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1.
Elife ; 132024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38860652

RESUMO

Adolescence is characterized by changes in reward-related behaviors, social behaviors, and decision making. These behavioral changes are necessary for the transition into adulthood, but they also increase vulnerability to the development of a range of psychiatric disorders. Major reorganization of the dopamine system during adolescence is thought to underlie, in part, the associated behavioral changes and increased vulnerability. Here, we utilized fast scan cyclic voltammetry and microdialysis to examine differences in dopamine release as well as mechanisms that underlie differential dopamine signaling in the nucleus accumbens (NAc) core of adolescent (P28-35) and adult (P70-90) male rats. We show baseline differences between adult and adolescent stimulated dopamine release in male rats, as well as opposite effects of the a6 nicotinic acetylcholine receptor (nAChR) on modulating dopamine release. The a6-selective blocker, a-conotoxin, increased dopamine release in early adolescent rats, but decreased dopamine release in rats beginning in middle adolescence and extending through adulthood. Strikingly, blockade of GABAA and GABAB receptors revealed that this a6-mediated increase in adolescent dopamine release requires NAc GABA signaling to occur. We confirm the role of a6 nAChR and GABA in mediating this effect in vivo using microdialysis. Results herein suggest a multisynaptic mechanism potentially unique to the period of development that includes early adolescence, involving acetylcholine acting at a6-containing nAChRs to drive inhibitory GABA tone on dopamine release.

2.
Synapse ; 75(4): e22190, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33025628

RESUMO

Metabotropic glutamate (mGlu) receptors are regulators of glutamate release and targets for development of therapies for hyperactive glutamatergic signaling. However, the effects of long-term stimulation of mGlu receptors on cellular signaling in the brain have not been described. This study investigated the effects of 2-day and 14-day osmotic mini-pump administration of the mGlu2,3 agonist LY379268 (3.0 mg kg-1  day-1 ) to rats on receptor-mediated G-protein activation and signaling in mesocorticolimbic regions in rat brain sections. A significant reduction in LY379268-stimulated [35 S]GTPγS binding was observed in the 14-day group in some cortical regions, prefrontal cortex, nucleus accumbens, and ventral pallidum. The 14-day LY379268 treatment group exhibited mGlu2 mRNA levels significantly lower in hippocampus, nucleus accumbens, caudate, and ventral pallidum. In both 2-day and 14-day treatment groups immunodetectable phosphorylated cAMP Response Element-Binding protein (CREB) was significantly reduced across all brain regions. In the 2-day group, we observed significantly lower immunodetectable CREB protein across all brain regions, which was subsequently increased in the 14-day group but failed to achieve control values. Neither immunodetectable extracellular signal-regulated kinase (ERK) protein nor phosphorylated ERK from 2-day or 14-day treatment groups differed significantly from control across all brain regions. However, the ratio of phosphorylated ERK to total ERK protein was significantly greater in the 14-day treatment group compared with the control. These results identify compensatory changes to mGlu2,3 signal transduction in rat brains after chronic systemic administration of agonist, which could be predictive of the mechanism of action in human pharmacotherapies.


Assuntos
Ácido Glutâmico , Receptores de Glutamato Metabotrópico , Animais , Encéfalo/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Ratos , Receptores de Glutamato Metabotrópico/agonistas , Transdução de Sinais
3.
Sci Rep ; 10(1): 173, 2020 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-31932634

RESUMO

Smoking remains the primary cause of preventable death in the United States and smoking related illness costs more than $300 billion annually. Nicotine (the primary reinforcer in cigarettes) causes changes in behavior and neurochemistry that lead to increased probability of relapse. Given the role of mesolimbic dopamine projections in motivation, substance use disorder, and drug relapse, we examined the effect of repeated nicotine on rapid dopamine signals in the nucleus accumbens (NAc) of rats. Adult, male Sprague-Dawley rats were exposed to nicotine (0.2 or 0.4 mg/kg, subcutaneous) once daily for 7 days. On day 8, dopamine release and uptake dynamics, and their modulation by nicotinic receptor agonists and antagonists, were assessed using fast scan cyclic voltammetry in the NAc core. Nicotine exposure decreased electrically-stimulated dopamine release across a range of stimulation frequencies and decreased α6ß2-containing nicotinic receptor control over dopamine release. Additionally, nicotine locomotor sensitization correlated with accumbal dopamine modulation by nicotine and mecamylamine. Taken together, our study suggests that repeated exposure to nicotine blunts dopamine release in the NAc core through changes in α6ß2 modulation of dopamine release and individual differences in the sensitivity to this outcome may predict variation in behavioral models of vulnerability to substance use disorder.


Assuntos
Dopamina/metabolismo , Locomoção/fisiologia , Atividade Motora/fisiologia , Nicotina/farmacologia , Agonistas Nicotínicos/farmacocinética , Núcleo Accumbens/metabolismo , Receptores Nicotínicos/metabolismo , Animais , Locomoção/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
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