Faculty Collaboration Database

Minocycline prevents chronic restraint stress-induced vulnerability to developing cocaine self-administration and associated glutamatergic mechanisms: a potential role of microglia. Brain Behav Immun 2022 Mar;101:359-376

Date

01/23/2022

Pubmed ID

35065197

DOI

10.1016/j.bbi.2022.01.014

Scopus ID

2-s2.0-85123990012 (requires institutional sign-in at Scopus site)   7 Citations

Abstract

Stressful experience-induced cocaine-related behaviors are associated with a significant impairment of glutamatergic mechanisms in the Nucleus Accumbens core (NAcore). The hallmarks of disrupted glutamate homeostasis following restraint stress are the enduring imbalance of glutamate efflux after a cocaine stimulus and increased basal concentrations of extracellular glutamate attributed to GLT-1 downregulation in the NAcore. Glutamate transmission is tightly linked to microglia functioning. However, the role of microglia in the biological basis of stress-induced addictive behaviors is still unknown. By using minocycline, a potent inhibitor of microglia activation with anti-inflammatory properties, we determined whether microglia could aid chronic restraint stress (CRS)-induced glutamate homeostasis disruption in the NAcore, underpinning stress-induced cocaine self-administration. In this study, adult male rats were restrained for 2 h/day for seven days (day 1-7). From day 16 until completing the experimental protocol, animals received a vehicle or minocycline treatment (30 mg/Kg/12h i.p.). On day 21, animals were assigned to microscopic, biochemical, neurochemical or behavioral studies. We confirm that the CRS-induced facilitation of cocaine self-administration is associated with enduring GLT-1 downregulation, an increase of basal extracellular glutamate and postsynaptic structural plasticity in the NAcore. These alterations were strongly related to the CRS-induced reactive microglia and increased TNF-α mRNA and protein expression, since by administering minocycline, the impaired glutamate homeostasis and the facilitation of cocaine self-administration were prevented. Our findings are the first to demonstrate that minocycline suppresses the CRS-induced facilitation of cocaine self-administration and glutamate homeostasis disruption in the NAcore. A role of microglia is proposed for the development of glutamatergic mechanisms underpinning stress-induced vulnerability to cocaine addiction.

Author List

Avalos MP, Guzman AS, Rigoni D, Gorostiza EA, Sanchez MA, Mongi-Bragato B, Garcia-Keller C, Perassi EM, Virgolini MB, Peralta Ramos JM, Iribarren P, Calfa GD, Bollati FA, Cancela LM

Author

Constanza Garcia Keller PhD Assistant Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Cocaine
Glutamic Acid
Male
Microglia
Minocycline
Nucleus Accumbens
Rats
Rats, Sprague-Dawley