Effects of Methamphetamine Self-Administration and Extinction on Astrocyte Structure and Function in the Nucleus Accumbens Core

B. M. Siemsen, C. M. Reichel, K. C. Leong, C. Garcia-Keller, C. D. Gipson, S. Spencer, J. A. McFaddin, K. N. Hooker, P. W. Kalivas, M. D. Scofield

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


Astrocytes provide support for neurons, regulate metabolic processes, and influence neuronal communication in a variety of ways, including through the homeostatic regulation of glutamate. Following 2-h cocaine or methamphetamine self-administration (SA) and extinction, rodents display decreased levels of basal glutamate in the nucleus accumbens core (NAcore), which transitions to elevated glutamate levels during drug seeking. We hypothesized that, like cocaine, this glutamate ‘overflow’ during methamphetamine seeking arises via decreased expression of the astroglial glutamate transporter GLT-1, and withdrawal of perisynaptic astroglial processes (PAPs) from synapses. As expected, methamphetamine self-administration and extinction decreased the level of contact made by PAPs in the NAcore, yet did not impact glutamate uptake, GLT-1 expression, or the general structural characteristics of astrocytes. Interestingly, systemic administration of N-acetylcysteine (NAC), a drug that both upregulates GLT-1 and promotes glial-glutamate release, reduced cued methamphetamine seeking. In order to test the impact of astrocyte activation and the induction of glial glutamate release within the NAcore, we employed astrocyte-specific expression of designer receptors exclusively activated by designer drugs (DREADDs). We show here that acute activation of Gq-coupled DREADDs in this region inhibited cued methamphetamine seeking. Taken together, these data indicate that cued methamphetamine seeking following two-hour SA is not mediated by deficient glutamate clearance in the NAcore, yet can be inhibited by engaging NAcore astrocytes.

Original languageEnglish (US)
Pages (from-to)528-541
Number of pages14
StatePublished - May 15 2019

Bibliographical note

Funding Information:
This work was supported by T32 DA007288 (MDS, BMS, KC), R01 DA033049 (CMR), 5 K99 DA041462 (SS), R00 DA036569, R21 DA044479, R03 DA045881 (CDG) R01 DA012513 and R01 DA003906 (PWK) R00 DA040004 (MDS). The authors report no biomedical financial interests or potential conflicts of interest.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

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