Rationale MDMA is one of the most widely consumed recreational drugs in Europe. However, the mech... more Rationale MDMA is one of the most widely consumed recreational drugs in Europe. However, the mechanisms involved in the reinforcing properties of MDMA are still unclear. In this sense, the establishment of a reliable model of MDMA self-administration in mice could represent an important approach to study the neuronal substrates associated with MDMA reward by using genetically modified mice. Objectives To develop a reliable model of operant intravenous MDMA self-administration in drug-naïve mice. Materials and methods Mice were trained to acquire intravenous self-administration of MDMA at different doses (0, 0.06, 0.125, 0.25, 0.5 and 1.0 mg/kg/infusion) on a FR1 schedule of reinforcement for 15 consecutive days. The motivational value of different doses of MDMA (0.125, 0.25 and 0.5 mg/kg/infusion) was then tested using a progressive ratio paradigm. Finally, [3H]-mazindol autoradiographic studies were carried out in order to quantitatively assess presynaptic dopamine transporter (DAT) binding sites in the striatum of mice trained to self-administer MDMA (0 and 1.0 mg/kg/infusion) during 15 days. Results The latency for discrimination between the active and inactive holes, as well as the number of animals acquiring stability criteria, varied as a function of the dose of MDMA. The mice responding for intermediate doses (0.125, 0.25 and 0.5 mg/kg/infusion) discriminated earlier than those responding for low (0.06 mg/kg/infusion) or high (1.0 mg/kg/infusion) doses. The percentage of animals achieving stability criteria increased with days of testing and was inversely proportional to the dose of MDMA. The breaking points achieved for doses of 0.125 and 0.25 mg/kg/infusion were significantly higher than for a dose of 0.5 mg/kg/infusion. No significant DAT neurotoxicity was observed in the striatum of animals self-administering MDMA at a dose of 1 mg/kg/infusion. Conclusions The present results show that MDMA can be reliably self-administered by drug-naïve mice.
Reinstatement of extinguished operant responding for drug is an appropriate model of relapse to d... more Reinstatement of extinguished operant responding for drug is an appropriate model of relapse to drug abuse. Due to the difficulty of implementing in mice the procedure of instrumental intravenous self-administration, mechanisms of reinstatement have so far been studied almost exclusively in rats. A mouse model of reinstatement of cocaine seeking has recently been characterized (Soria et al. 2008). The aim of the present study was to assess regional brain activation, as measured by induction of the immediate early genes (IEG) arc and zif268, during priming- or cue-elicited reinstatement of cocaine seeking using this new mouse model and the in situ hybridization technique. We have demonstrated that cue-elicited reinstatement of cocaine seeking was associated with induction of the IEG in the medial prefrontal cortex (prelimbic and infralimbic) and basolateral amygdala. Priming-induced reinstatement produced a more widespread up-regulation of those genes in forebrain regions including medial prefrontal, orbitofrontal and motor cortex, dorsal striatum and basolateral amygdala. These patterns of IEG expression are in agreement with previous results obtained in rats and thus indicate that the new mouse model of reinstatement is functionally equivalent to rat models. That comparability adds to the usefulness of the mouse model as a tool for addressing neurobiological mechanisms of addiction.
