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Glucocorticoid receptor gene inactivation in dopamine-innervated areas selectively decreases behavioral responses to amphetamine.

Parnaudeau S, Dongelmans ML, Turiault M, Ambroggi F, Delbes AS, Cansell C, Luquet S, Piazza PV, Tronche F, Barik J - Front Behav Neurosci (2014)

Bottom Line: Using mouse models carrying GR gene inactivation in either dopamine neurons or in dopamine-innervated areas, we found that GR in dopamine responsive neurons is essential to properly build amphetamine-induced conditioned place preference and locomotor sensitization. c-Fos quantification in the nucleus accumbens further confirmed defective neuronal activation following amphetamine injection.These diminished neuronal and behavioral responses to amphetamine may involve alterations in glutamate transmission as suggested by the decreased MK801-elicited hyperlocomotion and by the hyporeactivity to glutamate of a subpopulation of medium spiny neurons.In contrast, GR inactivation did not affect rewarding and reinforcing properties of food suggesting that responding for natural reward under basal conditions is preserved in these mice.

View Article: PubMed Central - PubMed

Affiliation: UMR 7224 CNRS, Physiopathologie des Maladies du Système Nerveux Central, "Gene Regulation and Adaptive Behaviors" Group Paris, France ; INSERM, UMRs 952, Physiopathologie des Maladies du Système Nerveux Central Paris, France ; Université Pierre et Marie Curie, Physiopathologie des Maladies du Système Nerveux Central Paris, France ; Department of Psychiatry, Columbia University New York, NY, USA.

ABSTRACT
The meso-cortico-limbic system, via dopamine release, encodes the rewarding and reinforcing properties of natural rewards. It is also activated in response to abused substances and is believed to support drug-related behaviors. Dysfunctions of this system lead to several psychiatric conditions including feeding disorders and drug addiction. These disorders are also largely influenced by environmental factors and in particular stress exposure. Stressors activate the corticotrope axis ultimately leading to glucocorticoid hormone (GCs) release. GCs bind the glucocorticoid receptor (GR) a transcription factor ubiquitously expressed including within the meso-cortico-limbic tract. While GR within dopamine-innervated areas drives cocaine's behavioral responses, its implication in responses to other psychostimulants such as amphetamine has never been clearly established. Moreover, while extensive work has been made to uncover the role of this receptor in addicted behaviors, its contribution to the rewarding and reinforcing properties of food has yet to be investigated. Using mouse models carrying GR gene inactivation in either dopamine neurons or in dopamine-innervated areas, we found that GR in dopamine responsive neurons is essential to properly build amphetamine-induced conditioned place preference and locomotor sensitization. c-Fos quantification in the nucleus accumbens further confirmed defective neuronal activation following amphetamine injection. These diminished neuronal and behavioral responses to amphetamine may involve alterations in glutamate transmission as suggested by the decreased MK801-elicited hyperlocomotion and by the hyporeactivity to glutamate of a subpopulation of medium spiny neurons. In contrast, GR inactivation did not affect rewarding and reinforcing properties of food suggesting that responding for natural reward under basal conditions is preserved in these mice.

No MeSH data available.


Related in: MedlinePlus

Normal D1-like dopamine receptor agonist induced locomotor activity, but impaired MK801-elicited hyperlocomotion in GRD1Cre mice. Locomotor responses are presented as ¼ turn per 5 min. (A) Locomotor response to saline and SKF81297 1.5 mg/kg (left panel) and 3 mg/kg (right panel) in control and GRD1Cre mice. Interaction Drug × Time for SKF81297 at 1.5 mg/kg [F(17, 714) = 10.3, P < 0.001] and 3 mg/kg [F(17, 714) = 9.4, P < 0.001], but no interaction Drug × Time × Genotype, F(17, 714) = 1.2, P > 0.05 and F(17, 714) = 0.8, P > 0.05, respectively. (B) MK801 elicited a stronger hyperlocomotion in control than GRD1Cre mice, interaction Drug × Time × Genotype, F(18, 756) = 1.9, P < 0.01. °°P < 0.01, control vs. mutant. n = 8–14 mice per group.
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Figure 4: Normal D1-like dopamine receptor agonist induced locomotor activity, but impaired MK801-elicited hyperlocomotion in GRD1Cre mice. Locomotor responses are presented as ¼ turn per 5 min. (A) Locomotor response to saline and SKF81297 1.5 mg/kg (left panel) and 3 mg/kg (right panel) in control and GRD1Cre mice. Interaction Drug × Time for SKF81297 at 1.5 mg/kg [F(17, 714) = 10.3, P < 0.001] and 3 mg/kg [F(17, 714) = 9.4, P < 0.001], but no interaction Drug × Time × Genotype, F(17, 714) = 1.2, P > 0.05 and F(17, 714) = 0.8, P > 0.05, respectively. (B) MK801 elicited a stronger hyperlocomotion in control than GRD1Cre mice, interaction Drug × Time × Genotype, F(18, 756) = 1.9, P < 0.01. °°P < 0.01, control vs. mutant. n = 8–14 mice per group.

