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Mutant DISC1 affects methamphetamine-induced sensitization and conditioned place preference: a comorbidity model.

ABSTRACT: Genetic factors involved in neuroplasticity have been implicated in major psychiatric illnesses such as schizophrenia, depression, and substance abuse. Given its extended interactome, variants in the Disrupted-In-Schizophrenia-1 (DISC1) gene could contribute to drug addiction and psychiatric diseases. Thus, we evaluated how dominant-negative mutant DISC1 influenced the neurobehavioral and molecular effects of methamphetamine (METH). Control and mutant DISC1 mice were studied before or after treatment with non-toxic escalating dose (ED) of METH. In naïve mice, we assessed METH-induced conditioned place preference (CPP), dopamine (DA) D2 receptor density and the basal and METH-induced activity of DISC1 partners, AKT and GSK-3? in the ventral striatum. In ED-treated mice, 4 weeks after METH treatment, we evaluated fear conditioning, depression-like responses in forced swim test, and the basal and METH-induced activity of AKT and GSK-3? in the ventral striatum. We found impairment in METH-induced CPP, decreased DA D2 receptor density and altered METH-induced phosphorylation of AKT and GSK-3? in naïve DISC1 female mice. The ED regimen was not neurotoxic as evidenced by unaltered brain regional monoamine tissue content. Mutant DISC1 significantly delayed METH ED-produced sensitization and affected drug-induced phosphorylation of AKT and GSK-3? in female mice. Our results suggest that perturbations in DISC1 functions in the ventral striatum may impact the molecular mechanisms of reward and sensitization, contributing to comorbidity between drug abuse and major mental diseases.

SUBMITTER: Pogorelov VM

PROVIDER: S-EPMC3115479 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Mutant DISC1 affects methamphetamine-induced sensitization and conditioned place preference: a comorbidity model.

Pogorelov Vladimir M VM Nomura Jun J Kim Jongho J Kannan Geetha G Ayhan Yavuz Y Yang Chunxia C Taniguchi Yu Y Abazyan Bagrat B Valentine Heather H Krasnova Irina N IN Kamiya Atsushi A Cadet Jean Lud JL Wong Dean F DF Pletnikov Mikhail V MV

Neuropharmacology 20110217 3

Genetic factors involved in neuroplasticity have been implicated in major psychiatric illnesses such as schizophrenia, depression, and substance abuse. Given its extended interactome, variants in the Disrupted-In-Schizophrenia-1 (DISC1) gene could contribute to drug addiction and psychiatric diseases. Thus, we evaluated how dominant-negative mutant DISC1 influenced the neurobehavioral and molecular effects of methamphetamine (METH). Control and mutant DISC1 mice were studied before or after trea ...[more]

PMID: 21315744

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Project description:Methamphetamine (METH) withdrawal anxiety symptom and relapse have been significant challenges for clinical practice, however, the underlying neuronal basis remains unclear. Our recent research has identified a specific subpopulation of choline acetyltransferase (ChAT+) neurons localized in the external lateral portion of parabrachial nucleus (eLPBChAT), which modulates METH primed-reinstatement of conditioned place preference (CPP). Here, the anatomical structures and functional roles of eLPBChAT projections in METH withdrawal anxiety and primed reinstatement were further explored. Methods: In the present study, a multifaceted approach was employed to dissect the LPBChAT+ projections in male mice, including anterograde and retrograde tracing, acetylcholine (Ach) indicator combined with fiber photometry recording, photogenetic and chemogenetic regulation, as well as electrophysiological recording. METH withdrawal anxiety-like behaviors and METH-primed reinstatement of conditioned place preference (CPP) were assessed in male mice. Results: We identified that eLPBChAT send projections to PKCδ-positive (PKCδ+) neurons in lateral portion of central nucleus of amygdala (lCeAPKCδ) and oval portion of bed nucleus of the stria terminalis (ovBNSTPKCδ), forming eLPBChAT-lCeAPKCδ and eLPBChAT-ovBNSTPKCδ pathways. At least in part, the eLPBChAT neurons positively innervate lCeAPKCδ neurons and ovBNSTPKCδ neurons through regulating synaptic elements of presynaptic Ach release and postsynaptic nicotinic acetylcholine receptors (nAChRs). METH withdrawal anxiety and METH-primed reinstatement of CPP respectively recruit eLPBChAT-lCeAPKCδ pathway and eLPBChAT-ovBNSTPKCδ pathway in male mice. Conclusion: Our findings put new insights into the complex neural networks, especially focusing on the eLPBChAT projections. The eLPBChAT is a critical node in the neural networks governing METH withdrawal anxiety and primed-reinstatement of CPP through its projections to the lCeAPKCδ and ovBNSTPKCδ, respectively.

Project description:Abstract Drug relapse is a big clinical challenge in the treatment of addiction, but its neural circuit mechanism is far from being fully understood. Here, we identified a novel cholinergic pathway from choline acetyltransferase-positive neurons in the external lateral parabrachial nucleus (eLPBChAT) to the GABAergic neurons in the central nucleus of the amygdala (CeAGABA) and explored its role in methamphetamine priming-induced reinstatement of conditioned place preference. The anatomical structure and functional innervation of the eLPBChAT–CeAGABA pathway were investigated by various methods such as fluorescent micro-optical sectioning tomography, virus-based neural tracing, fibre photometry, patch-clamp and designer receptor exclusively activated by a designer drug. The role of the eLPBChAT–CeAGABA pathway in methamphetamine relapse was assessed using methamphetamine priming-induced reinstatement of conditioned place preference behaviours in male mice. We found that the eLPBChAT neurons mainly projected to the central nucleus of the amygdala. A chemogenetic activation of the eLPBChAT neurons in vitro or in vivo triggered the excitabilities of the CeAGABA neurons, which is at least in part mediated via the cholinergic receptor system. Most importantly, the chemogenetic activation of either the eLPBChAT neurons or the eLPBChAT neurons that project onto the central nucleus of the amygdala decreased the methamphetamine priming-induced reinstatement of conditioned place preference in mice. Our findings revealed a previously undiscovered cholinergic pathway of the eLPBChAT–CeAGABA and showed that the activation of this pathway decreased the methamphetamine priming-induced reinstatement of conditioned place preference. He et al. identified a novel cholinergic projection from choline acetyltransferase-positive neurons in the external lateral parabrachial nucleus (eLPBChAT) to the GABAergic neurons in the central nucleus of the amygdala (CeAGABA), which is involved in methamphetamine relapse. The chemogenetic activation of either the LPBChAT neurons or the eLPBChAT–CeAGABA pathway attenuated the methamphetamine-primed reinstatement of conditioned place preference. Graphical Abstract Graphical abstract

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Mutant DISC1 affects methamphetamine-induced sensitization and conditioned place preference: a comorbidity model.

Publications

Mutant DISC1 affects methamphetamine-induced sensitization and conditioned place preference: a comorbidity model.

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