Within the endogenous opioid system, mu opioid receptors are necessary for most drugs of abuse to... more Within the endogenous opioid system, mu opioid receptors are necessary for most drugs of abuse to exert their rewarding properties. Data from pharmacological and gene knockout approaches have suggested that delta opioid receptors might play a similar role. Yet, a major difficulty when assessing drug reinforcement in animal models lies in the tight intertwining of reward and learning processes. We hence tested the hypothesis that delta receptor inactivation might affect drug reinforcement by altering learning rather than reward. We showed that delta opioid receptor knockout (Oprd1-/-) mice display impaired appetitive (morphine) and aversive (lithium) place conditioning, which can be restored, however, by providing additional non-spatial cues. In contrast, these mice show intact acquisition of morphine self-administration as compared to wild-type (WT) counterparts, and reach similar, or even higher, break-points. Thus the reinforcing and motivational properties of morphine are maintai...
A recent social motivation theory suggests that disrupted social communication and skills in auti... more A recent social motivation theory suggests that disrupted social communication and skills in autism result from early compromised social motivation and reward. Mu opioid receptors are central to reward processes; however the possibility that disrupted receptor function could cause the development of an autistic-like syndrome has not been tested. We found that mice lacking the mu opioid receptor (Oprm1-/-) fully recapitulate core and secondary behavioral symptoms of autism, including deficient social abilities, aggressiveness and stereotyped behaviors, high anxiety, impaired motor coordination and increased sensitivity to seizures. These animals also display anatomical, neurochemical and genetic landmarks of the disease. Of particular interest, genetic deletion of mu opioid receptors affects GABA signaling in dorsal and ventral striatal regions, as evidenced by modifications in the number of inhibitory synapses and expression of multiple GABA-related genes. Glutamate signaling is als...
Addiction is a relapsing brain disorder. Chronic exposure to drugs of abuse causes neural adaptat... more Addiction is a relapsing brain disorder. Chronic exposure to drugs of abuse causes neural adaptations, which persist long after drug effects and acute withdrawal have dissipated. Prolonged abstinence from drugs of abuse involves dysphoria, high stress responsiveness and craving, however the neurobiology of drug abstinence is poorly understood. We have recently developed a unique mouse model of protracted abstinence to morphine [1] that we now extend to other drugs of abuse. We will present a set of studies that reveal common adaptations at behavioral (unpublished) and gene regulation [2, 3] level in the extended amygdala of animals abstinent from chronic morphine, nicotine, D9- tetrahydrocannabinol or alcohol. Our data uncover yet unexplored aspects of long-term drug effects, that may provide a novel unitary mechanism underlying addictive disorders, including alcoholism, as well as novel gene target opportunities for addiction treatment. [1] Goeldner C, Lutz PE, Darcq E, Halter T, C...
We have identified a collection of about 100 genes which expression is specifically modulated by ... more We have identified a collection of about 100 genes which expression is specifically modulated by the activation of the mu opiate receptor. These mu-receptor dependent genes are regulated in the extended amygdala after escalating chronic morphine treatment in wild-type mice but not in mu knock-out mice. Some of these genes were still found regulated after 4 weeks of abstinence following morphine exposure. The aim of our project was to test whether mu-receptor dependent genes of this collection would also be regulated after chronic treatment with other drugs of abuse, namely nicotine (minipumps, 25 mg/Kg/day for 6 days), THC (i.p. injections, 20 mg/kg twice a day for 6 days) or ethanol (vapors, 1.5g/l for 72 hours), and whether these regulations would still be detected after 4 weeks of abstinence. We assessed regulations of gene expression using quantitative RT-PCR. A hierarchical clustering was performed on PCR data to compare patterns of gene regulation across the different experime...
