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Neural bases for addictive properties of benzodiazepines.

Tan KR, Brown M, Labouèbe G, Yvon C, Creton C, Fritschy JM, Rudolph U, Lüscher C - Nature (2010)

Bottom Line: Here we show that benzodiazepines increase firing of dopamine neurons of the ventral tegmental area through the positive modulation of GABA(A) (gamma-aminobutyric acid type A) receptors in nearby interneurons.Such disinhibition, which relies on alpha1-containing GABA(A) receptors 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 alpha1-containing GABA(A) receptors in the ventral tegmental area.

View Article: PubMed Central - PubMed

Affiliation: Department of Basic Neurosciences, Medical Faculty, University of Geneva, CH-1211 Geneva, Switzerland.

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 behaviour. 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) (gamma-aminobutyric acid type A) receptors in nearby interneurons. Such disinhibition, which relies on alpha1-containing GABA(A) receptors 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 alpha1-containing GABA(A) receptors in the ventral tegmental area. The data also indicate that subunit-selective benzodiazepines sparing alpha1 may be devoid of addiction liability.

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α1 is selectively expressed in GABA neurons of the VTAa, Immunohistochemical staining for tyrosine hydroxylase (TH, red) and ༟1 (blue) in VTA slices of GAD67-GFP (green) knock-in mice. Concentric pie charts represent the fraction of α1-positive cells (inner segment), and quantification of the two cell types (outer segment, n = 4 mice). Overlap between inner and outer segments represents colocalization. b, Example trace of mIPSCs recordings in GABA and DA neurons obtained in slices from WT mice. c, Representative averaged mIPSC trace from a GABA and a DA neuron. The overlay shows the difference in kinetics when the two currents are normalized to the average mIPSC peak amplitude. d, Box-plots represent group data for charge transfer and amplitude of mIPSCs obtained from GABA and DA neurons in slices from WT mice. t(75) = 7.55 and t(75) = 3.16, respectively. (n = 25-48). e, Representative average traces of mIPSCs before (solid line) and after (dotted line) application of MDZ (100 nM) in slices from WT and α1(H101R) mice. f, Corresponding box-plots representing group data for relative increase in charge transfer and frequency after MDZ bath-application. t(14) = 3.06 and t(14) = 3.23. n = 6-10.
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Figure 3: α1 is selectively expressed in GABA neurons of the VTAa, Immunohistochemical staining for tyrosine hydroxylase (TH, red) and ༟1 (blue) in VTA slices of GAD67-GFP (green) knock-in mice. Concentric pie charts represent the fraction of α1-positive cells (inner segment), and quantification of the two cell types (outer segment, n = 4 mice). Overlap between inner and outer segments represents colocalization. b, Example trace of mIPSCs recordings in GABA and DA neurons obtained in slices from WT mice. c, Representative averaged mIPSC trace from a GABA and a DA neuron. The overlay shows the difference in kinetics when the two currents are normalized to the average mIPSC peak amplitude. d, Box-plots represent group data for charge transfer and amplitude of mIPSCs obtained from GABA and DA neurons in slices from WT mice. t(75) = 7.55 and t(75) = 3.16, respectively. (n = 25-48). e, Representative average traces of mIPSCs before (solid line) and after (dotted line) application of MDZ (100 nM) in slices from WT and α1(H101R) mice. f, Corresponding box-plots representing group data for relative increase in charge transfer and frequency after MDZ bath-application. t(14) = 3.06 and t(14) = 3.23. n = 6-10.

Mentions: To identify α1-expressing cells in the VTA, we next carried out immunohistochemical staining for tyrosine hydroxylase (TH) and the α1 subunit isoform in GAD-67 GFP mice (Fig. 3a). These experiments confirmed that α1 was expressed mainly in GFP-positive neurons, but not in TH-positive DA neurons. Quantifications revealed that 81% of the GABA neurons contained the α1 subunit isoform, while this was the case only in 7% of the DA neurons (Inset Fig. 3a). We also observed α1-staining that could neither be associated to TH-positive nor GAD67-GFP-expressing cells. This may reflect the pool of the so-called tertiary cells that are neither DA- nor GABA-neurons16,17 or be due to detectability limits in fine processes.


