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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

Unaltered responses to food reward in GRD1Cre mice. CPP scores represent the time difference between post-conditioning and pre-conditioning phases that mice spent in the reward-paired chamber. (A) Control and GRD1Cre mice show similar levels of CPP when normal chow pellet were use as a conditioning stimulus. Effect of Food F(1, 33) = 4.4, P < 0.05, but no effect of genotype F(1, 33) = 0.9, P > 0.05. (B) Similar responses were also obtained when control and GRD1Cre mice were paired with palatable food, which significantly increased the time spent in the paired chamber [F(1, 35) = 45.8, P < 0.001] regardless of the genotype [F(1, 35) = 0.9, P > 0.05]. (C) In operant chambers, both control and GRD1Cre mice exhibited similar responses for palatable food reward either under a fixed ratio 1 schedule [no effect of genotype F(1, 40) = 0.8, P > 0.05], or (D) a more stringent progressive ratio schedule [no effect of genotype, F(1, 60) = 0.9, P > 0.05]. For CPP n = 8–12 mice per group and for operant responding for palatable food n = 6 mice per group. ns: non-significant *P < 0.05, **P < 0.01.
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Figure 6: Unaltered responses to food reward in GRD1Cre mice. CPP scores represent the time difference between post-conditioning and pre-conditioning phases that mice spent in the reward-paired chamber. (A) Control and GRD1Cre mice show similar levels of CPP when normal chow pellet were use as a conditioning stimulus. Effect of Food F(1, 33) = 4.4, P < 0.05, but no effect of genotype F(1, 33) = 0.9, P > 0.05. (B) Similar responses were also obtained when control and GRD1Cre mice were paired with palatable food, which significantly increased the time spent in the paired chamber [F(1, 35) = 45.8, P < 0.001] regardless of the genotype [F(1, 35) = 0.9, P > 0.05]. (C) In operant chambers, both control and GRD1Cre mice exhibited similar responses for palatable food reward either under a fixed ratio 1 schedule [no effect of genotype F(1, 40) = 0.8, P > 0.05], or (D) a more stringent progressive ratio schedule [no effect of genotype, F(1, 60) = 0.9, P > 0.05]. For CPP n = 8–12 mice per group and for operant responding for palatable food n = 6 mice per group. ns: non-significant *P < 0.05, **P < 0.01.

Mentions: As the processing of natural rewards and addictive drugs activate overlapping pathways, we sought to determine whether GR gene inactivation in dopaminoceptive neurons resulted in a general impairment of natural reward-seeking. As we did for amphetamine, we first tested control and mutant mice in two CPP experiments in response to normal (chow pellets) or palatable (chocolate) food. Mice were exposed for 30 min to either food in the paired chamber and spent the same amount of time, without food, in the opposite (unpaired) chamber on alternate days. Following 8 days of conditioning, the time increase in the paired chamber was used as an index of place preference. Both normal and palatable food elicited significant CPP in control animals. However, unlike our results with amphetamine, CPP remained unaltered in GRD1Cre mice (Figures 6A,B respectively).


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)

Unaltered responses to food reward in GRD1Cre mice. CPP scores represent the time difference between post-conditioning and pre-conditioning phases that mice spent in the reward-paired chamber. (A) Control and GRD1Cre mice show similar levels of CPP when normal chow pellet were use as a conditioning stimulus. Effect of Food F(1, 33) = 4.4, P < 0.05, but no effect of genotype F(1, 33) = 0.9, P > 0.05. (B) Similar responses were also obtained when control and GRD1Cre mice were paired with palatable food, which significantly increased the time spent in the paired chamber [F(1, 35) = 45.8, P < 0.001] regardless of the genotype [F(1, 35) = 0.9, P > 0.05]. (C) In operant chambers, both control and GRD1Cre mice exhibited similar responses for palatable food reward either under a fixed ratio 1 schedule [no effect of genotype F(1, 40) = 0.8, P > 0.05], or (D) a more stringent progressive ratio schedule [no effect of genotype, F(1, 60) = 0.9, P > 0.05]. For CPP n = 8–12 mice per group and for operant responding for palatable food n = 6 mice per group. ns: non-significant *P < 0.05, **P < 0.01.
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Figure 6: Unaltered responses to food reward in GRD1Cre mice. CPP scores represent the time difference between post-conditioning and pre-conditioning phases that mice spent in the reward-paired chamber. (A) Control and GRD1Cre mice show similar levels of CPP when normal chow pellet were use as a conditioning stimulus. Effect of Food F(1, 33) = 4.4, P < 0.05, but no effect of genotype F(1, 33) = 0.9, P > 0.05. (B) Similar responses were also obtained when control and GRD1Cre mice were paired with palatable food, which significantly increased the time spent in the paired chamber [F(1, 35) = 45.8, P < 0.001] regardless of the genotype [F(1, 35) = 0.9, P > 0.05]. (C) In operant chambers, both control and GRD1Cre mice exhibited similar responses for palatable food reward either under a fixed ratio 1 schedule [no effect of genotype F(1, 40) = 0.8, P > 0.05], or (D) a more stringent progressive ratio schedule [no effect of genotype, F(1, 60) = 0.9, P > 0.05]. For CPP n = 8–12 mice per group and for operant responding for palatable food n = 6 mice per group. ns: non-significant *P < 0.05, **P < 0.01.
Mentions: As the processing of natural rewards and addictive drugs activate overlapping pathways, we sought to determine whether GR gene inactivation in dopaminoceptive neurons resulted in a general impairment of natural reward-seeking. As we did for amphetamine, we first tested control and mutant mice in two CPP experiments in response to normal (chow pellets) or palatable (chocolate) food. Mice were exposed for 30 min to either food in the paired chamber and spent the same amount of time, without food, in the opposite (unpaired) chamber on alternate days. Following 8 days of conditioning, the time increase in the paired chamber was used as an index of place preference. Both normal and palatable food elicited significant CPP in control animals. However, unlike our results with amphetamine, CPP remained unaltered in GRD1Cre mice (Figures 6A,B respectively).

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