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      Neural bases for addictive properties of benzodiazepines

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          Abstract

          Benzodiazepines are widely used in clinics and for recreational purposes, but will lead to addiction in vulnerable individuals. Addictive drugs increase the levels of dopamine and also trigger long-lasting synaptic adaptations in the mesolimbic reward system that ultimately may induce the pathological behavior. The neural basis for the addictive nature of benzodiazepines however remains elusive. Here we show that benzodiazepines increase firing of dopamine neurons of the ventral tegmental area through the positive modulation of GABA A receptors in nearby interneurons. Such disinhibition, which relies on α1-containing GABA ARs expressed in these cells, triggers drug-evoked synaptic plasticity in excitatory afferents onto dopamine neurons and underlies drug reinforcement. Taken together, our data provide evidence that benzodiazepines share defining pharmacological features of addictive drugs through cell type-specific expression of α1-containing GABA ARs in the ventral tegmental area. The data also suggest that subunitselective benzodiazepines sparing α1 may be devoid of addiction liability.

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          Green fluorescent protein expression and colocalization with calretinin, parvalbumin, and somatostatin in the GAD67-GFP knock-in mouse.

          Takeshi Kaneko, Kunihiko Obata, Jun-Ichi Miyazaki … (2003)
          Gamma-aminobutyric acid (GABA)ergic neurons in the central nervous system regulate the activity of other neurons and play a crucial role in information processing. To assist an advance in the research of GABAergic neurons, here we produced two lines of glutamic acid decarboxylase-green fluorescence protein (GAD67-GFP) knock-in mouse. The distribution pattern of GFP-positive somata was the same as that of the GAD67 in situ hybridization signal in the central nervous system. We encountered neither any apparent ectopic GFP expression in GAD67-negative cells nor any apparent lack of GFP expression in GAD67-positive neurons in the two GAD67-GFP knock-in mouse lines. The timing of GFP expression also paralleled that of GAD67 expression. Hence, we constructed a map of GFP distribution in the knock-in mouse brain. Moreover, we used the knock-in mice to investigate the colocalization of GFP with NeuN, calretinin (CR), parvalbumin (PV), and somatostatin (SS) in the frontal motor cortex. The proportion of GFP-positive cells among NeuN-positive cells (neocortical neurons) was approximately 19.5%. All the CR-, PV-, and SS-positive cells appeared positive for GFP. The CR-, PV, and SS-positive cells emitted GFP fluorescence at various intensities characteristics to them. The proportions of CR-, PV-, and SS-positive cells among GFP-positive cells were 13.9%, 40.1%, and 23.4%, respectively. Thus, the three subtypes of GABAergic neurons accounted for 77.4% of the GFP-positive cells. They accounted for 6.5% in layer I. In accord with unidentified GFP-positive cells, many medium-sized spherical somata emitting intense GFP fluorescence were observed in layer I. Copyright 2003 Wiley-Liss, Inc.
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            Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons.

            Daniel Saal, Yan Dong, Antonello Bonci … (2003)
            Drug seeking and drug self-administration in both animals and humans can be triggered by drugs of abuse themselves or by stressful events. Here, we demonstrate that in vivo administration of drugs of abuse with different molecular mechanisms of action as well as acute stress both increase strength at excitatory synapses on midbrain dopamine neurons. Psychoactive drugs with minimal abuse potential do not cause this change. The synaptic effects of stress, but not of cocaine, are blocked by the glucocorticoid receptor antagonist RU486. These results suggest that plasticity at excitatory synapses on dopamine neurons may be a key neural adaptation contributing to addiction and its interactions with stress and thus may be an attractive therapeutic target for reducing the risk of addiction.
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              Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes.

              U Rudolph, F Crestani, D Benke … (1999)
              GABA(A) (gamma-aminobutyric acid(A)) receptors are molecular substrates for the regulation of vigilance, anxiety, muscle tension, epileptogenic activity and memory functions, which is evident from the spectrum of actions elicited by clinically effective drugs acting at their modulatory benzodiazepine-binding site. Here we show, by introducing a histidine-to-arginine point mutation at position 101 of the murine alpha1-subunit gene, that alpha1-type GABA(A) receptors, which are mainly expressed in cortical areas and thalamus, are rendered insensitive to allosteric modulation by benzodiazepine-site ligands, whilst regulation by the physiological neurotransmitter gamma-aminobutyric acid is preserved. alpha1(H101R) mice failed to show the sedative, amnesic and partly the anticonvulsant action of diazepam. In contrast, the anxiolytic-like, myorelaxant, motor-impairing and ethanol-potentiating effects were fully retained, and are attributed to the nonmutated GABA(A) receptors found in the limbic system (alpha2, alpha5), in monoaminergic neurons (alpha3) and in motoneurons (alpha2, alpha5). Thus, benzodiazepine-induced behavioural responses are mediated by specific GABA(A) receptor subtypes in distinct neuronal circuits, which is of interest for drug design.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 0410462
                Journal ID (pubmed-jr-id): 6011
                Journal ID (nlm-ta): Nature
                Title: Nature
                ISSN (Print): 0028-0836
                ISSN (Electronic): 1476-4687
                Publication date Nihms-submitted: 11 February 2010
                Publication date (Print): 11 February 2010
                Publication date PMC-release: 11 August 2010
                Volume: 463
                Issue: 7282
                Pages: 769-774
                Affiliations
                [1 ]Dept. of Basic Neurosciences, Medical Faculty, University of Geneva, CH-1211 Geneva, Switzerland
                [2 ]Dept. of Pharmacology and Toxicology, University of Zurich, CH-8057 Zurich, Switzerland
                [3 ]Laboratory of Genetic Neuropharmacology, McLean Hospital and Dept. of Psychiatry, Harvard Medical School, Belmont, MA 02478
                [4 ]Clinic of Neurology, Dept. of Clinical Neurosciences, Geneva University Hospital, CH-1211 Geneva, Switzerland
                [5 ]Geneva Neuroscience Center, CH-1211 Geneva, Switzerland
                Author notes
                [*]

                Equally contributed

                Article
                Manuscript ID: nihpa165709
                DOI: 10.1038/nature08758
                PMC ID: 2871668
                PubMed ID: 20148031
                SO-VID: fe7fd8b1-57e4-49c3-a8f7-a1ac2de5fd47
                History
                Funding
                Funded by: National Institute on Drug Abuse : NIDA
                Award ID: R01 DA019022-04 ||DA
                Categories
                Subject: Article

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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