Prefrontal Gamma-Aminobutyric Acid Type A Receptor Insertion Controls Cue-Induced Relapse to Nicotine Seeking

doi:10.1016/j.biopsych.2014.02.001

Biological Psychiatry

Volume 76, Issue 9, 1 November 2014, Pages 750-758

https://doi.org/10.1016/j.biopsych.2014.02.001 Get rights and content

Background

Current smoking cessation therapies offer limited success, as relapse rates remain high. Nicotine, which is the major component of tobacco smoke, is thought to be primarily responsible for the addictive properties of tobacco. However, little is known about the molecular mechanisms underlying nicotine relapse, hampering development of more effective therapies. The objective of this study was to elucidate the role of medial prefrontal cortex (mPFC) glutamatergic and gamma-aminobutyric acid (GABA)ergic receptors in controlling relapse to nicotine seeking.

Methods

Using an intravenous self-administration model, we studied glutamate and gamma-aminobutyric acid receptor regulation in the synaptic membrane fraction of the rat mPFC following extinction and cue-induced relapse to nicotine seeking. Subsequently, we locally intervened at the level of GABAergic signaling by using a mimetic peptide of the GABA receptor associated protein–interacting domain of GABA type A (GABA_A) receptor subunit γ2 (TAT-GABAγ2) and muscimol, a GABA_A receptor agonist.

Results

Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid and N-methyl-D-aspartate receptors were not regulated after the 30-min relapse test. However, GABA_A receptor subunits α1 and γ2 were upregulated, and interference with GABA_A receptor insertion in the cell membrane using the TAT-GABAγ2 peptide in the dorsal mPFC, but not the ventral mPFC, significantly increased responding during relapse. Increasing GABA_A transmission with muscimol in the dorsal and ventral mPFC attenuated relapse.

Conclusions

These data indicate that cue-induced relapse entails a GABAergic plasticity mechanism that limits nicotine seeking by restoring inhibitory control in the dorsal mPFC. GABA_A receptor–mediated neurotransmission in the dorsal mPFC constitutes a possible future therapeutic target for maintaining smoking abstinence.

Section snippets

Animals

Male Wistar rats (Harlan CPB, Horst, The Netherlands), weighing 300–375 g at the time of surgery, were single housed in Makrolon cages (Tecniplast, Milan, Italy) with ad libitum food and water. All experiments were conducted during the dark phase of a reversed 12 hour light-dark cycle and approved by the Animal Care Committee of the VU University Amsterdam.

Drugs

[–]Nicotine hydrogen tartrate salt and muscimol (Sigma, St. Louis, Missouri) were dissolved in sterile saline. The TAT-GABAγ2 peptide

Experiment 1: Nicotine Self-Administration and Relapse to Nicotine Seeking

To evaluate protein regulation during relapse to nicotine seeking, rats were trained to self-administer saline or nicotine. Saline animals did not alter their behavior after the shift to FR2 and FR4, whereas animals receiving nicotine substantially increased responding on these schedules with a higher ratio of active over inactive hole responding (Figure 1A) (repeated-measures two-way ANOVA: session × drug × hole interaction [F_7.1,254.3 = 5.94, p < .001]). Subsequent extinction training reduced

Discussion

We identified an acute GABAergic plasticity mechanism in the dorsal mPFC that controls cue-induced relapse to nicotine seeking. Peptide mimetic intervention with the GABAergic system in this brain area was sufficient to affect responding to nicotine-associated cues. Specifically, blocking GABARAP-mediated insertion of GABA_A receptors in the dorsal mPFC membrane augmented responding during the relapse test. This enhancing effect was dependent on cue-induced GABA_A receptor regulation because it