Background and purpose:The purinergic system through the A2A adenosine receptor regulates addicti... more Background and purpose:The purinergic system through the A2A adenosine receptor regulates addiction induced by different drugs of abuse. The aim of the present study was to investigate the specific role of A2A adenosine receptors (A2ARs) in the behavioural and neurochemical responses to morphine associated with its motivational properties.The purinergic system through the A2A adenosine receptor regulates addiction induced by different drugs of abuse. The aim of the present study was to investigate the specific role of A2A adenosine receptors (A2ARs) in the behavioural and neurochemical responses to morphine associated with its motivational properties.Experimental approach:Mice lacking A2ARs (A2A knockout (KO) mice) and wild-type littermates were used to evaluate behavioural responses induced by morphine. Antinociception was assessed using the tail-immersion and the hot-plate tests. Place-conditioning paradigms were used to evaluate the rewarding effects of morphine and the dysphoric responses of morphine withdrawal. Microdialysis studies were carried out to evaluate changes in the extracellular levels of dopamine in the nucleus accumbens of A2A KO mice after morphine administration.Mice lacking A2ARs (A2A knockout (KO) mice) and wild-type littermates were used to evaluate behavioural responses induced by morphine. Antinociception was assessed using the tail-immersion and the hot-plate tests. Place-conditioning paradigms were used to evaluate the rewarding effects of morphine and the dysphoric responses of morphine withdrawal. Microdialysis studies were carried out to evaluate changes in the extracellular levels of dopamine in the nucleus accumbens of A2A KO mice after morphine administration.Key results:The acute administration of morphine induced a similar enhancement of locomotor activity and antinociceptive responses in both genotypes. However, the rewarding effects induced by morphine were completely blocked in A2A KO mice. Also, naloxone did not induce place aversion in animals lacking the A2ARs.The acute administration of morphine induced a similar enhancement of locomotor activity and antinociceptive responses in both genotypes. However, the rewarding effects induced by morphine were completely blocked in A2A KO mice. Also, naloxone did not induce place aversion in animals lacking the A2ARs.Conclusions and implications:Our findings demonstrate that the rewarding and aversive effects associated with morphine abstinence were abolished in A2A KO mice, supporting a differential role of the A2A adenosine receptor in the somatic and motivational effects of morphine addiction. This study provides evidence for the role of A2ARs as general modulators of the motivational properties of drugs of abuse. Pharmacological manipulation of these receptors may represent a new target in the management of drug addiction.British Journal of Pharmacology (2008) 155, 757–766; doi:10.1038/bjp.2008.299; published online 28 July 2008Our findings demonstrate that the rewarding and aversive effects associated with morphine abstinence were abolished in A2A KO mice, supporting a differential role of the A2A adenosine receptor in the somatic and motivational effects of morphine addiction. This study provides evidence for the role of A2ARs as general modulators of the motivational properties of drugs of abuse. Pharmacological manipulation of these receptors may represent a new target in the management of drug addiction.British Journal of Pharmacology (2008) 155, 757–766; doi:10.1038/bjp.2008.299; published online 28 July 2008
Rationale Cocaine addiction is a relapsing psychiatric disorder with a high prevalence in develop... more Rationale Cocaine addiction is a relapsing psychiatric disorder with a high prevalence in developed countries. To date, the reinstatement model has been difficult to implement in mice. The design of an appropriate reinstatement model in mice is required in order to use genetically modified animals with the aim of clarifying the mechanisms involved in cocaine relapse. Objectives Our aim was to develop an appropriate model of reinstatement of cocaine-seeking behavior and to investigate the factors that can trigger this reinstatement by using an operant intravenous self-administration procedure in mice. Discrete cues, priming injection of cocaine, and exposure to stress were the stimuli used to reinstate cocaine-seeking behavior. Material and methods Mice were trained to acquire intravenous self-administration of cocaine (1 mg/kg per infusion) on a fixed ratio 1 (FR1) schedule of reinforcement. After achieving the acquisition criteria, animals were led to extinguish the operant behavior. Subsequently, under extinction conditions, mice were tested after the administration of a cocaine priming injection (10 mg/kg i.p.), the presentation of a light cue associated with cocaine administration, or the exposure to a stressful situation (0.21 mA electric footshock). Results Under our experimental conditions the three stimuli successfully reinstated an extinguished cocaine-seeking behavior. Reexposure to cocaine effects by a priming injection was revealed as the strongest stimulus, capable of reinstating cocaine-seeking behavior. Conclusions The effective reinstatement model that we have developed will become a useful tool for future understanding of the neurobiological basis of cocaine addiction and relapse, specifically, with the use of genetically modified mice.
