminino , Masculino , Camundongos , Estresse Psicológico
3.
Sci Rep ; 10(1): 14751, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32901079

RESUMO

Drugs of abuse cause significant neuroadaptations within the ventral tegmental area (VTA), with alterations in gene expression tied to changes in reward behavior. Serum- and glucocorticoid-inducible kinase 1 (SGK1) transcription, catalytic activity, and phosphorylation are upregulated in the VTA by chronic cocaine or morphine treatment, positioning SGK1 as a critical mediator of reward behavior. Using transgenic mouse models, we investigated the effect of SGK1 knockout in the VTA and in dopamine (DA) neurons to evaluate the necessity of protein expression for natural and drug reward behaviors. SGK1 knockdown in the VTA did not impact reward behaviors. Given VTA cellular heterogeneity, we also investigated a DA neuron-specific SGK1 knockout (KO). DA SGK1 KO significantly decreased body weight of adult mice as well as increased general locomotor activity; however, reward behaviors were similarly unaltered. Given that SGK1 mutants virally overexpressed in the VTA are capable of altering drug-associated behavior, our current results suggest that changes in SGK1 protein signaling may be distinct from expression. This work yields novel information on the impact of SGK1 deletion, critical for understanding the role of SGK1 signaling in the central nervous system and evaluating SGK1 as a potential therapeutic target for treatment of substance use disorders.


Assuntos
Comportamento Animal/efeitos dos fármacos , Cocaína/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Proteínas Imediatamente Precoces/fisiologia , Proteínas Serina-Treonina Quinases/fisiologia , Recompensa , Área Tegmentar Ventral/efeitos dos fármacos , Animais , Inibidores da Captação de Dopamina/farmacologia , Neurônios Dopaminérgicos/patologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais , Área Tegmentar Ventral/patologia
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