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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

Impaired molecular but not locomotor responses following an acute amphetamine challenge in GRD1Cre mice. (A) Representative example of c-Fos induction in the NAc core of a control and a GRD1Cre mouse in response to saline, amphetamine 1 and 2 mg/kg. (B) Amphetamine-induced c-Fos expression in the caudate-putamen (left panel), the nucleus accumbens core (middle panel), and shell (right panel) of control and GRD1Cre mice. n = 4–8 animals per group; saline vs. drug: *P < 0.05; **P < 0.01; control vs. mutant: °°P < 0.01. Locomotor activity is expressed as the sum of ¼ turns in a circular cylinder per 5 min following acute drug (gray or black) or saline (white) injections in control (circles), GRDATCre (diamonds), and GR1Cre (squares) mice. (C) Similar locomotor response to a single injection of saline and amphetamine (1 mg/kg) in control and GRDATCre mice. Interaction Drug × Time F(29, 840) = 7.9, P < 0.001, with no genotype effect F(1, 420) = 1.3, P > 0.05. (D) Control and GRD1Cre mice equally respond to an acute 1 mg/kg of amphetamine. Interaction Drug × Time F(87, 780) = 1.7, P < 0.001, with no genotype effect F(1, 656) = 0.1, P > 0.05. (E,F) Amphetamine (2 mg/kg) induced a robust increase in locomotor response regardless of the genotype in control and GRDATCre mice [(E), no genotype effect F(1, 637) = 0.3, P > 0.05] and control and GRD1Cre mice [(F), no genotype effect F(1, 686) = 0.8, P > 0.05].
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Figure 1: Impaired molecular but not locomotor responses following an acute amphetamine challenge in GRD1Cre mice. (A) Representative example of c-Fos induction in the NAc core of a control and a GRD1Cre mouse in response to saline, amphetamine 1 and 2 mg/kg. (B) Amphetamine-induced c-Fos expression in the caudate-putamen (left panel), the nucleus accumbens core (middle panel), and shell (right panel) of control and GRD1Cre mice. n = 4–8 animals per group; saline vs. drug: *P < 0.05; **P < 0.01; control vs. mutant: °°P < 0.01. Locomotor activity is expressed as the sum of ¼ turns in a circular cylinder per 5 min following acute drug (gray or black) or saline (white) injections in control (circles), GRDATCre (diamonds), and GR1Cre (squares) mice. (C) Similar locomotor response to a single injection of saline and amphetamine (1 mg/kg) in control and GRDATCre mice. Interaction Drug × Time F(29, 840) = 7.9, P < 0.001, with no genotype effect F(1, 420) = 1.3, P > 0.05. (D) Control and GRD1Cre mice equally respond to an acute 1 mg/kg of amphetamine. Interaction Drug × Time F(87, 780) = 1.7, P < 0.001, with no genotype effect F(1, 656) = 0.1, P > 0.05. (E,F) Amphetamine (2 mg/kg) induced a robust increase in locomotor response regardless of the genotype in control and GRDATCre mice [(E), no genotype effect F(1, 637) = 0.3, P > 0.05] and control and GRD1Cre mice [(F), no genotype effect F(1, 686) = 0.8, P > 0.05].

Mentions: We studied neuronal activation upon amphetamine response by quantifying c-Fos expression in mutant and control littermates. Consistent with previous findings (Moratalla et al., 1996), amphetamine (1 and 2 mg/kg) elicited a significant increase in the number of c-Fos-positive cells within the CPu and the NAc core and shell of control animals (Figures 1A,B). This effect was significantly diminished within the NAc subdivisions and displayed a trend toward a decrease in the CPu when GRD1Cre mice were administered 1 mg/kg of the drug (Figures 1A,B). No significant genotype difference was observed when animals were administrated a higher dose (2 mg/kg) of amphetamine (Figures 1A,B). These results indicate a hyporesponsiveness of the NAc of GRD1Cre mice to low doses of 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)