Rationale MDMA is one of the most widely consumed recreational drugs in Europe. However, the mech... more Rationale MDMA is one of the most widely consumed recreational drugs in Europe. However, the mechanisms involved in the reinforcing properties of MDMA are still unclear. In this sense, the establishment of a reliable model of MDMA self-administration in mice could represent an important approach to study the neuronal substrates associated with MDMA reward by using genetically modified mice. Objectives To develop a reliable model of operant intravenous MDMA self-administration in drug-naïve mice. Materials and methods Mice were trained to acquire intravenous self-administration of MDMA at different doses (0, 0.06, 0.125, 0.25, 0.5 and 1.0 mg/kg/infusion) on a FR1 schedule of reinforcement for 15 consecutive days. The motivational value of different doses of MDMA (0.125, 0.25 and 0.5 mg/kg/infusion) was then tested using a progressive ratio paradigm. Finally, [3H]-mazindol autoradiographic studies were carried out in order to quantitatively assess presynaptic dopamine transporter (DAT) binding sites in the striatum of mice trained to self-administer MDMA (0 and 1.0 mg/kg/infusion) during 15 days. Results The latency for discrimination between the active and inactive holes, as well as the number of animals acquiring stability criteria, varied as a function of the dose of MDMA. The mice responding for intermediate doses (0.125, 0.25 and 0.5 mg/kg/infusion) discriminated earlier than those responding for low (0.06 mg/kg/infusion) or high (1.0 mg/kg/infusion) doses. The percentage of animals achieving stability criteria increased with days of testing and was inversely proportional to the dose of MDMA. The breaking points achieved for doses of 0.125 and 0.25 mg/kg/infusion were significantly higher than for a dose of 0.5 mg/kg/infusion. No significant DAT neurotoxicity was observed in the striatum of animals self-administering MDMA at a dose of 1 mg/kg/infusion. Conclusions The present results show that MDMA can be reliably self-administered by drug-naïve mice.
Reinstatement of extinguished operant responding for drug is an appropriate model of relapse to d... more Reinstatement of extinguished operant responding for drug is an appropriate model of relapse to drug abuse. Due to the difficulty of implementing in mice the procedure of instrumental intravenous self-administration, mechanisms of reinstatement have so far been studied almost exclusively in rats. A mouse model of reinstatement of cocaine seeking has recently been characterized (Soria et al. 2008). The aim of the present study was to assess regional brain activation, as measured by induction of the immediate early genes (IEG) arc and zif268, during priming- or cue-elicited reinstatement of cocaine seeking using this new mouse model and the in situ hybridization technique. We have demonstrated that cue-elicited reinstatement of cocaine seeking was associated with induction of the IEG in the medial prefrontal cortex (prelimbic and infralimbic) and basolateral amygdala. Priming-induced reinstatement produced a more widespread up-regulation of those genes in forebrain regions including medial prefrontal, orbitofrontal and motor cortex, dorsal striatum and basolateral amygdala. These patterns of IEG expression are in agreement with previous results obtained in rats and thus indicate that the new mouse model of reinstatement is functionally equivalent to rat models. That comparability adds to the usefulness of the mouse model as a tool for addressing neurobiological mechanisms of addiction.
Background and purpose:The purinergic system through the A2A adenosine receptor regulates addicti... more Background and purpose:The purinergic system through the A2A adenosine receptor regulates addiction induced by different drugs of abuse. The aim of the present study was to investigate the specific role of A2A adenosine receptors (A2ARs) in the behavioural and neurochemical responses to morphine associated with its motivational properties.The purinergic system through the A2A adenosine receptor regulates addiction induced by different drugs of abuse. The aim of the present study was to investigate the specific role of A2A adenosine receptors (A2ARs) in the behavioural and neurochemical responses to morphine associated with its motivational properties.Experimental approach:Mice lacking A2ARs (A2A knockout (KO) mice) and wild-type littermates were used to evaluate behavioural responses induced by morphine. Antinociception was assessed using the tail-immersion and the hot-plate tests. Place-conditioning paradigms were used to evaluate the rewarding effects of morphine and the dysphoric responses of morphine withdrawal. Microdialysis studies were carried out to evaluate changes in the extracellular levels of dopamine in the nucleus accumbens of A2A KO mice after morphine administration.Mice lacking A2ARs (A2A knockout (KO) mice) and wild-type littermates were used to evaluate behavioural responses induced by morphine. Antinociception was assessed using the tail-immersion and the hot-plate tests. Place-conditioning paradigms were used to evaluate the rewarding effects of morphine and the dysphoric responses of morphine withdrawal. Microdialysis studies were carried out to evaluate changes in the extracellular levels of dopamine in the nucleus accumbens of A2A KO mice after morphine administration.Key results:The acute administration of morphine induced a similar enhancement of locomotor activity and antinociceptive responses in both genotypes. However, the rewarding effects induced by morphine