The conditioned place preference (CPP) paradigm has been used as a measure of the rewarding effec... more The conditioned place preference (CPP) paradigm has been used as a measure of the rewarding effects of a number of stimuli. Critically, this classical conditioning procedure requires the formation of associations between a rewarding stimulus and environmental cues, and the ability of these cues to direct subsequent behaviour. The purpose of the current experiments was to examine the role of glutamatergic transmission via subunit-specific populations of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors in the formation of stimulus--reward associations involving contextual stimuli. We investigated the ability of cocaine and food to induce a CPP in mice lacking either the GluR1 or GluR2 subunits of the AMPA receptor [gria1 or gria2 knockout (KO) mice]. In separate experiments, food pellets or cocaine (5--20 mg/kg IP) were paired with one compartment of the CPP apparatus, while no-food or vehicle was paired with an alternative compartment. Following conditioning, gria1 KOs displayed a significant preference for the food or cocaine-paired compartment, and did not differ from wild-type (WT) controls. However, gria2 knockouts displayed a preference for a cocaine-paired compartment, but not a food-paired compartment, indicating a specific deficit in place preference conditioning to food. These results obtained using knockout mice indicate that GluR2-containing AMPA receptors may be critical for learning about contextual stimuli relevant to food rewards, but not drug rewards. When the results are considered in relation to our previous findings with gria1 and gria2 knockout mice, they also raise questions about the CPP paradigm representing a model of conditioned reward over a conditioned approach interpretation. However, it would be important to confirm these findings with alternative approaches, should selective ligands become available.
ABSTRACT Although intracranial self-administration (ICSA) is a powerful method to identify the ce... more ABSTRACT Although intracranial self-administration (ICSA) is a powerful method to identify the central sites of action of addictive drugs, only a few studies have investigated the ICSA of ethanol. The reinforcing properties of ethanol are thought to be dependent on the mesolimbic dopamine system originating in the ventral tegmental area (VTA) and projecting to the nucleus accumbens (NAc) as shown by rats which self-administer ethanol into the VTA. The aim of the present set of experiments was to further investigate the brain circuitry and mechanisms underlying the rewarding effects of ethanol using an ICSA protocol in mice combined with pharmacological and brain imaging approaches. We first demonstrated that mice rapidly acquire a robust and dose-dependent self-administration response for intra-VTA ethanol microinjections (3-100 mg% doses of ethanol), associated with an increased Fos expression within the mesolimbic and mesocortical pathways (NAc, striatum and prefrontal cortex). This response was specific to the VTA, since injection of ethanol (at doses inducing intra-VTA self-administration) 0.8 mm above this structure did not induce an ICSA response. The D1 antagonist SCH 23390 completely blocked acquisition as well as expression of the self-administration behaviour, and concomitantly abolished Fos expression within the mesolimbic pathway. The requirement for Fos induction during acquisition of the ethanol ICSA behaviour was further demonstrated by infusing Fos antisense oligodeoxynucleotides into the nucleus accumbens. Finally, we demonstrated that mice submitted to an extinction of intra-VTA ethanol self-administration behaviour displayed a persistent high level of Fos expression within the mesolimbic and mesocortical pathways as compared to animals that only received vehicle injections in the same context. Taken together, these data confirm the reinforcing properties of ethanol and show that the recruitment of dopaminergic pathways originating in the VTA plays a crucial role in supporting the rewarding properties of this addictive drug.
BACKGROUND: GPR88 is an orphan G protein coupled receptor highly enriched in the striatum, and pr... more BACKGROUND: GPR88 is an orphan G protein coupled receptor highly enriched in the striatum, and previous studies have focused on GPR88 function in striatal physiology. The receptor is also expressed in other brain areas, and here we examined whether GPR88 function extends beyond striatal-mediated responses. METHODS: We created Gpr88 knockout mice and examined both striatal and extrastriatal regions at molecular and cellular levels. We also tested striatum-, hippocampus-, and amygdala-dependent behaviors in Gpr88 2/2 mice using extensive behavioral testing. RESULTS: We found increased G protein coupling for delta opioid receptor (DOR) and mu opioid, but not other Gi/o coupled receptors, in the striatum of Gpr88 knockout mice. We also found modifications in gene transcription, dopamine and serotonin contents, and dendritic morphology inside and outside the striatum. Behavioral testing confirmed striatal deficits (hyperactivity, stereotypies, motor impairment in rotarod). In addition, mutant mice performed better in spatial tasks dependent on hippocampus (Y-maze, novel object recognition, dual solution cross-maze) and also showed markedly reduced levels of anxiety (elevated plus maze, marble burying, novelty suppressed feeding). Strikingly, chronic blockade of DOR using naltrindole partially improved motor coordination and normalized spatial navigation and anxiety of Gpr88 2/2 mice. CONCLUSIONS: We demonstrate that GPR88 is implicated in a large repertoire of behavioral responses that engage motor activity, spatial learning, and emotional processing. Our data also reveal functional antagonism between GPR88 and DOR activities in vivo. The therapeutic potential of GPR88 therefore extends to cognitive and anxiety disorders, possibly in interaction with other receptor systems.
