Limits...
Designer receptors show role for ventral pallidum input to ventral tegmental area in cocaine seeking.

Mahler SV, Vazey EM, Beckley JT, Keistler CR, McGlinchey EM, Kaufling J, Wilson SP, Deisseroth K, Woodward JJ, Aston-Jones G - Nat. Neurosci. (2014)

Bottom Line: The ventral pallidum is centrally positioned within mesocorticolimbic reward circuits, and its dense projection to the ventral tegmental area (VTA) regulates neuronal activity there.However, the ventral pallidum is a heterogeneous structure, and how this complexity affects its role within wider reward circuits is unclear.We found that projections to VTA from the rostral ventral pallidum (RVP), but not the caudal ventral pallidum (CVP), were robustly Fos activated during cue-induced reinstatement of cocaine seeking--a rat model of relapse in addiction.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina, USA.

ABSTRACT
The ventral pallidum is centrally positioned within mesocorticolimbic reward circuits, and its dense projection to the ventral tegmental area (VTA) regulates neuronal activity there. However, the ventral pallidum is a heterogeneous structure, and how this complexity affects its role within wider reward circuits is unclear. We found that projections to VTA from the rostral ventral pallidum (RVP), but not the caudal ventral pallidum (CVP), were robustly Fos activated during cue-induced reinstatement of cocaine seeking--a rat model of relapse in addiction. Moreover, designer receptor-mediated transient inactivation of RVP neurons, their terminals in VTA or functional connectivity between RVP and VTA dopamine neurons blocked the ability of drug-associated cues (but not a cocaine prime) to reinstate cocaine seeking. In contrast, CVP neuronal inhibition blocked cocaine-primed, but not cue-induced, reinstatement. This double dissociation in ventral pallidum subregional roles in drug seeking is likely to be important for understanding the mesocorticolimbic circuits underlying reward seeking and addiction.

Show MeSH

Related in: MedlinePlus

GABAA-mediated disinhibition of VTA dopamine neurons enhances cue-induced reinstatementa) Example of Fos staining after nearby VTA gabazine microinjection (10 μM/0.3 μl). b) Example tyrosine hydroxylase (TH) staining of the same tissue. c) Overlay of Fos and TH staining. d) Magnified view of Fos+TH overlay. Arrows point to co-labelled neurons. n=5. e) Compared to vehicle microinjection, gabazine induced Fos in TH+ neurons, but did not affect the number of TH+ neurons. f) Gabazine increased the percentage of TH+ neurons that expressed Fos. g) Gabazine injection sites within VTA from cue-induced reinstatement animals. Gabazine was injected at equivalent sites as Fos/TH stained section in panel a. h) VTA gabazine (10 μM) increased active, but not inactive lever pressing during cued reinstatement. In a subset of animals, gabazine (100 μM) robustly increased pressing on both levers, which was very likely related to intense non-specific locomotor activation observed. *p<0.05. Bars=m±SEM. Scale bar=100 μm.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3973180&req=5

Figure 7: GABAA-mediated disinhibition of VTA dopamine neurons enhances cue-induced reinstatementa) Example of Fos staining after nearby VTA gabazine microinjection (10 μM/0.3 μl). b) Example tyrosine hydroxylase (TH) staining of the same tissue. c) Overlay of Fos and TH staining. d) Magnified view of Fos+TH overlay. Arrows point to co-labelled neurons. n=5. e) Compared to vehicle microinjection, gabazine induced Fos in TH+ neurons, but did not affect the number of TH+ neurons. f) Gabazine increased the percentage of TH+ neurons that expressed Fos. g) Gabazine injection sites within VTA from cue-induced reinstatement animals. Gabazine was injected at equivalent sites as Fos/TH stained section in panel a. h) VTA gabazine (10 μM) increased active, but not inactive lever pressing during cued reinstatement. In a subset of animals, gabazine (100 μM) robustly increased pressing on both levers, which was very likely related to intense non-specific locomotor activation observed. *p<0.05. Bars=m±SEM. Scale bar=100 μm.

Mentions: GABAergic VP projections to VTA can tonically inhibit VTA dopamine neurons5, and inactivating this projection with DREADDs can disinhibit dopamine neurons (Fig. 4). We therefore asked if disinhibition of VTA dopamine neurons could have contributed to the attenuation of reinstatement we observed after inactivating RVP inputs to VTA with DREADDs. If so, then direct disinhibition of VTA dopamine neurons with the GABAA antagonist gabazine should also attenuate reinstatement. Instead, we observed that intra-VTA gabazine (10 μM/0.3 μl) strongly increased cued reinstatement (n=6 rats; F2,17=9.43, p=0.002; veh vs. 10 μM gabazine active lever: t6=2.62, p=0.04; Fig. 7g–h), and robustly induced Fos in nearby dopamine neurons (veh n=3, gabazine n=5 rats; no effect on number of TH+ cells: t6=0.2, n.s.; total Fos+ TH+ cells: t4.4=5.55, p=0.001; percent Fos+ TH cells: t6=8.84, p=0.0001; Fig. 7a–f). This indicates that simple disinhibition of dopamine neurons is not likely the mechanism by which inhibiting RVP inputs to VTA reduces cued reinstatement.