were completely blocked in A2A KO mice. Also, naloxone did not induce place aversion in animals lacking the A2ARs.The acute administration of morphine induced a similar enhancement of locomotor activity and antinociceptive responses in both genotypes. However, the rewarding effects induced by morphine were completely blocked in A2A KO mice. Also, naloxone did not induce place aversion in animals lacking the A2ARs.Conclusions and implications:Our findings demonstrate that the rewarding and aversive effects associated with morphine abstinence were abolished in A2A KO mice, supporting a differential role of the A2A adenosine receptor in the somatic and motivational effects of morphine addiction. This study provides evidence for the role of A2ARs as general modulators of the motivational properties of drugs of abuse. Pharmacological manipulation of these receptors may represent a new target in the management of drug addiction.British Journal of Pharmacology (2008) 155, 757–766; doi:10.1038/bjp.2008.299; published online 28 July 2008Our findings demonstrate that the rewarding and aversive effects associated with morphine abstinence were abolished in A2A KO mice, supporting a differential role of the A2A adenosine receptor in the somatic and motivational effects of morphine addiction. This study provides evidence for the role of A2ARs as general modulators of the motivational properties of drugs of abuse. Pharmacological manipulation of these receptors may represent a new target in the management of drug addiction.British Journal of Pharmacology (2008) 155, 757–766; doi:10.1038/bjp.2008.299; published online 28 July 2008
Rationale Cocaine addiction is a relapsing psychiatric disorder with a high prevalence in develop... more Rationale Cocaine addiction is a relapsing psychiatric disorder with a high prevalence in developed countries. To date, the reinstatement model has been difficult to implement in mice. The design of an appropriate reinstatement model in mice is required in order to use genetically modified animals with the aim of clarifying the mechanisms involved in cocaine relapse. Objectives Our aim was to develop an appropriate model of reinstatement of cocaine-seeking behavior and to investigate the factors that can trigger this reinstatement by using an operant intravenous self-administration procedure in mice. Discrete cues, priming injection of cocaine, and exposure to stress were the stimuli used to reinstate cocaine-seeking behavior. Material and methods Mice were trained to acquire intravenous self-administration of cocaine (1 mg/kg per infusion) on a fixed ratio 1 (FR1) schedule of reinforcement. After achieving the acquisition criteria, animals were led to extinguish the operant behavior. Subsequently, under extinction conditions, mice were tested after the administration of a cocaine priming injection (10 mg/kg i.p.), the presentation of a light cue associated with cocaine administration, or the exposure to a stressful situation (0.21 mA electric footshock). Results Under our experimental conditions the three stimuli successfully reinstated an extinguished cocaine-seeking behavior. Reexposure to cocaine effects by a priming injection was revealed as the strongest stimulus, capable of reinstating cocaine-seeking behavior. Conclusions The effective reinstatement model that we have developed will become a useful tool for future understanding of the neurobiological basis of cocaine addiction and relapse, specifically, with the use of genetically modified mice.
Rationale MDMA is one of the most widely consumed recreational drugs in Europe. However, the mech... more Rationale MDMA is one of the most widely consumed recreational drugs in Europe. However, the mechanisms involved in the reinforcing properties of MDMA are still unclear. In this sense, the establishment of a reliable model of MDMA self-administration in mice could represent an important approach to study the neuronal substrates associated with MDMA reward by using genetically modified mice. Objectives To develop a reliable model of operant intravenous MDMA self-administration in drug-naïve mice. Materials and methods Mice were trained to acquire intravenous self-administration of MDMA at different doses (0, 0.06, 0.125, 0.25, 0.5 and 1.0 mg/kg/infusion) on a FR1 schedule of reinforcement for 15 consecutive days. The motivational value of different doses of MDMA (0.125, 0.25 and 0.5 mg/kg/infusion) was then tested using a progressive ratio paradigm. Finally, [3H]-mazindol autoradiographic studies were carried out in order to quantitatively assess presynaptic dopamine transporter (DAT) binding sites in the striatum of mice trained to self-administer MDMA (0 and 1.0 mg/kg/infusion) during 15 days. Results The latency for discrimination between the active and inactive holes, as well as the number of animals acquiring stability criteria, varied as a function of the dose of MDMA. The mice responding for intermediate doses (0.125, 0.25 and 0.5 mg/kg/infusion) discriminated earlier than those responding for low (0.06 mg/kg/infusion) or high (1.0 mg/kg/infusion) doses. The percentage of animals achieving stability criteria increased with days of testing and was inversely proportional to the dose of MDMA. The breaking points achieved for doses of 0.125 and 0.25 mg/kg/infusion were significantly higher than for a dose of 0.5 mg/kg/infusion. No significant DAT neurotoxicity was observed in the striatum of animals self-administering MDMA at a dose of 1 mg/kg/infusion. Conclusions The present results show that MDMA can be reliably self-administered by drug-naïve mice.