Mentions: In response to abused drugs, the increase of dopamine release within the CPu and NAc is thought to filter and selectively reinforce connections arising from excitatory corticostriatal projections (Bamford et al., 2004). Hence this dopamine/glutamate interaction is key to shape medium spiny neurons responsiveness at both electrophysiological and molecular levels, with a central implication of D1 dopamine receptors and NMDA glutamate receptors in these processes (Nicola et al., 2000; Pascoli et al., 2011). We therefore, examined whether GR gene inactivation within dopaminoceptive neurons could impact on dopamine and glutamate receptor functions that may explain the observed phenotype. To challenge D1 dopamine receptor, we injected SKF81297, a selective D1-like receptor agonist and measured subsequent locomotor responses. As previously reported (Corvol et al., 2007), acute systemic SKF81297 injection elicited hyperlocomotion in control animals (Figure 4A). At the 2 doses examined (1.5 and 3 mg/kg), GRD1Cre mice did not differ from their respective control littermates (Figure 4A) ruling out an impaired functionality of D1 dopamine receptors. To determine the state of glutamate transmission in GRD1Cre mice, we then assessed the ability of MK801, a non-competitive NMDA antagonist, to elicit hyperlocomotion (Qi et al., 2008). Systemic injection of MK801 (0.2 mg/kg) triggered a robust hyperlocomotion in controls that was significantly decreased in mutant mice (Figure 4B). Therefore, this set of experiments suggests that the impaired glutamate response may play a role in the diminished response to amphetamine.


Glucocorticoid receptor gene inactivation in dopamine-innervated areas selectively decreases behavioral responses to amphetamine.

Parnaudeau S, Dongelmans ML, Turiault M, Ambroggi F, Delbes AS, Cansell C, Luquet S, Piazza PV, Tronche F, Barik J - Front Behav Neurosci (2014)

Normal D1-like dopamine receptor agonist induced locomotor activity, but impaired MK801-elicited hyperlocomotion in GRD1Cre mice. Locomotor responses are presented as ¼ turn per 5 min. (A) Locomotor response to saline and SKF81297 1.5 mg/kg (left panel) and 3 mg/kg (right panel) in control and GRD1Cre mice. Interaction Drug × Time for SKF81297 at 1.5 mg/kg [F(17, 714) = 10.3, P < 0.001] and 3 mg/kg [F(17, 714) = 9.4, P < 0.001], but no interaction Drug × Time × Genotype, F(17, 714) = 1.2, P > 0.05 and F(17, 714) = 0.8, P > 0.05, respectively. (B) MK801 elicited a stronger hyperlocomotion in control than GRD1Cre mice, interaction Drug × Time × Genotype, F(18, 756) = 1.9, P < 0.01. °°P < 0.01, control vs. mutant. n = 8–14 mice per group.
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Figure 4: Normal D1-like dopamine receptor agonist induced locomotor activity, but impaired MK801-elicited hyperlocomotion in GRD1Cre mice. Locomotor responses are presented as ¼ turn per 5 min. (A) Locomotor response to saline and SKF81297 1.5 mg/kg (left panel) and 3 mg/kg (right panel) in control and GRD1Cre mice. Interaction Drug × Time for SKF81297 at 1.5 mg/kg [F(17, 714) = 10.3, P < 0.001] and 3 mg/kg [F(17, 714) = 9.4, P < 0.001], but no interaction Drug × Time × Genotype, F(17, 714) = 1.2, P > 0.05 and F(17, 714) = 0.8, P > 0.05, respectively. (B) MK801 elicited a stronger hyperlocomotion in control than GRD1Cre mice, interaction Drug × Time × Genotype, F(18, 756) = 1.9, P < 0.01. °°P < 0.01, control vs. mutant. n = 8–14 mice per group.
Mentions: In response to abused drugs, the increase of dopamine release within the CPu and NAc is thought to filter and selectively reinforce connections arising from excitatory corticostriatal projections (Bamford et al., 2004). Hence this dopamine/glutamate interaction is key to shape medium spiny neurons responsiveness at both electrophysiological and molecular levels, with a central implication of D1 dopamine receptors and NMDA glutamate receptors in these processes (Nicola et al., 2000; Pascoli et al., 2011). We therefore, examined whether GR gene inactivation within dopaminoceptive neurons could impact on dopamine and glutamate receptor functions that may explain the observed phenotype. To challenge D1 dopamine receptor, we injected SKF81297, a selective D1-like receptor agonist and measured subsequent locomotor responses. As previously reported (Corvol et al., 2007), acute systemic SKF81297 injection elicited hyperlocomotion in control animals (Figure 4A). At the 2 doses examined (1.5 and 3 mg/kg), GRD1Cre mice did not differ from their respective control littermates (Figure 4A) ruling out an impaired functionality of D1 dopamine receptors. To determine the state of glutamate transmission in GRD1Cre mice, we then assessed the ability of MK801, a non-competitive NMDA antagonist, to elicit hyperlocomotion (Qi et al., 2008). Systemic injection of MK801 (0.2 mg/kg) triggered a robust hyperlocomotion in controls that was significantly decreased in mutant mice (Figure 4B). Therefore, this set of experiments suggests that the impaired glutamate response may play a role in the diminished response to amphetamine.