Impaired molecular but not locomotor responses following an acute amphetamine challenge in GRD1Cre mice. (A) Representative example of c-Fos induction in the NAc core of a control and a GRD1Cre mouse in response to saline, amphetamine 1 and 2 mg/kg. (B) Amphetamine-induced c-Fos expression in the caudate-putamen (left panel), the nucleus accumbens core (middle panel), and shell (right panel) of control and GRD1Cre mice. n = 4–8 animals per group; saline vs. drug: *P < 0.05; **P < 0.01; control vs. mutant: °°P < 0.01. Locomotor activity is expressed as the sum of ¼ turns in a circular cylinder per 5 min following acute drug (gray or black) or saline (white) injections in control (circles), GRDATCre (diamonds), and GR1Cre (squares) mice. (C) Similar locomotor response to a single injection of saline and amphetamine (1 mg/kg) in control and GRDATCre mice. Interaction Drug × Time F(29, 840) = 7.9, P < 0.001, with no genotype effect F(1, 420) = 1.3, P > 0.05. (D) Control and GRD1Cre mice equally respond to an acute 1 mg/kg of amphetamine. Interaction Drug × Time F(87, 780) = 1.7, P < 0.001, with no genotype effect F(1, 656) = 0.1, P > 0.05. (E,F) Amphetamine (2 mg/kg) induced a robust increase in locomotor response regardless of the genotype in control and GRDATCre mice [(E), no genotype effect F(1, 637) = 0.3, P > 0.05] and control and GRD1Cre mice [(F), no genotype effect F(1, 686) = 0.8, P > 0.05].
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3921555&req=5

Figure 1: Impaired molecular but not locomotor responses following an acute amphetamine challenge in GRD1Cre mice. (A) Representative example of c-Fos induction in the NAc core of a control and a GRD1Cre mouse in response to saline, amphetamine 1 and 2 mg/kg. (B) Amphetamine-induced c-Fos expression in the caudate-putamen (left panel), the nucleus accumbens core (middle panel), and shell (right panel) of control and GRD1Cre mice. n = 4–8 animals per group; saline vs. drug: *P < 0.05; **P < 0.01; control vs. mutant: °°P < 0.01. Locomotor activity is expressed as the sum of ¼ turns in a circular cylinder per 5 min following acute drug (gray or black) or saline (white) injections in control (circles), GRDATCre (diamonds), and GR1Cre (squares) mice. (C) Similar locomotor response to a single injection of saline and amphetamine (1 mg/kg) in control and GRDATCre mice. Interaction Drug × Time F(29, 840) = 7.9, P < 0.001, with no genotype effect F(1, 420) = 1.3, P > 0.05. (D) Control and GRD1Cre mice equally respond to an acute 1 mg/kg of amphetamine. Interaction Drug × Time F(87, 780) = 1.7, P < 0.001, with no genotype effect F(1, 656) = 0.1, P > 0.05. (E,F) Amphetamine (2 mg/kg) induced a robust increase in locomotor response regardless of the genotype in control and GRDATCre mice [(E), no genotype effect F(1, 637) = 0.3, P > 0.05] and control and GRD1Cre mice [(F), no genotype effect F(1, 686) = 0.8, P > 0.05].
Mentions: We studied neuronal activation upon amphetamine response by quantifying c-Fos expression in mutant and control littermates. Consistent with previous findings (Moratalla et al., 1996), amphetamine (1 and 2 mg/kg) elicited a significant increase in the number of c-Fos-positive cells within the CPu and the NAc core and shell of control animals (Figures 1A,B). This effect was significantly diminished within the NAc subdivisions and displayed a trend toward a decrease in the CPu when GRD1Cre mice were administered 1 mg/kg of the drug (Figures 1A,B). No significant genotype difference was observed when animals were administrated a higher dose (2 mg/kg) of amphetamine (Figures 1A,B). These results indicate a hyporesponsiveness of the NAc of GRD1Cre mice to low doses of 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