Reinstatement of extinguished operant responding for drug is an appropriate model of relapse to d... more Reinstatement of extinguished operant responding for drug is an appropriate model of relapse to drug abuse. Due to the difficulty of implementing in mice the procedure of instrumental intravenous self-administration, mechanisms of reinstatement have so far been studied almost exclusively in rats. A mouse model of reinstatement of cocaine seeking has recently been characterized (Soria et al. 2008). The aim of the present study was to assess regional brain activation, as measured by induction of the immediate early genes (IEG) arc and zif268, during priming- or cue-elicited reinstatement of cocaine seeking using this new mouse model and the in situ hybridization technique. We have demonstrated that cue-elicited reinstatement of cocaine seeking was associated with induction of the IEG in the medial prefrontal cortex (prelimbic and infralimbic) and basolateral amygdala. Priming-induced reinstatement produced a more widespread up-regulation of those genes in forebrain regions including medial prefrontal, orbitofrontal and motor cortex, dorsal striatum and basolateral amygdala. These patterns of IEG expression are in agreement with previous results obtained in rats and thus indicate that the new mouse model of reinstatement is functionally equivalent to rat models. That comparability adds to the usefulness of the mouse model as a tool for addressing neurobiological mechanisms of addiction.
Background and purpose:The purinergic system through the A2A adenosine receptor regulates addicti... more Background and purpose:The purinergic system through the A2A adenosine receptor regulates addiction induced by different drugs of abuse. The aim of the present study was to investigate the specific role of A2A adenosine receptors (A2ARs) in the behavioural and neurochemical responses to morphine associated with its motivational properties.The purinergic system through the A2A adenosine receptor regulates addiction induced by different drugs of abuse. The aim of the present study was to investigate the specific role of A2A adenosine receptors (A2ARs) in the behavioural and neurochemical responses to morphine associated with its motivational properties.Experimental approach:Mice lacking A2ARs (A2A knockout (KO) mice) and wild-type littermates were used to evaluate behavioural responses induced by morphine. Antinociception was assessed using the tail-immersion and the hot-plate tests. Place-conditioning paradigms were used to evaluate the rewarding effects of morphine and the dysphoric responses of morphine withdrawal. Microdialysis studies were carried out to evaluate changes in the extracellular levels of dopamine in the nucleus accumbens of A2A KO mice after morphine administration.Mice lacking A2ARs (A2A knockout (KO) mice) and wild-type littermates were used to evaluate behavioural responses induced by morphine. Antinociception was assessed using the tail-immersion and the hot-plate tests. Place-conditioning paradigms were used to evaluate the rewarding effects of morphine and the dysphoric responses of morphine withdrawal. Microdialysis studies were carried out to evaluate changes in the extracellular levels of dopamine in the nucleus accumbens of A2A KO mice after morphine administration.Key results:The acute administration of morphine induced a similar enhancement of locomotor activity and antinociceptive responses in both genotypes. However, the rewarding effects induced by morphine were completely blocked in A2A KO mice. Also, naloxone did not induce place aversion in animals lacking the A2ARs.The acute administration of morphine induced a similar enhancement of locomotor activity and antinociceptive responses in both genotypes. However, the rewarding effects induced by morphine were completely blocked in A2A KO mice. Also, naloxone did not induce place aversion in animals lacking the A2ARs.Conclusions and implications:Our findings demonstrate that the rewarding and aversive effects associated with morphine abstinence were abolished in A2A KO mice, supporting a differential role of the A2A adenosine receptor in the somatic and motivational effects of morphine addiction. This study provides evidence for the role of A2ARs as general modulators of the motivational properties of drugs of abuse. Pharmacological manipulation of these receptors may represent a new target in the management of drug addiction.British Journal of Pharmacology (2008) 155, 757–766; doi:10.1038/bjp.2008.299; published online 28 July 2008Our findings demonstrate that the rewarding and aversive effects associated with morphine abstinence were abolished in A2A KO mice, supporting a differential role of the A2A adenosine receptor in the somatic and motivational effects of morphine addiction. This study provides evidence for the role of A2ARs as general modulators of the motivational properties of drugs of abuse. Pharmacological manipulation of these receptors may represent a new target in the management of drug addiction.British Journal of Pharmacology (2008) 155, 757–766; doi:10.1038/bjp.2008.299; published online 28 July 2008
