Differential response of glial fibrillary acidic protein-positive astrocytes in the rat prefrontal cortex following ethanol self-administration.

BACKGROUND: Prefrontal cortex (PFC) dysfunction is believed to contribute to the transition from controlled substance use to abuse. Because astrocytes have been suggested to play a key role in the development and maintenance of drug-seeking behaviors, we sought to determine whether PFC astrocytes are affected by ethanol (EtOH) self-administration. METHODS: EtOH consumption was modeled in rats by 3 self-administration paradigms where EtOH was made concurrently available with water in the home cage either continuously (CEA) or intermittently (IEA). In the third paradigm, EtOH was only available in the operant chamber (OEA). To avoid the potential confound of acute EtOH effects, all rats were sacrificed after either 24-hour or 3-week abstinence. In all groups, the effect of EtOH consumption on PFC astrocytes was measured using unbiased stereological counting of cells expressing the astrocyte marker glial fibrillary acidic protein (GFAP). GFAP immunoreactivity commonly changes in response to pharmacological insult or injury. RESULTS: GFAP-positive astrocyte number increased in the prelimbic and anterior cingulate cortex regions of the PFC after IEA. No change was found in the infralimbic or orbitofrontal cortex after IEA. After 3-week abstinence, there was a reduction of astrocytes in the prelimbic and orbitofrontal cortex of the CEA cohort as well as a reduction in the orbitofrontal cortex of the OEA cohort. CONCLUSIONS: These findings demonstrate that discrete PFC subregions contain GFAP-positive astrocyte populations that respond differentially to distinct EtOH consumption paradigms. A better understanding of how specific astrocyte populations uniquely adapt to EtOH consumption could provide insight for targeted therapeutic interventions.

Rat nucleus accumbens core astrocytes modulate reward and the motivation to self-administer ethanol after abstinence.

Our understanding of the active role that astrocytes play in modulating neuronal function and behavior is rapidly expanding, but little is known about the role that astrocytes may play in drug-seeking behavior for commonly abused substances. Given that the nucleus accumbens is critically involved in substance abuse and motivation, we sought to determine whether nucleus accumbens astrocytes influence the motivation to self-administer ethanol following abstinence. We found that the packing density of astrocytes that were expressing glial fibrillary acidic protein increased in the nucleus accumbens core (NAcore) during abstinence from EtOH self-administration. No change was observed in the nucleus accumbens shell. This increased NAcore astrocyte density positively correlated with the motivation for ethanol. Astrocytes can communicate with one another and influence neuronal activity through gap-junction hemichannels. Because of this, the effect of blocking gap-junction hemichannels on the motivation for ethanol was examined. The motivation to self-administer ethanol after 3 weeks abstinence was increased following microinjection of gap-junction hemichannel blockers into the NAcore at doses that block both neuronal and astrocytic channels. In contrast, no effect was observed following microinjection of doses that are not thought to block astrocytic channels or following microinjection of either dose into the nucleus accumbens shell. Additionally, the motivation for sucrose after 3 weeks abstinence was unaffected by NAcore gap-junction hemichannel blockers. Next, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) were selectively expressed in NAcore astrocytes to test the effect of astrocyte stimulation. DREADD activation increased cytosolic calcium in primary astrocytes, facilitated responding for rewarding brain stimulation, and reduced the motivation for ethanol after 3 weeks abstinence. This is the first work to modulate drug-seeking behavior with astrocyte-specific DREADDs. Taken together, our findings demonstrate that NAcore astrocytes can shape the motivation to self-administer ethanol; suggesting that the development of ligands which selectively stimulate astrocytes may be a successful strategy to abate ethanol-seeking behavior.