Title | Prefrontal glutamate correlates of methamphetamine sensitization and preference. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Lominac KD, Quadir SG, Barrett HM, McKenna CL, Schwartz LM, Ruiz PN, Wroten MG, Campbell RR, Miller BW, Holloway JJ, Travis KO, Rajasekar G, Maliniak D, Thompson AB, Urman LE, Kippin TE, Phillips TJ, Szumlinski KK |
Journal | Eur J Neurosci |
Volume | 43 |
Issue | 5 |
Pagination | 689-702 |
Date Published | 2016 Mar |
ISSN | 1460-9568 |
Keywords | Amino Acid Transport System X-AG, Animals, Central Nervous System Sensitization, Central Nervous System Stimulants, Conditioning, Classical, Glutamic Acid, Homer Scaffolding Proteins, Male, Methamphetamine, Mice, Mice, Inbred C57BL, Phenotype, Prefrontal Cortex, Receptors, AMPA, Receptors, N-Methyl-D-Aspartate, Self Administration, Synaptic Transmission |
Abstract | Methamphetamine (MA) is a widely misused, highly addictive psychostimulant that elicits pronounced deficits in neurocognitive function related to hypo-functioning of the prefrontal cortex (PFC). Our understanding of how repeated MA impacts excitatory glutamatergic transmission within the PFC is limited, as is information about the relationship between PFC glutamate and addiction vulnerability/resiliency. In vivo microdialysis and immunoblotting studies characterized the effects of MA (ten injections of 2 mg/kg, i.p.) upon extracellular glutamate in C57BL/6J mice and upon glutamate receptor and transporter expression, within the medial PFC. Glutamatergic correlates of both genetic and idiopathic variance in MA preference/intake were determined through studies of high vs. low MA-drinking selectively bred mouse lines (MAHDR vs. MALDR, respectively) and inbred C57BL/6J mice exhibiting spontaneously divergent place-conditioning phenotypes. Repeated MA sensitized drug-induced glutamate release and lowered indices of N-methyl-d-aspartate receptor expression in C57BL/6J mice, but did not alter basal extracellular glutamate content or total protein expression of Homer proteins, or metabotropic or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors. Elevated basal glutamate, blunted MA-induced glutamate release and ERK activation, as well as reduced protein expression of mGlu2/3 and Homer2a/b were all correlated biochemical traits of selection for high vs. low MA drinking, and Homer2a/b levels were inversely correlated with the motivational valence of MA in C57BL/6J mice. These data provide novel evidence that repeated, low-dose MA is sufficient to perturb pre- and post-synaptic aspects of glutamate transmission within the medial PFC and that glutamate anomalies within this region may contribute to both genetic and idiopathic variance in MA addiction vulnerability/resiliency. |
DOI | 10.1111/ejn.13159 |
Alternate Journal | Eur. J. Neurosci. |
PubMed ID | 26742098 |
PubMed Central ID | PMC4783259 |
Grant List | P50 DA018165 / DA / NIDA NIH HHS / United States R01 DA024038 / DA / NIDA NIH HHS / United States R24 AA020245 / AA / NIAAA NIH HHS / United States I01 BX002106 / BX / BLRD VA / United States R01 DA027525 / DA / NIDA NIH HHS / United States DA027525 / DA / NIDA NIH HHS / United States DA024038 / DA / NIDA NIH HHS / United States |