Rationale Cocaine addiction is a relapsing psychiatric disorder with a high prevalence in develop... more Rationale Cocaine addiction is a relapsing psychiatric disorder with a high prevalence in developed countries. To date, the reinstatement model has been difficult to implement in mice. The design of an appropriate reinstatement model in mice is required in order to use genetically modified animals with the aim of clarifying the mechanisms involved in cocaine relapse. Objectives Our aim was to develop an appropriate model of reinstatement of cocaine-seeking behavior and to investigate the factors that can trigger this reinstatement by using an operant intravenous self-administration procedure in mice. Discrete cues, priming injection of cocaine, and exposure to stress were the stimuli used to reinstate cocaine-seeking behavior. Material and methods Mice were trained to acquire intravenous self-administration of cocaine (1 mg/kg per infusion) on a fixed ratio 1 (FR1) schedule of reinforcement. After achieving the acquisition criteria, animals were led to extinguish the operant behavior. Subsequently, under extinction conditions, mice were tested after the administration of a cocaine priming injection (10 mg/kg i.p.), the presentation of a light cue associated with cocaine administration, or the exposure to a stressful situation (0.21 mA electric footshock). Results Under our experimental conditions the three stimuli successfully reinstated an extinguished cocaine-seeking behavior. Reexposure to cocaine effects by a priming injection was revealed as the strongest stimulus, capable of reinstating cocaine-seeking behavior. Conclusions The effective reinstatement model that we have developed will become a useful tool for future understanding of the neurobiological basis of cocaine addiction and relapse, specifically, with the use of genetically modified mice.
Rationale MDMA is one of the most widely consumed recreational drugs in Europe. However, the mech... more Rationale MDMA is one of the most widely consumed recreational drugs in Europe. However, the mechanisms involved in the reinforcing properties of MDMA are still unclear. In this sense, the establishment of a reliable model of MDMA self-administration in mice could represent an important approach to study the neuronal substrates associated with MDMA reward by using genetically modified mice. Objectives To develop a reliable model of operant intravenous MDMA self-administration in drug-naïve mice. Materials and methods Mice were trained to acquire intravenous self-administration of MDMA at different doses (0, 0.06, 0.125, 0.25, 0.5 and 1.0 mg/kg/infusion) on a FR1 schedule of reinforcement for 15 consecutive days. The motivational value of different doses of MDMA (0.125, 0.25 and 0.5 mg/kg/infusion) was then tested using a progressive ratio paradigm. Finally, [3H]-mazindol autoradiographic studies were carried out in order to quantitatively assess presynaptic dopamine transporter (DAT) binding sites in the striatum of mice trained to self-administer MDMA (0 and 1.0 mg/kg/infusion) during 15 days. Results The latency for discrimination between the active and inactive holes, as well as the number of animals acquiring stability criteria, varied as a function of the dose of MDMA. The mice responding for intermediate doses (0.125, 0.25 and 0.5 mg/kg/infusion) discriminated earlier than those responding for low (0.06 mg/kg/infusion) or high (1.0 mg/kg/infusion) doses. The percentage of animals achieving stability criteria increased with days of testing and was inversely proportional to the dose of MDMA. The breaking points achieved for doses of 0.125 and 0.25 mg/kg/infusion were significantly higher than for a dose of 0.5 mg/kg/infusion. No significant DAT neurotoxicity was observed in the striatum of animals self-administering MDMA at a dose of 1 mg/kg/infusion. Conclusions The present results show that MDMA can be reliably self-administered by drug-naïve mice.
Reinstatement of extinguished operant responding for drug is an appropriate model of relapse to d... more Reinstatement of extinguished operant responding for drug is an appropriate model of relapse to drug abuse. Due to the difficulty of implementing in mice the procedure of instrumental intravenous self-administration, mechanisms of reinstatement have so far been studied almost exclusively in rats. A mouse model of reinstatement of cocaine seeking has recently been characterized (Soria et al. 2008). The aim of the present study was to assess regional brain activation, as measured by induction of the immediate early genes (IEG) arc and zif268, during priming- or cue-elicited reinstatement of cocaine seeking using this new mouse model and the in situ hybridization technique. We have demonstrated that cue-elicited reinstatement of cocaine seeking was associated with induction of the IEG in the medial prefrontal cortex (prelimbic and infralimbic) and basolateral amygdala. Priming-induced reinstatement produced a more widespread up-regulation of those genes in forebrain regions including medial prefrontal, orbitofrontal and motor cortex, dorsal striatum and basolateral amygdala. These patterns of IEG expression are in agreement with previous results obtained in rats and thus indicate that the new mouse model of reinstatement is functionally equivalent to rat models. That comparability adds to the usefulness of the mouse model as a tool for addressing neurobiological mechanisms of addiction.