Within the endogenous opioid system, mu opioid receptors are necessary for most drugs of abuse to... more Within the endogenous opioid system, mu opioid receptors are necessary for most drugs of abuse to exert their rewarding properties. Data from pharmacological and gene knockout approaches have suggested that delta opioid receptors might play a similar role. Yet, a major difficulty when assessing drug reinforcement in animal models lies in the tight intertwining of reward and learning processes. We hence tested the hypothesis that delta receptor inactivation might affect drug reinforcement by altering learning rather than reward. We showed that delta opioid receptor knockout (Oprd1-/-) mice display impaired appetitive (morphine) and aversive (lithium) place conditioning, which can be restored, however, by providing additional non-spatial cues. In contrast, these mice show intact acquisition of morphine self-administration as compared to wild-type (WT) counterparts, and reach similar, or even higher, break-points. Thus the reinforcing and motivational properties of morphine are maintai...
A recent social motivation theory suggests that disrupted social communication and skills in auti... more A recent social motivation theory suggests that disrupted social communication and skills in autism result from early compromised social motivation and reward. Mu opioid receptors are central to reward processes; however the possibility that disrupted receptor function could cause the development of an autistic-like syndrome has not been tested. We found that mice lacking the mu opioid receptor (Oprm1-/-) fully recapitulate core and secondary behavioral symptoms of autism, including deficient social abilities, aggressiveness and stereotyped behaviors, high anxiety, impaired motor coordination and increased sensitivity to seizures. These animals also display anatomical, neurochemical and genetic landmarks of the disease. Of particular interest, genetic deletion of mu opioid receptors affects GABA signaling in dorsal and ventral striatal regions, as evidenced by modifications in the number of inhibitory synapses and expression of multiple GABA-related genes. Glutamate signaling is als...
Addiction is a relapsing brain disorder. Chronic exposure to drugs of abuse causes neural adaptat... more Addiction is a relapsing brain disorder. Chronic exposure to drugs of abuse causes neural adaptations, which persist long after drug effects and acute withdrawal have dissipated. Prolonged abstinence from drugs of abuse involves dysphoria, high stress responsiveness and craving, however the neurobiology of drug abstinence is poorly understood. We have recently developed a unique mouse model of protracted abstinence to morphine [1] that we now extend to other drugs of abuse. We will present a set of studies that reveal common adaptations at behavioral (unpublished) and gene regulation [2, 3] level in the extended amygdala of animals abstinent from chronic morphine, nicotine, D9- tetrahydrocannabinol or alcohol. Our data uncover yet unexplored aspects of long-term drug effects, that may provide a novel unitary mechanism underlying addictive disorders, including alcoholism, as well as novel gene target opportunities for addiction treatment. [1] Goeldner C, Lutz PE, Darcq E, Halter T, C...
We have identified a collection of about 100 genes which expression is specifically modulated by ... more We have identified a collection of about 100 genes which expression is specifically modulated by the activation of the mu opiate receptor. These mu-receptor dependent genes are regulated in the extended amygdala after escalating chronic morphine treatment in wild-type mice but not in mu knock-out mice. Some of these genes were still found regulated after 4 weeks of abstinence following morphine exposure. The aim of our project was to test whether mu-receptor dependent genes of this collection would also be regulated after chronic treatment with other drugs of abuse, namely nicotine (minipumps, 25 mg/Kg/day for 6 days), THC (i.p. injections, 20 mg/kg twice a day for 6 days) or ethanol (vapors, 1.5g/l for 72 hours), and whether these regulations would still be detected after 4 weeks of abstinence. We assessed regulations of gene expression using quantitative RT-PCR. A hierarchical clustering was performed on PCR data to compare patterns of gene regulation across the different experime...
