title: Cocaine-induced neuroadaptations in the dorsal striatum: glutamate dynamics and behavioral sensitization.
abstract: Recent evidence suggests that diminished ability to control cocaine seeking arises from perturbations in glutamate homeostasis in the nucleus accumbens. However, the neurochemical substrates underlying cocaine-induced neuroadaptations in the dorsal striatum and how these mechanisms link to behavioral plasticity is not clear. We employed glutamate-sensitive microelectrodes and amperometry to study the impact of repeated cocaine administration on glutamate dynamics in the dorsolateral striatum of awake freely-moving rats. Depolarization-evoked glutamate release was robustly increased in cocaine-pretreated rats challenged with cocaine. Moreover, the clearance of glutamate signals elicited either by terminal depolarization or blockade of non-neuronal glutamate transporters slowed down dramatically in cocaine-sensitized rats. Repeated cocaine exposure also reduced the neuronal tone of striatal glutamate. Ceftriaxone, a β-lactam antibiotic that activates the astrocytic glutamate transporter, attenuated the effects of repeated cocaine exposure on synaptic glutamate release and glutamate clearance kinetics. Finally, the antagonism of AMPA glutamate receptors in the dorsolateral striatum blocked the development of behavioral sensitization to repeated cocaine administration. Collectively, these data suggest that repeated cocaine exposure disrupts presynaptic glutamate transmission and transporter-mediated clearance mechanisms in the dorsal striatum. Moreover, such alterations produce an over activation of AMPA receptors in this brain region leading to the sensitized behavioral response to repeated cocaine.
authors.affiliation: Department of Psychology and Neuroscience Program, Temple University, Philadelphia, United States. Electronic address: vinay.parikh@temple.edu.
authors.forename: Vinay
authors.initials: V
authors.lastname: Parikh
authors.affiliation: Department of Psychology and Neuroscience Program, Temple University, Philadelphia, United States.
authors.forename: Sean X
authors.initials: SX
authors.lastname: Naughton
authors.affiliation: Department of Pharmacology and Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA, United States.
authors.forename: Xiangdang
authors.initials: X
authors.lastname: Shi
authors.affiliation: Department of Psychology and Neuroscience Program, Temple University, Philadelphia, United States; Department of Pharmacology and Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA, United States.
authors.forename: Leslie K
authors.initials: LK
authors.lastname: Kelley
authors.affiliation: Department of Psychology and Neuroscience Program, Temple University, Philadelphia, United States.
authors.forename: Brittney
authors.initials: B
authors.lastname: Yegla
authors.affiliation: Department of Pharmacology and Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA, United States.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Tallarida
authors.affiliation: Department of Pharmacology and Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA, United States.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Rawls
authors.affiliation: Department of Pharmacology and Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA, United States.
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Unterwald
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003042:Cocaine / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar
chemical_list: D018698:Glutamic Acid; D003042:Cocaine
keywords: Amperometry; Behavioral sensitization; Ceftriaxone; Cocaine; Dorsal striatum; Glutamate