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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.

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Effects of inactivating rostral or caudal VP on reinstatement of cocaine seekinga) Daily m±SEM cocaine infusions and active/inactive lever presses for the last 6 days of criterion self- administration (>10 infusions/day), and active/inactive lever presses for the first 7 days of extinction training. b) Active lever presses during cue-induced reinstatement following different doses of the DREADD agonist clozapine-n-oxide (CNO; dose=bar color; vehicle, 0.1, 1, 10, 20 mg/kg), in animals with bilateral RVP or CVP Syn-hM4Di-HA-GFP virus, bilateral VP control virus (Syn-GFP), or no virus expression. Inactive lever presses during reinstatement are shown with overlaid black bars. *Vehicle vs. 10 mg/kg CNO: p=0.001, vehicle vs. 20 mg/kg CNO: p=0.015. c) Active and inactive lever presses during cocaine primed reinstatement following different doses of CNO (Vehicle, 10, 20 mg/kg), in animals with RVP or CVP Syn-hM4Di-HA-GFP virus, or controls (Syn-GFP or no virus expression animals). *Vehicle vs. 20 mg/kg CNO: p=0.008. Bars and lines=m±SEM. d) The anatomical localization of virus expression sites (as visualized with HA or GFP immunoreactivity) is represented for animals injected with Syn-hM4Di-HA-GFP in RVP (black) or CVP (grey), or Syn-GFP (grey; inset).
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Figure 2: Effects of inactivating rostral or caudal VP on reinstatement of cocaine seekinga) Daily m±SEM cocaine infusions and active/inactive lever presses for the last 6 days of criterion self- administration (>10 infusions/day), and active/inactive lever presses for the first 7 days of extinction training. b) Active lever presses during cue-induced reinstatement following different doses of the DREADD agonist clozapine-n-oxide (CNO; dose=bar color; vehicle, 0.1, 1, 10, 20 mg/kg), in animals with bilateral RVP or CVP Syn-hM4Di-HA-GFP virus, bilateral VP control virus (Syn-GFP), or no virus expression. Inactive lever presses during reinstatement are shown with overlaid black bars. *Vehicle vs. 10 mg/kg CNO: p=0.001, vehicle vs. 20 mg/kg CNO: p=0.015. c) Active and inactive lever presses during cocaine primed reinstatement following different doses of CNO (Vehicle, 10, 20 mg/kg), in animals with RVP or CVP Syn-hM4Di-HA-GFP virus, or controls (Syn-GFP or no virus expression animals). *Vehicle vs. 20 mg/kg CNO: p=0.008. Bars and lines=m±SEM. d) The anatomical localization of virus expression sites (as visualized with HA or GFP immunoreactivity) is represented for animals injected with Syn-hM4Di-HA-GFP in RVP (black) or CVP (grey), or Syn-GFP (grey; inset).

Mentions: We used a DREADD-based strategy to remotely control VP neurons in vivo and manipulate the VP-VTA circuit. We injected a synapsin-driven lentiviral vector yielding expression of the Gi-coupled DREADD, hM4Di24, or a control virus lacking the DREADD gene (Syn-GFP) into RVP or CVP, and allowed animals to survive 6+ weeks before analyzing brain tissue for virus expression. The Syn-hM4Di-HA-GFP virus (Fig. 1a) caused robust hM4Di expression within RVP or CVP [visualized with immunoreactivity for the hemagglutinin (HA) tag, or green fluorescent protein (GFP) reporter]. These injections yielded limited expression outside the borders of VP (<30% labeling outside VP borders; Figs.1b–e, 2d, Supplemental Fig. 1). Syn-hM4Di-HA-GFP and Syn-GFP viruses yielded comparable zones of somatic GFP or hM4Di expression centered at the injection site [GFP: 0.82(0.21) mm3; hM4Di: 0.89(0.05) mm3].


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)

Effects of inactivating rostral or caudal VP on reinstatement of cocaine seekinga) Daily m±SEM cocaine infusions and active/inactive lever presses for the last 6 days of criterion self- administration (>10 infusions/day), and active/inactive lever presses for the first 7 days of extinction training. b) Active lever presses during cue-induced reinstatement following different doses of the DREADD agonist clozapine-n-oxide (CNO; dose=bar color; vehicle, 0.1, 1, 10, 20 mg/kg), in animals with bilateral RVP or CVP Syn-hM4Di-HA-GFP virus, bilateral VP control virus (Syn-GFP), or no virus expression. Inactive lever presses during reinstatement are shown with overlaid black bars. *Vehicle vs. 10 mg/kg CNO: p=0.001, vehicle vs. 20 mg/kg CNO: p=0.015. c) Active and inactive lever presses during cocaine primed reinstatement following different doses of CNO (Vehicle, 10, 20 mg/kg), in animals with RVP or CVP Syn-hM4Di-HA-GFP virus, or controls (Syn-GFP or no virus expression animals). *Vehicle vs. 20 mg/kg CNO: p=0.008. Bars and lines=m±SEM. d) The anatomical localization of virus expression sites (as visualized with HA or GFP immunoreactivity) is represented for animals injected with Syn-hM4Di-HA-GFP in RVP (black) or CVP (grey), or Syn-GFP (grey; inset).
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Figure 2: Effects of inactivating rostral or caudal VP on reinstatement of cocaine seekinga) Daily m±SEM cocaine infusions and active/inactive lever presses for the last 6 days of criterion self- administration (>10 infusions/day), and active/inactive lever presses for the first 7 days of extinction training. b) Active lever presses during cue-induced reinstatement following different doses of the DREADD agonist clozapine-n-oxide (CNO; dose=bar color; vehicle, 0.1, 1, 10, 20 mg/kg), in animals with bilateral RVP or CVP Syn-hM4Di-HA-GFP virus, bilateral VP control virus (Syn-GFP), or no virus expression. Inactive lever presses during reinstatement are shown with overlaid black bars. *Vehicle vs. 10 mg/kg CNO: p=0.001, vehicle vs. 20 mg/kg CNO: p=0.015. c) Active and inactive lever presses during cocaine primed reinstatement following different doses of CNO (Vehicle, 10, 20 mg/kg), in animals with RVP or CVP Syn-hM4Di-HA-GFP virus, or controls (Syn-GFP or no virus expression animals). *Vehicle vs. 20 mg/kg CNO: p=0.008. Bars and lines=m±SEM. d) The anatomical localization of virus expression sites (as visualized with HA or GFP immunoreactivity) is represented for animals injected with Syn-hM4Di-HA-GFP in RVP (black) or CVP (grey), or Syn-GFP (grey; inset).
Mentions: We used a DREADD-based strategy to remotely control VP neurons in vivo and manipulate the VP-VTA circuit. We injected a synapsin-driven lentiviral vector yielding expression of the Gi-coupled DREADD, hM4Di24, or a control virus lacking the DREADD gene (Syn-GFP) into RVP or CVP, and allowed animals to survive 6+ weeks before analyzing brain tissue for virus expression. The Syn-hM4Di-HA-GFP virus (Fig. 1a) caused robust hM4Di expression within RVP or CVP [visualized with immunoreactivity for the hemagglutinin (HA) tag, or green fluorescent protein (GFP) reporter]. These injections yielded limited expression outside the borders of VP (<30% labeling outside VP borders; Figs.1b–e, 2d, Supplemental Fig. 1). Syn-hM4Di-HA-GFP and Syn-GFP viruses yielded comparable zones of somatic GFP or hM4Di expression centered at the injection site [GFP: 0.82(0.21) mm3; hM4Di: 0.89(0.05) mm3].

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