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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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The total current generated by sIPSC in DA neurons is decreased by MDZa, Example trace of sIPSCs recordings in GABA and DA neurons obtained before and after application of MDZ in slices from WT and α1(H101R) mice. sIPSCs were abolished with picrotoxin (PTX, 100 μM, not shown). b, Group data for the relative increase in the overall charge transfer (1 min) after MDZ bath-application. Note that in WT mice the total current in DA neurons decreases with MDZ application while in α1(H101R) mice there is an increase. GABA/WT vs GABA/α1(H101R) t(9) = 6.39, DA/WT vs DA/α1(H101R) t(15) = 5.50. n = 6-7.
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Figure 4: The total current generated by sIPSC in DA neurons is decreased by MDZa, Example trace of sIPSCs recordings in GABA and DA neurons obtained before and after application of MDZ in slices from WT and α1(H101R) mice. sIPSCs were abolished with picrotoxin (PTX, 100 μM, not shown). b, Group data for the relative increase in the overall charge transfer (1 min) after MDZ bath-application. Note that in WT mice the total current in DA neurons decreases with MDZ application while in α1(H101R) mice there is an increase. GABA/WT vs GABA/α1(H101R) t(9) = 6.39, DA/WT vs DA/α1(H101R) t(15) = 5.50. n = 6-7.

Mentions: In WT mice, mIPSCs in both GABA and DA neurons were enhanced by BDZs. However, when BDZs are administered whilst transmission is intact, the extent of current amplification in DA neurons depends on the frequency of synaptic events, which originate in the interneurons upstream. We therefore monitored the effect of MDZ on spike-driven, spontaneous IPSCs (sIPSC) in DA neurons (Fig. 4). Although, the charge transfer of sIPSCs on average increased after MDZ (in line with the mIPSC data), there was a strong reduction of the frequency of spike-driven events in DA neurons (Supplementary Fig. 7). As a result, when we integrated the charge transfer of sIPSCs over time before and after application of MDZ (relative total current), we found a significant decrease (Fig. 4b). Because interneurons are efficiently inhibited by MDZ, fewer spikes are generated, strongly decreasing the number of sIPSC, an effect that predominates over the MDZ amplification of the individual event. In α1(H101R) mice, in contrast, we observed an increased total current in DA neurons because the GABA neurons were insensitive to MDZ. In summary, in the WT mice, MDZ led to a net decrease of the total inhibitory current in DA neurons, which could be sufficient to cause their disinhibition (see supplementary Fig. 1 for schematics).


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)

The total current generated by sIPSC in DA neurons is decreased by MDZa, Example trace of sIPSCs recordings in GABA and DA neurons obtained before and after application of MDZ in slices from WT and α1(H101R) mice. sIPSCs were abolished with picrotoxin (PTX, 100 μM, not shown). b, Group data for the relative increase in the overall charge transfer (1 min) after MDZ bath-application. Note that in WT mice the total current in DA neurons decreases with MDZ application while in α1(H101R) mice there is an increase. GABA/WT vs GABA/α1(H101R) t(9) = 6.39, DA/WT vs DA/α1(H101R) t(15) = 5.50. n = 6-7.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2871668&req=5

Figure 4: The total current generated by sIPSC in DA neurons is decreased by MDZa, Example trace of sIPSCs recordings in GABA and DA neurons obtained before and after application of MDZ in slices from WT and α1(H101R) mice. sIPSCs were abolished with picrotoxin (PTX, 100 μM, not shown). b, Group data for the relative increase in the overall charge transfer (1 min) after MDZ bath-application. Note that in WT mice the total current in DA neurons decreases with MDZ application while in α1(H101R) mice there is an increase. GABA/WT vs GABA/α1(H101R) t(9) = 6.39, DA/WT vs DA/α1(H101R) t(15) = 5.50. n = 6-7.
Mentions: In WT mice, mIPSCs in both GABA and DA neurons were enhanced by BDZs. However, when BDZs are administered whilst transmission is intact, the extent of current amplification in DA neurons depends on the frequency of synaptic events, which originate in the interneurons upstream. We therefore monitored the effect of MDZ on spike-driven, spontaneous IPSCs (sIPSC) in DA neurons (Fig. 4). Although, the charge transfer of sIPSCs on average increased after MDZ (in line with the mIPSC data), there was a strong reduction of the frequency of spike-driven events in DA neurons (Supplementary Fig. 7). As a result, when we integrated the charge transfer of sIPSCs over time before and after application of MDZ (relative total current), we found a significant decrease (Fig. 4b). Because interneurons are efficiently inhibited by MDZ, fewer spikes are generated, strongly decreasing the number of sIPSC, an effect that predominates over the MDZ amplification of the individual event. In α1(H101R) mice, in contrast, we observed an increased total current in DA neurons because the GABA neurons were insensitive to MDZ. In summary, in the WT mice, MDZ led to a net decrease of the total inhibitory current in DA neurons, which could be sufficient to cause their disinhibition (see supplementary Fig. 1 for schematics).

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