The conditioned place preference (CPP) paradigm has been used as a measure of the rewarding effec... more The conditioned place preference (CPP) paradigm has been used as a measure of the rewarding effects of a number of stimuli. Critically, this classical conditioning procedure requires the formation of associations between a rewarding stimulus and environmental cues, and the ability of these cues to direct subsequent behaviour. The purpose of the current experiments was to examine the role of glutamatergic transmission via subunit-specific populations of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors in the formation of stimulus--reward associations involving contextual stimuli. We investigated the ability of cocaine and food to induce a CPP in mice lacking either the GluR1 or GluR2 subunits of the AMPA receptor [gria1 or gria2 knockout (KO) mice]. In separate experiments, food pellets or cocaine (5--20 mg/kg IP) were paired with one compartment of the CPP apparatus, while no-food or vehicle was paired with an alternative compartment. Following conditioning, gria1 KOs displayed a significant preference for the food or cocaine-paired compartment, and did not differ from wild-type (WT) controls. However, gria2 knockouts displayed a preference for a cocaine-paired compartment, but not a food-paired compartment, indicating a specific deficit in place preference conditioning to food. These results obtained using knockout mice indicate that GluR2-containing AMPA receptors may be critical for learning about contextual stimuli relevant to food rewards, but not drug rewards. When the results are considered in relation to our previous findings with gria1 and gria2 knockout mice, they also raise questions about the CPP paradigm representing a model of conditioned reward over a conditioned approach interpretation. However, it would be important to confirm these findings with alternative approaches, should selective ligands become available.
ABSTRACT Although intracranial self-administration (ICSA) is a powerful method to identify the ce... more ABSTRACT Although intracranial self-administration (ICSA) is a powerful method to identify the central sites of action of addictive drugs, only a few studies have investigated the ICSA of ethanol. The reinforcing properties of ethanol are thought to be dependent on the mesolimbic dopamine system originating in the ventral tegmental area (VTA) and projecting to the nucleus accumbens (NAc) as shown by rats which self-administer ethanol into the VTA. The aim of the present set of experiments was to further investigate the brain circuitry and mechanisms underlying the rewarding effects of ethanol using an ICSA protocol in mice combined with pharmacological and brain imaging approaches. We first demonstrated that mice rapidly acquire a robust and dose-dependent self-administration response for intra-VTA ethanol microinjections (3-100 mg% doses of ethanol), associated with an increased Fos expression within the mesolimbic and mesocortical pathways (NAc, striatum and prefrontal cortex). This response was specific to the VTA, since injection of ethanol (at doses inducing intra-VTA self-administration) 0.8 mm above this structure did not induce an ICSA response. The D1 antagonist SCH 23390 completely blocked acquisition as well as expression of the self-administration behaviour, and concomitantly abolished Fos expression within the mesolimbic pathway. The requirement for Fos induction during acquisition of the ethanol ICSA behaviour was further demonstrated by infusing Fos antisense oligodeoxynucleotides into the nucleus accumbens. Finally, we demonstrated that mice submitted to an extinction of intra-VTA ethanol self-administration behaviour displayed a persistent high level of Fos expression within the mesolimbic and mesocortical pathways as compared to animals that only received vehicle injections in the same context. Taken together, these data confirm the reinforcing properties of ethanol and show that the recruitment of dopaminergic pathways originating in the VTA plays a crucial role in supporting the rewarding properties of this addictive drug.
BACKGROUND: GPR88 is an orphan G protein coupled receptor highly enriched in the striatum, and pr... more BACKGROUND: GPR88 is an orphan G protein coupled receptor highly enriched in the striatum, and previous studies have focused on GPR88 function in striatal physiology. The receptor is also expressed in other brain areas, and here we examined whether GPR88 function extends beyond striatal-mediated responses. METHODS: We created Gpr88 knockout mice and examined both striatal and extrastriatal regions at molecular and cellular levels. We also tested striatum-, hippocampus-, and amygdala-dependent behaviors in Gpr88 2/2 mice using extensive behavioral testing. RESULTS: We found increased G protein coupling for delta opioid receptor (DOR) and mu opioid, but not other Gi/o coupled receptors, in the striatum of Gpr88 knockout mice. We also found modifications in gene transcription, dopamine and serotonin contents, and dendritic morphology inside and outside the striatum. Behavioral testing confirmed striatal deficits (hyperactivity, stereotypies, motor impairment in rotarod). In addition, mutant mice performed better in spatial tasks dependent on hippocampus (Y-maze, novel object recognition, dual solution cross-maze) and also showed markedly reduced levels of anxiety (elevated plus maze, marble burying, novelty suppressed feeding). Strikingly, chronic blockade of DOR using naltrindole partially improved motor coordination and normalized spatial navigation and anxiety of Gpr88 2/2 mice. CONCLUSIONS: We demonstrate that GPR88 is implicated in a large repertoire of behavioral responses that engage motor activity, spatial learning, and emotional processing. Our data also reveal functional antagonism between GPR88 and DOR activities in vivo. The therapeutic potential of GPR88 therefore extends to cognitive and anxiety disorders, possibly in interaction with other receptor systems.
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Papers by Julie Le Merrer