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However, evidence suggests that the IL can promote drug seeking following extinction training as well. Pharmacological IL inhibition via GABAA+B agonism and vmPFC (dorsal IL and ventral PL) inhibition via GABAA agonism following extinction training decreases cue-induced methamphetamine seeking (Rocha and Kalivas, 2010) and nicotine seeking (Lubbers et al., 2014). Other studies have found that pharmacological IL inactivation via GABAA+B agonism following extinction training reduces cue-induced, heroin-primed, and contextual reinstatement of heroin seeking (Bossert et al., 2011; Rogers et al., 2008).
The rodent infralimbic cortex (IL) is implicated in higher order executive functions such as reward seeking and flexible decision making. However, the precise nature of its role in these processes is unclear. Early evidence indicated that the IL promotes the extinction and ongoing inhibition of fear conditioning and cocaine seeking. However, evidence spanning other behavioral domains, such as natural reward seeking and habit-based learning, suggests a more nuanced understanding of IL function. As techniques have advanced and more studies have examined IL function, identifying a unifying explanation for its behavioral function has become increasingly difficult. Here, we discuss evidence of IL function across motivated behaviors, including associative learning, drug seeking, natural reward seeking, and goal-directed versus habit-based behaviors, and emphasize how context-specific encoding and heterogeneous IL neuronal populations may underlie seemingly conflicting findings in the literature. Together, the evidence suggests that a major IL function is to facilitate the encoding and updating of contingencies between cues and behaviors to guide subsequent behaviors.
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This disinhibition would render the cortico-accumbens pathway more responsive to convergent PL excitatory inputs, including those activated by stimuli that trigger cocaine seeking. This hypothesis is consistent with a previous report that attenuated GABAergic neurotransmission in the medial prefrontal cortex facilitates cue-induced reinstatement to nicotine seeking (54). However, this requires further study, as it is unknown whether corticosterone-potentiated reinstatement results in increased activation of the cortico-accumbens pathway, and there are several possible PL projection pathways that can regulate potentiated cocaine seeking.
Clinical reports suggest that rather than directly driving cocaine use, stress may create a biological context within which other triggers for drug use become more potent. We hypothesize that stress-induced increases in corticosterone “set the stage” for relapse by promoting endocannabinoid-induced attenuation of inhibitory transmission in the prelimbic cortex (PL).
We have established a rat model for these stage-setting effects of stress. In this model, neither a stressor (electric footshock) nor stress-level corticosterone treatment alone reinstates cocaine seeking following self-administration and extinction, but each treatment potentiates reinstatement in response to an otherwise subthreshold cocaine priming dose (2.5 mg/kg, intraperitoneal). The contributions of endocannabinoid signaling in the PL to the effects of stress-level corticosterone on PL neurotransmission and cocaine seeking were determined using intra-PL microinfusions. Endocannabinoid-dependent effects of corticosterone on inhibitory synaptic transmission in the rat PL were determined using whole-cell recordings in layer V pyramidal neurons.
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Indeed, in humans the strength of corticostriatal connections is correlated to cigarette smoking and may characterize smokers in general [226,227]. In recent animal studies, a GABAergic plasticity mechanism in the dorsal mPFC was identified as a molecular switch in driving nicotine seeking [228] while increased glutamate release and synaptic potentiation in the NAc core were found to be associated with cue-induced relapse to nicotine seeking [229]. Combined, these studies indicate that repeated nicotine self-administration results in corticostriatal neuroplasticity mechanisms that are causally linked to the vulnerability to relapse.
Nicotine addiction is highly prevalent in current society and is often comorbid with other diseases. In the central nervous system, nicotine acts as an agonist for nicotinic acetylcholine receptors (nAChRs) and its effects depend on location and receptor composition. Although nicotinic receptors are found in most brain regions, many studies on addiction have focused on the mesolimbic system and its reported behavioral correlates such as reward processing and reinforcement learning. Profound modulatory cholinergic input from the pedunculopontine and laterodorsal tegmentum to dopaminergic midbrain nuclei as well as local cholinergic interneuron projections to dopamine neuron axons in the striatum may play a major role in the effects of nicotine. Moreover, an indirect mesocorticolimbic feedback loop involving the medial prefrontal cortex may be involved in behavioral characteristics of nicotine addiction. Therefore, this review will highlight current understanding of the effects of nicotine on the function of mesolimbic and mesocortical dopamine projections in the mesocorticolimbic circuit.
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¹: Authors TJDV and SS contributed equally to this work.

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Archival ReportPrefrontal Gamma-Aminobutyric Acid Type A Receptor Insertion Controls Cue-Induced Relapse to Nicotine Seeking

Background

Methods

Results

Conclusions

Section snippets

Animals

Drugs

Experiment 1: Nicotine Self-Administration and Relapse to Nicotine Seeking

Discussion

Lancet

Curr Opin Pharmacol

Neurosci Biobehav Rev

Curr Opin Pharmacol

Neuropharmacology

Appl Psychophysiol Biofeedback

Behav Brain Res

Neuron

Neuroscience

Neuron

Brain Res

Biol Psychiatry

Prog Neuropsychopharmacol Biol Psychiatry

Neuropharmacology

Neuropharmacology

Behav Brain Res

Trends Neurosci

Neuropharmacology

Neuron

Biol Psychiatry

Neurosci Biobehav Rev

Neuroscience

Neuron

Curr Opin Neurobiol

Brain Res

Comparative epidemiology of dependence on tobacco, alcohol, controlled substances, and inhalants: Basic findings from the National Comorbidity Survey

Exp Clin Psychopharmacol

Cocaine-induced neuroadaptations in glutamate transmission: Potential therapeutic targets for craving and addiction

Ann N Y Acad Sci

The synaptic pathology of drug addiction

Adv Exp Med Biol

Neuronal mechanisms underlying development of nicotine dependence: Implications for novel smoking-cessation treatments

Addict Sci Clin Pract

Neural substrates of abstinence-induced cigarette cravings in chronic smokers

J Neurosci

Brain activation patterns associated with cue reactivity and craving in abstinent problem gamblers, heavy smokers and healthy controls: an fMRI study

Addict Biol

Magnetic resonance imaging studies of cigarette smoking

Handb Exp Pharmacol

The reinstatement model of drug relapse: History, methodology and major findings

Psychopharmacology

Repeated administration of the GABAB receptor agonist CGP44532 decreased nicotine self-administration, and acute administration decreased cue-induced reinstatement of nicotine-seeking in rats

Neuropsychopharmacology

Effects of nicotine in experimental animals and humans: An update on addictive properties

Handb Exp Pharmacol

Glutamate release in the nucleus accumbens core is necessary for heroin seeking

J Neurosci

Archival Report
Prefrontal Gamma-Aminobutyric Acid Type A Receptor Insertion Controls Cue-Induced Relapse to Nicotine Seeking