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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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Oral self-administration of MDZa, Protocol for behavioral experiment. b, Total consumption successively with water, sucrose, and MDZ (0.005 mg/ml) + sucrose (4 %) in WT mice (black) and α1(H101R) mice (red). Note that WT and α1(H101R) mice drink similar amounts of liquids. c, Relative MDZ consumption in WT and α1(H101R) mice. d, Corresponding box plots for relative average consumption of MDZ at days indicated. n = 12-18 mice in 4-6 cages. F(3;16) = 5.39
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Figure 6: Oral self-administration of MDZa, Protocol for behavioral experiment. b, Total consumption successively with water, sucrose, and MDZ (0.005 mg/ml) + sucrose (4 %) in WT mice (black) and α1(H101R) mice (red). Note that WT and α1(H101R) mice drink similar amounts of liquids. c, Relative MDZ consumption in WT and α1(H101R) mice. d, Corresponding box plots for relative average consumption of MDZ at days indicated. n = 12-18 mice in 4-6 cages. F(3;16) = 5.39

Mentions: The results above demonstrate that α1-containing GABAAR mediate the increase of mesolimbic DA in response to BDZs. Furthermore DA antagonists can reduce self-administration of and preference to these drugs26,27. We therefore tested the impact of the α1 subunit isoform on oral self-administration of MDZ, by offering the mice a free choice of two drinking solutions (Fig. 6a). During the first three days the two bottles contained water. Sucrose was then added in both bottles to mask any bitter taste. This led to an increase of the overall consumption, but no particular preference. Finally, MDZ was added to one of the two bottles. During the test period with MDZ, the total consumption did not change in either genotype (Fig 6b). A preference for the MDZ solution developed rapidly in WT mice, but not α1(H101R) mice (Fig. 6c, d). WT mice drank between 0.8-1.1 mg/kg/24h of MDZ, which corresponds to a pharmacological dose. Two control experiments were carried out using a similar protocol. First, we offered α1(H101R) mice a choice between water and a sucrose solution. Both WT and mutant mice developed a strong preference for sucrose, indicating that α1(H101R) mice are not generally deficient in reward reinforcement (Supplementary Fig. 9). We also tested whether α3(H126R) mice, where MDZ caused a normal disinhibition of DA neurons (Supplementary Fig. 8) would develop a preference for MDZ, which was indeed the case (Supplementary Fig. 10). Although BDZs, particularly MDZ, may enhance taste perception28, this is unlikely to influence the interpretation of these data, as several studies have shown that BDZ-mediated taste enhancement is independent of α1-containing GABAAR29,30.


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)

Oral self-administration of MDZa, Protocol for behavioral experiment. b, Total consumption successively with water, sucrose, and MDZ (0.005 mg/ml) + sucrose (4 %) in WT mice (black) and α1(H101R) mice (red). Note that WT and α1(H101R) mice drink similar amounts of liquids. c, Relative MDZ consumption in WT and α1(H101R) mice. d, Corresponding box plots for relative average consumption of MDZ at days indicated. n = 12-18 mice in 4-6 cages. F(3;16) = 5.39
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2871668&req=5

Figure 6: Oral self-administration of MDZa, Protocol for behavioral experiment. b, Total consumption successively with water, sucrose, and MDZ (0.005 mg/ml) + sucrose (4 %) in WT mice (black) and α1(H101R) mice (red). Note that WT and α1(H101R) mice drink similar amounts of liquids. c, Relative MDZ consumption in WT and α1(H101R) mice. d, Corresponding box plots for relative average consumption of MDZ at days indicated. n = 12-18 mice in 4-6 cages. F(3;16) = 5.39
Mentions: The results above demonstrate that α1-containing GABAAR mediate the increase of mesolimbic DA in response to BDZs. Furthermore DA antagonists can reduce self-administration of and preference to these drugs26,27. We therefore tested the impact of the α1 subunit isoform on oral self-administration of MDZ, by offering the mice a free choice of two drinking solutions (Fig. 6a). During the first three days the two bottles contained water. Sucrose was then added in both bottles to mask any bitter taste. This led to an increase of the overall consumption, but no particular preference. Finally, MDZ was added to one of the two bottles. During the test period with MDZ, the total consumption did not change in either genotype (Fig 6b). A preference for the MDZ solution developed rapidly in WT mice, but not α1(H101R) mice (Fig. 6c, d). WT mice drank between 0.8-1.1 mg/kg/24h of MDZ, which corresponds to a pharmacological dose. Two control experiments were carried out using a similar protocol. First, we offered α1(H101R) mice a choice between water and a sucrose solution. Both WT and mutant mice developed a strong preference for sucrose, indicating that α1(H101R) mice are not generally deficient in reward reinforcement (Supplementary Fig. 9). We also tested whether α3(H126R) mice, where MDZ caused a normal disinhibition of DA neurons (Supplementary Fig. 8) would develop a preference for MDZ, which was indeed the case (Supplementary Fig. 10). Although BDZs, particularly MDZ, may enhance taste perception28, this is unlikely to influence the interpretation of these data, as several studies have shown that BDZ-mediated taste enhancement is independent of α1-containing GABAAR29,30.

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