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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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BDZ-evoked synaptic plasticity is abolished in α1(H101R) mutant micea, Top panel; normalized AMPAR-EPSCs obtained at -65, 0 and +35 mV in slices from WT mice i.p. injected with saline, MDZ (0.5 mg/kg) or Mor (15 mg/kg) 24 h prior to sacrifice. Middle panel; corresponding iv-curves. Bottom panel; bar graphs represent group data for the RI. F(2;21) = 9.08. b, AMPAR-EPSCs, iv-curves and RI (top, middle and bottom panel, respectively) observed when ACSF or MDZ were injected into the VTA in WT mice. t(11) = 5.43. c, Similar experiments performed with α1(H101R) mice. Note that Mor induces a rectification that is similar in WT and mutant mice. F(2;16) = 17.88. d, Similar experiments performed with α1(H101R) mice when MDZ was injected intra-VTA. n = 6-10.
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Figure 1: BDZ-evoked synaptic plasticity is abolished in α1(H101R) mutant micea, Top panel; normalized AMPAR-EPSCs obtained at -65, 0 and +35 mV in slices from WT mice i.p. injected with saline, MDZ (0.5 mg/kg) or Mor (15 mg/kg) 24 h prior to sacrifice. Middle panel; corresponding iv-curves. Bottom panel; bar graphs represent group data for the RI. F(2;21) = 9.08. b, AMPAR-EPSCs, iv-curves and RI (top, middle and bottom panel, respectively) observed when ACSF or MDZ were injected into the VTA in WT mice. t(11) = 5.43. c, Similar experiments performed with α1(H101R) mice. Note that Mor induces a rectification that is similar in WT and mutant mice. F(2;16) = 17.88. d, Similar experiments performed with α1(H101R) mice when MDZ was injected intra-VTA. n = 6-10.

Mentions: In slices obtained 24 h after the i.p. injection of midazolam (MDZ), diazepam (DZ), or flunitrazepam (FZ), the rectification index (RI = EPSC−65 mV/EPSC+35 mV) was significantly higher than in slices from saline-injected controls (Fig. 1a and Supplementary Fig. 2). Similar rectification was measured after an injection of morphine (Mor), a member of the class of drugs that cause disinhibition of DA neurons8. The BDZ antagonist flumazenil (Flu) blocked rectification when co-injected with MDZ but was without effect when co-injected with a control saline solution (Fig. 2 and Supplementary Fig. 2). The adaptive plasticity induced by systemic BDZs was also observed 24 h after local application of MDZ into the VTA by stereotactic injection (0.5 μl of a 8 mg/ml solution over 10 minutes; Fig. 1b). Thus, BDZ-dependent effects on VTA circuitry are sufficient to induce this cellular hallmark of addictive drugs.


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)

BDZ-evoked synaptic plasticity is abolished in α1(H101R) mutant micea, Top panel; normalized AMPAR-EPSCs obtained at -65, 0 and +35 mV in slices from WT mice i.p. injected with saline, MDZ (0.5 mg/kg) or Mor (15 mg/kg) 24 h prior to sacrifice. Middle panel; corresponding iv-curves. Bottom panel; bar graphs represent group data for the RI. F(2;21) = 9.08. b, AMPAR-EPSCs, iv-curves and RI (top, middle and bottom panel, respectively) observed when ACSF or MDZ were injected into the VTA in WT mice. t(11) = 5.43. c, Similar experiments performed with α1(H101R) mice. Note that Mor induces a rectification that is similar in WT and mutant mice. F(2;16) = 17.88. d, Similar experiments performed with α1(H101R) mice when MDZ was injected intra-VTA. n = 6-10.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2871668&req=5

Figure 1: BDZ-evoked synaptic plasticity is abolished in α1(H101R) mutant micea, Top panel; normalized AMPAR-EPSCs obtained at -65, 0 and +35 mV in slices from WT mice i.p. injected with saline, MDZ (0.5 mg/kg) or Mor (15 mg/kg) 24 h prior to sacrifice. Middle panel; corresponding iv-curves. Bottom panel; bar graphs represent group data for the RI. F(2;21) = 9.08. b, AMPAR-EPSCs, iv-curves and RI (top, middle and bottom panel, respectively) observed when ACSF or MDZ were injected into the VTA in WT mice. t(11) = 5.43. c, Similar experiments performed with α1(H101R) mice. Note that Mor induces a rectification that is similar in WT and mutant mice. F(2;16) = 17.88. d, Similar experiments performed with α1(H101R) mice when MDZ was injected intra-VTA. n = 6-10.
Mentions: In slices obtained 24 h after the i.p. injection of midazolam (MDZ), diazepam (DZ), or flunitrazepam (FZ), the rectification index (RI = EPSC−65 mV/EPSC+35 mV) was significantly higher than in slices from saline-injected controls (Fig. 1a and Supplementary Fig. 2). Similar rectification was measured after an injection of morphine (Mor), a member of the class of drugs that cause disinhibition of DA neurons8. The BDZ antagonist flumazenil (Flu) blocked rectification when co-injected with MDZ but was without effect when co-injected with a control saline solution (Fig. 2 and Supplementary Fig. 2). The adaptive plasticity induced by systemic BDZs was also observed 24 h after local application of MDZ into the VTA by stereotactic injection (0.5 μl of a 8 mg/ml solution over 10 minutes; Fig. 1b). Thus, BDZ-dependent effects on VTA circuitry are sufficient to induce this cellular hallmark of addictive drugs.

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