Bottom Line: Using mouse models carrying GR gene inactivation in either dopamine neurons or in dopamine-innervated areas, we found that GR in dopamine responsive neurons is essential to properly build amphetamine-induced conditioned place preference and locomotor sensitization. c-Fos quantification in the nucleus accumbens further confirmed defective neuronal activation following amphetamine injection.These diminished neuronal and behavioral responses to amphetamine may involve alterations in glutamate transmission as suggested by the decreased MK801-elicited hyperlocomotion and by the hyporeactivity to glutamate of a subpopulation of medium spiny neurons.In contrast, GR inactivation did not affect rewarding and reinforcing properties of food suggesting that responding for natural reward under basal conditions is preserved in these mice.

View Article: PubMed Central - PubMed

Affiliation: UMR 7224 CNRS, Physiopathologie des Maladies du Système Nerveux Central, "Gene Regulation and Adaptive Behaviors" Group Paris, France ; INSERM, UMRs 952, Physiopathologie des Maladies du Système Nerveux Central Paris, France ; Université Pierre et Marie Curie, Physiopathologie des Maladies du Système Nerveux Central Paris, France ; Department of Psychiatry, Columbia University New York, NY, USA.

ABSTRACT
The meso-cortico-limbic system, via dopamine release, encodes the rewarding and reinforcing properties of natural rewards. It is also activated in response to abused substances and is believed to support drug-related behaviors. Dysfunctions of this system lead to several psychiatric conditions including feeding disorders and drug addiction. These disorders are also largely influenced by environmental factors and in particular stress exposure. Stressors activate the corticotrope axis ultimately leading to glucocorticoid hormone (GCs) release. GCs bind the glucocorticoid receptor (GR) a transcription factor ubiquitously expressed including within the meso-cortico-limbic tract. While GR within dopamine-innervated areas drives cocaine's behavioral responses, its implication in responses to other psychostimulants such as amphetamine has never been clearly established. Moreover, while extensive work has been made to uncover the role of this receptor in addicted behaviors, its contribution to the rewarding and reinforcing properties of food has yet to be investigated. Using mouse models carrying GR gene inactivation in either dopamine neurons or in dopamine-innervated areas, we found that GR in dopamine responsive neurons is essential to properly build amphetamine-induced conditioned place preference and locomotor sensitization. c-Fos quantification in the nucleus accumbens further confirmed defective neuronal activation following amphetamine injection. These diminished neuronal and behavioral responses to amphetamine may involve alterations in glutamate transmission as suggested by the decreased MK801-elicited hyperlocomotion and by the hyporeactivity to glutamate of a subpopulation of medium spiny neurons. In contrast, GR inactivation did not affect rewarding and reinforcing properties of food suggesting that responding for natural reward under basal conditions is preserved in these mice.

No MeSH data available.


Related in: MedlinePlus