Neural bases for addictive properties of benzodiazepines.

Tan KR, Brown M, Labouèbe G, Yvon C, Creton C, Fritschy JM, Rudolph U, Lüscher C - Nature (2010)

α1 is selectively expressed in GABA neurons of the VTAa, Immunohistochemical staining for tyrosine hydroxylase (TH, red) and ༟1 (blue) in VTA slices of GAD67-GFP (green) knock-in mice. Concentric pie charts represent the fraction of α1-positive cells (inner segment), and quantification of the two cell types (outer segment, n = 4 mice). Overlap between inner and outer segments represents colocalization. b, Example trace of mIPSCs recordings in GABA and DA neurons obtained in slices from WT mice. c, Representative averaged mIPSC trace from a GABA and a DA neuron. The overlay shows the difference in kinetics when the two currents are normalized to the average mIPSC peak amplitude. d, Box-plots represent group data for charge transfer and amplitude of mIPSCs obtained from GABA and DA neurons in slices from WT mice. t(75) = 7.55 and t(75) = 3.16, respectively. (n = 25-48). e, Representative average traces of mIPSCs before (solid line) and after (dotted line) application of MDZ (100 nM) in slices from WT and α1(H101R) mice. f, Corresponding box-plots representing group data for relative increase in charge transfer and frequency after MDZ bath-application. t(14) = 3.06 and t(14) = 3.23. n = 6-10.
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Figure 3: α1 is selectively expressed in GABA neurons of the VTAa, Immunohistochemical staining for tyrosine hydroxylase (TH, red) and ༟1 (blue) in VTA slices of GAD67-GFP (green) knock-in mice. Concentric pie charts represent the fraction of α1-positive cells (inner segment), and quantification of the two cell types (outer segment, n = 4 mice). Overlap between inner and outer segments represents colocalization. b, Example trace of mIPSCs recordings in GABA and DA neurons obtained in slices from WT mice. c, Representative averaged mIPSC trace from a GABA and a DA neuron. The overlay shows the difference in kinetics when the two currents are normalized to the average mIPSC peak amplitude. d, Box-plots represent group data for charge transfer and amplitude of mIPSCs obtained from GABA and DA neurons in slices from WT mice. t(75) = 7.55 and t(75) = 3.16, respectively. (n = 25-48). e, Representative average traces of mIPSCs before (solid line) and after (dotted line) application of MDZ (100 nM) in slices from WT and α1(H101R) mice. f, Corresponding box-plots representing group data for relative increase in charge transfer and frequency after MDZ bath-application. t(14) = 3.06 and t(14) = 3.23. n = 6-10.
Mentions: To identify α1-expressing cells in the VTA, we next carried out immunohistochemical staining for tyrosine hydroxylase (TH) and the α1 subunit isoform in GAD-67 GFP mice (Fig. 3a). These experiments confirmed that α1 was expressed mainly in GFP-positive neurons, but not in TH-positive DA neurons. Quantifications revealed that 81% of the GABA neurons contained the α1 subunit isoform, while this was the case only in 7% of the DA neurons (Inset Fig. 3a). We also observed α1-staining that could neither be associated to TH-positive nor GAD67-GFP-expressing cells. This may reflect the pool of the so-called tertiary cells that are neither DA- nor GABA-neurons16,17 or be due to detectability limits in fine processes.

Bottom Line: Here we show that benzodiazepines increase firing of dopamine neurons of the ventral tegmental area through the positive modulation of GABA(A) (gamma-aminobutyric acid type A) receptors in nearby interneurons.Such disinhibition, which relies on alpha1-containing GABA(A) receptors 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 alpha1-containing GABA(A) receptors in the ventral tegmental area.

View Article: PubMed Central - PubMed

Affiliation: Department of Basic Neurosciences, Medical Faculty, University of Geneva, CH-1211 Geneva, Switzerland.

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 behaviour. 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) (gamma-aminobutyric acid type A) receptors in nearby interneurons. Such disinhibition, which relies on alpha1-containing GABA(A) receptors 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 alpha1-containing GABA(A) receptors in the ventral tegmental area. The data also indicate that subunit-selective benzodiazepines sparing alpha1 may be devoid of addiction liability.

Show MeSH
Related in: MedlinePlus