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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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Rostral VP projections to VTA are Fos-activated during cued reinstatementa) Predominantly ipsilateral projections from RVP and CVP to VTA are diagrammed in the horizontal plane. b) Axon terminals in VTA express the anterogradely-transported, HA-tagged hM4Di receptor (black axonal processes) after Syn-hM4Di-HA-GFP injection in ipsilateral RVP (red Nissl counterstain in VTA). Coronal view, scale bar=50 μm. Image is representative of VP axonal DREADD expression in VTA of experimental animals, group ns listed in Results. c) Mean±SEM percentages of VTA-projecting (CTb+) RVP or CVP cells that express Fos after cue-induced reinstatement (CS+), or control behavioral conditions, where animals were exposed to: the extinguished self-administration environment without cues or cocaine (Ext), a tone/light stimulus not associated with cocaine (CS−), or a locomotion- enhancing novel environment (Loco). A greater proportion of VTA-projecting neurons in RVP were Fos-activated in CS+ than in control animals [*CS+ different from: Ext (p=0.01), CS− (p=0.005), and Loco (p=0.025)]. No significant behavior-specific activation of VTA-projecting neurons was detected in CVP. Bars=m±SEM. d) Cue-induced reinstatement behavior was positively correlated with Fos activation of VTA-projecting neurons in RVP (*Pearson correlation: p=0.02), but not CVP (not significant).
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Figure 3: Rostral VP projections to VTA are Fos-activated during cued reinstatementa) Predominantly ipsilateral projections from RVP and CVP to VTA are diagrammed in the horizontal plane. b) Axon terminals in VTA express the anterogradely-transported, HA-tagged hM4Di receptor (black axonal processes) after Syn-hM4Di-HA-GFP injection in ipsilateral RVP (red Nissl counterstain in VTA). Coronal view, scale bar=50 μm. Image is representative of VP axonal DREADD expression in VTA of experimental animals, group ns listed in Results. c) Mean±SEM percentages of VTA-projecting (CTb+) RVP or CVP cells that express Fos after cue-induced reinstatement (CS+), or control behavioral conditions, where animals were exposed to: the extinguished self-administration environment without cues or cocaine (Ext), a tone/light stimulus not associated with cocaine (CS−), or a locomotion- enhancing novel environment (Loco). A greater proportion of VTA-projecting neurons in RVP were Fos-activated in CS+ than in control animals [*CS+ different from: Ext (p=0.01), CS− (p=0.005), and Loco (p=0.025)]. No significant behavior-specific activation of VTA-projecting neurons was detected in CVP. Bars=m±SEM. d) Cue-induced reinstatement behavior was positively correlated with Fos activation of VTA-projecting neurons in RVP (*Pearson correlation: p=0.02), but not CVP (not significant).

Mentions: We next asked whether the role for RVP in cued reinstatement behavior involves projections to VTA. First, we examined Fos expression in RVP or CVP VTA-projecting neurons during cued reinstatement, or control behaviors (Fig. 3a; Supplemental Fig. 2). The retrograde tracer cholera toxin beta subunit (CTb) was injected into rostral or caudal VTA. Animals (n=25) were trained to self-administer i.v. cocaine+cues, extinguished, then given a 2 h cue-induced reinstatement test or control behavioral test, as described in Online Methods. Animals were sacrificed immediately after this test session, and VP slices were co-stained for Fos and CTb.


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)

Rostral VP projections to VTA are Fos-activated during cued reinstatementa) Predominantly ipsilateral projections from RVP and CVP to VTA are diagrammed in the horizontal plane. b) Axon terminals in VTA express the anterogradely-transported, HA-tagged hM4Di receptor (black axonal processes) after Syn-hM4Di-HA-GFP injection in ipsilateral RVP (red Nissl counterstain in VTA). Coronal view, scale bar=50 μm. Image is representative of VP axonal DREADD expression in VTA of experimental animals, group ns listed in Results. c) Mean±SEM percentages of VTA-projecting (CTb+) RVP or CVP cells that express Fos after cue-induced reinstatement (CS+), or control behavioral conditions, where animals were exposed to: the extinguished self-administration environment without cues or cocaine (Ext), a tone/light stimulus not associated with cocaine (CS−), or a locomotion- enhancing novel environment (Loco). A greater proportion of VTA-projecting neurons in RVP were Fos-activated in CS+ than in control animals [*CS+ different from: Ext (p=0.01), CS− (p=0.005), and Loco (p=0.025)]. No significant behavior-specific activation of VTA-projecting neurons was detected in CVP. Bars=m±SEM. d) Cue-induced reinstatement behavior was positively correlated with Fos activation of VTA-projecting neurons in RVP (*Pearson correlation: p=0.02), but not CVP (not significant).
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Figure 3: Rostral VP projections to VTA are Fos-activated during cued reinstatementa) Predominantly ipsilateral projections from RVP and CVP to VTA are diagrammed in the horizontal plane. b) Axon terminals in VTA express the anterogradely-transported, HA-tagged hM4Di receptor (black axonal processes) after Syn-hM4Di-HA-GFP injection in ipsilateral RVP (red Nissl counterstain in VTA). Coronal view, scale bar=50 μm. Image is representative of VP axonal DREADD expression in VTA of experimental animals, group ns listed in Results. c) Mean±SEM percentages of VTA-projecting (CTb+) RVP or CVP cells that express Fos after cue-induced reinstatement (CS+), or control behavioral conditions, where animals were exposed to: the extinguished self-administration environment without cues or cocaine (Ext), a tone/light stimulus not associated with cocaine (CS−), or a locomotion- enhancing novel environment (Loco). A greater proportion of VTA-projecting neurons in RVP were Fos-activated in CS+ than in control animals [*CS+ different from: Ext (p=0.01), CS− (p=0.005), and Loco (p=0.025)]. No significant behavior-specific activation of VTA-projecting neurons was detected in CVP. Bars=m±SEM. d) Cue-induced reinstatement behavior was positively correlated with Fos activation of VTA-projecting neurons in RVP (*Pearson correlation: p=0.02), but not CVP (not significant).
Mentions: We next asked whether the role for RVP in cued reinstatement behavior involves projections to VTA. First, we examined Fos expression in RVP or CVP VTA-projecting neurons during cued reinstatement, or control behaviors (Fig. 3a; Supplemental Fig. 2). The retrograde tracer cholera toxin beta subunit (CTb) was injected into rostral or caudal VTA. Animals (n=25) were trained to self-administer i.v. cocaine+cues, extinguished, then given a 2 h cue-induced reinstatement test or control behavioral test, as described in Online Methods. Animals were sacrificed immediately after this test session, and VP slices were co-stained for Fos and CTb.

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