Designer receptors show role for ventral pallidum input to ventral tegmental area in cocaine seeking.

Mahler SV, Vazey EM, Beckley JT, Keistler CR, McGlinchey EM, Kaufling J, Wilson SP, Deisseroth K, Woodward JJ, Aston-Jones G - Nat. Neurosci. (2014)

GABAA-mediated disinhibition of VTA dopamine neurons enhances cue-induced reinstatementa) Example of Fos staining after nearby VTA gabazine microinjection (10 μM/0.3 μl). b) Example tyrosine hydroxylase (TH) staining of the same tissue. c) Overlay of Fos and TH staining. d) Magnified view of Fos+TH overlay. Arrows point to co-labelled neurons. n=5. e) Compared to vehicle microinjection, gabazine induced Fos in TH+ neurons, but did not affect the number of TH+ neurons. f) Gabazine increased the percentage of TH+ neurons that expressed Fos. g) Gabazine injection sites within VTA from cue-induced reinstatement animals. Gabazine was injected at equivalent sites as Fos/TH stained section in panel a. h) VTA gabazine (10 μM) increased active, but not inactive lever pressing during cued reinstatement. In a subset of animals, gabazine (100 μM) robustly increased pressing on both levers, which was very likely related to intense non-specific locomotor activation observed. *p<0.05. Bars=m±SEM. Scale bar=100 μm.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3973180&req=5

Figure 7: GABAA-mediated disinhibition of VTA dopamine neurons enhances cue-induced reinstatementa) Example of Fos staining after nearby VTA gabazine microinjection (10 μM/0.3 μl). b) Example tyrosine hydroxylase (TH) staining of the same tissue. c) Overlay of Fos and TH staining. d) Magnified view of Fos+TH overlay. Arrows point to co-labelled neurons. n=5. e) Compared to vehicle microinjection, gabazine induced Fos in TH+ neurons, but did not affect the number of TH+ neurons. f) Gabazine increased the percentage of TH+ neurons that expressed Fos. g) Gabazine injection sites within VTA from cue-induced reinstatement animals. Gabazine was injected at equivalent sites as Fos/TH stained section in panel a. h) VTA gabazine (10 μM) increased active, but not inactive lever pressing during cued reinstatement. In a subset of animals, gabazine (100 μM) robustly increased pressing on both levers, which was very likely related to intense non-specific locomotor activation observed. *p<0.05. Bars=m±SEM. Scale bar=100 μm.
Mentions: GABAergic VP projections to VTA can tonically inhibit VTA dopamine neurons5, and inactivating this projection with DREADDs can disinhibit dopamine neurons (Fig. 4). We therefore asked if disinhibition of VTA dopamine neurons could have contributed to the attenuation of reinstatement we observed after inactivating RVP inputs to VTA with DREADDs. If so, then direct disinhibition of VTA dopamine neurons with the GABAA antagonist gabazine should also attenuate reinstatement. Instead, we observed that intra-VTA gabazine (10 μM/0.3 μl) strongly increased cued reinstatement (n=6 rats; F2,17=9.43, p=0.002; veh vs. 10 μM gabazine active lever: t6=2.62, p=0.04; Fig. 7g–h), and robustly induced Fos in nearby dopamine neurons (veh n=3, gabazine n=5 rats; no effect on number of TH+ cells: t6=0.2, n.s.; total Fos+ TH+ cells: t4.4=5.55, p=0.001; percent Fos+ TH cells: t6=8.84, p=0.0001; Fig. 7a–f). This indicates that simple disinhibition of dopamine neurons is not likely the mechanism by which inhibiting RVP inputs to VTA reduces cued reinstatement.

Bottom Line: The ventral pallidum is centrally positioned within mesocorticolimbic reward circuits, and its dense projection to the ventral tegmental area (VTA) regulates neuronal activity there.However, the ventral pallidum is a heterogeneous structure, and how this complexity affects its role within wider reward circuits is unclear.We found that projections to VTA from the rostral ventral pallidum (RVP), but not the caudal ventral pallidum (CVP), were robustly Fos activated during cue-induced reinstatement of cocaine seeking--a rat model of relapse in addiction.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina, USA.

ABSTRACT
The ventral pallidum is centrally positioned within mesocorticolimbic reward circuits, and its dense projection to the ventral tegmental area (VTA) regulates neuronal activity there. However, the ventral pallidum is a heterogeneous structure, and how this complexity affects its role within wider reward circuits is unclear. We found that projections to VTA from the rostral ventral pallidum (RVP), but not the caudal ventral pallidum (CVP), were robustly Fos activated during cue-induced reinstatement of cocaine seeking--a rat model of relapse in addiction. Moreover, designer receptor-mediated transient inactivation of RVP neurons, their terminals in VTA or functional connectivity between RVP and VTA dopamine neurons blocked the ability of drug-associated cues (but not a cocaine prime) to reinstate cocaine seeking. In contrast, CVP neuronal inhibition blocked cocaine-primed, but not cue-induced, reinstatement. This double dissociation in ventral pallidum subregional roles in drug seeking is likely to be important for understanding the mesocorticolimbic circuits underlying reward seeking and addiction.

Show MeSH
Related in: MedlinePlus