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Basolateral amygdala-driven augmentation of medial prefrontal cortex GABAergic neurotransmission in response to environmental stimuli associated with cocaine administration.

ABSTRACT: Basolateral amygdala (BLA) and medial prefrontal cortex (mPFC) interactions have been implicated in cue-elicited craving and drug seeking. However, the neurochemical mechanisms underlying drug/environment associations are ill-defined. We used in vivo microdialysis and pharmacological inactivation techniques to identify alterations in mPFC glutamate (GLU) and gamma-aminobutyric acid (GABA) transmission in response to cues previously associated with experimenter-administered cocaine (COC) and the BLA contribution to these effects. Rats received alternate day injections of COC and saline (SAL) paired with a distinct environment for 6 days. Behavioral, neurochemical and immunohistochemical studies were conducted, in drug-free animals, 24?h after the last conditioning session. Animals exposed to a COC-paired environment demonstrated an augmented locomotor activity (LMA) relative to those exposed to the SAL-paired environment. mPFC GABA neurotransmission in the COC-paired environment was significantly increased, whereas GLU overflow was unaltered. Dual labeling of cFos and glutamic acid decarboxylase 67 immunoreactivity in mPFC neurons revealed significantly greater colocalization of these proteins following exposure to the COC-associated environment (CAE) relative to pseudo-conditioned rats or rats exposed to the SAL-associated environment indicating that the conditioned neurochemical response to the COC-paired environment is associated with activation of intrinsic mPFC GABA neurons. BLA inactivation prevented the increase in LMA and the augmentation of mPFC GABA transmission produced by cue exposure. Intra-mPFC application of the AMPA/KA receptor antagonist, NBQX, produced similar effects. These findings indicate that exposure to a CAE increases mPFC GABA transmission by enhancing excitatory drive from the BLA and activation of AMPA/KA receptors on mPFC GABA neurons.

SUBMITTER: Chefer VI

PROVIDER: S-EPMC3158319 | biostudies-other | 2011 Sep

REPOSITORIES: biostudies-other

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Basolateral amygdala-driven augmentation of medial prefrontal cortex GABAergic neurotransmission in response to environmental stimuli associated with cocaine administration.

Chefer Vladimir I VI Wang Ruizhong R Shippenberg Toni S TS

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20110601 10

Basolateral amygdala (BLA) and medial prefrontal cortex (mPFC) interactions have been implicated in cue-elicited craving and drug seeking. However, the neurochemical mechanisms underlying drug/environment associations are ill-defined. We used in vivo microdialysis and pharmacological inactivation techniques to identify alterations in mPFC glutamate (GLU) and gamma-aminobutyric acid (GABA) transmission in response to cues previously associated with experimenter-administered cocaine (COC) and the ...[more]

PMID: 21633339

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Project description:The ability to inhibit drinking is a significant challenge for recovering alcoholics, especially in the presence of alcohol-associated cues. Previous studies have demonstrated that the regulation of cue-guided alcohol seeking is mediated by the basolateral amygdala (BLA), nucleus accumbens (NAc), and medial prefrontal cortex (mPFC). However, given the high interconnectivity between these structures, it is unclear how mPFC projections to each subcortical structure, as well as projections between BLA and NAc, mediate alcohol-seeking behaviors. Here, we evaluate how cortico-striatal, cortico-amygdalar, and amygdalo-striatal projections control extinction and relapse in a rat model of alcohol seeking. Specifically, we used a combinatorial viral technique to express diphtheria toxin receptors in specific neuron populations based on their projection targets. We then used this strategy to create directionally selective ablations of three distinct pathways after acquisition of ethanol self-administration but before extinction and reinstatement. We demonstrate that ablation of mPFC neurons projecting to NAc, but not BLA, blocks cue-induced reinstatement of alcohol seeking and neither pathway is necessary for extinction of responding. Further, we show that ablating BLA neurons that project to NAc disrupts extinction of alcohol approach behaviors and attenuates reinstatement. Together, these data provide evidence that the mPFC→NAc pathway is necessary for cue-induced reinstatement of alcohol seeking, expand our understanding of how the BLA→NAc pathway regulates alcohol behavior, and introduce a new methodology for the manipulation of target-specific neural projections.SIGNIFICANCE STATEMENT The vast majority of recovering alcoholics will relapse at least once and understanding how the brain regulates relapse will be key to developing more effective behavior and pharmacological therapies for alcoholism. Given the high interconnectivity of cortical, striatal, and limbic structures that regulate alcohol intake, it has been difficult to disentangle how separate projections between them may control different aspects of these complex behaviors. Here, we demonstrate a new approach for noninvasively ablating each of these pathways and testing their necessity for both extinction and relapse. We show that inputs to the nucleus accumbens from medial prefrontal cortex and amygdala regulate alcohol-seeking behaviors differentially, adding to our understanding of the neural control of alcoholism.

Dataset Information

Basolateral amygdala-driven augmentation of medial prefrontal cortex GABAergic neurotransmission in response to environmental stimuli associated with cocaine administration.

Publications

Basolateral amygdala-driven augmentation of medial prefrontal cortex GABAergic neurotransmission in response to environmental stimuli associated with cocaine administration.

Similar Datasets

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