Background and purpose:The purinergic system through the A2A adenosine receptor regulates addicti... more Background and purpose:The purinergic system through the A2A adenosine receptor regulates addiction induced by different drugs of abuse. The aim of the present study was to investigate the specific role of A2A adenosine receptors (A2ARs) in the behavioural and neurochemical responses to morphine associated with its motivational properties.The purinergic system through the A2A adenosine receptor regulates addiction induced by different drugs of abuse. The aim of the present study was to investigate the specific role of A2A adenosine receptors (A2ARs) in the behavioural and neurochemical responses to morphine associated with its motivational properties.Experimental approach:Mice lacking A2ARs (A2A knockout (KO) mice) and wild-type littermates were used to evaluate behavioural responses induced by morphine. Antinociception was assessed using the tail-immersion and the hot-plate tests. Place-conditioning paradigms were used to evaluate the rewarding effects of morphine and the dysphoric responses of morphine withdrawal. Microdialysis studies were carried out to evaluate changes in the extracellular levels of dopamine in the nucleus accumbens of A2A KO mice after morphine administration.Mice lacking A2ARs (A2A knockout (KO) mice) and wild-type littermates were used to evaluate behavioural responses induced by morphine. Antinociception was assessed using the tail-immersion and the hot-plate tests. Place-conditioning paradigms were used to evaluate the rewarding effects of morphine and the dysphoric responses of morphine withdrawal. Microdialysis studies were carried out to evaluate changes in the extracellular levels of dopamine in the nucleus accumbens of A2A KO mice after morphine administration.Key results:The acute administration of morphine induced a similar enhancement of locomotor activity and antinociceptive responses in both genotypes. However, the rewarding effects induced by morphine were completely blocked in A2A KO mice. Also, naloxone did not induce place aversion in animals lacking the A2ARs.The acute administration of morphine induced a similar enhancement of locomotor activity and antinociceptive responses in both genotypes. However, the rewarding effects induced by morphine were completely blocked in A2A KO mice. Also, naloxone did not induce place aversion in animals lacking the A2ARs.Conclusions and implications:Our findings demonstrate that the rewarding and aversive effects associated with morphine abstinence were abolished in A2A KO mice, supporting a differential role of the A2A adenosine receptor in the somatic and motivational effects of morphine addiction. This study provides evidence for the role of A2ARs as general modulators of the motivational properties of drugs of abuse. Pharmacological manipulation of these receptors may represent a new target in the management of drug addiction.British Journal of Pharmacology (2008) 155, 757–766; doi:10.1038/bjp.2008.299; published online 28 July 2008Our findings demonstrate that the rewarding and aversive effects associated with morphine abstinence were abolished in A2A KO mice, supporting a differential role of the A2A adenosine receptor in the somatic and motivational effects of morphine addiction. This study provides evidence for the role of A2ARs as general modulators of the motivational properties of drugs of abuse. Pharmacological manipulation of these receptors may represent a new target in the management of drug addiction.British Journal of Pharmacology (2008) 155, 757–766; doi:10.1038/bjp.2008.299; published online 28 July 2008
Rationale Cocaine addiction is a relapsing psychiatric disorder with a high prevalence in develop... more Rationale Cocaine addiction is a relapsing psychiatric disorder with a high prevalence in developed countries. To date, the reinstatement model has been difficult to implement in mice. The design of an appropriate reinstatement model in mice is required in order to use genetically modified animals with the aim of clarifying the mechanisms involved in cocaine relapse. Objectives Our aim was to develop an appropriate model of reinstatement of cocaine-seeking behavior and to investigate the factors that can trigger this reinstatement by using an operant intravenous self-administration procedure in mice. Discrete cues, priming injection of cocaine, and exposure to stress were the stimuli used to reinstate cocaine-seeking behavior. Material and methods Mice were trained to acquire intravenous self-administration of cocaine (1 mg/kg per infusion) on a fixed ratio 1 (FR1) schedule of reinforcement. After achieving the acquisition criteria, animals were led to extinguish the operant behavior. Subsequently, under extinction conditions, mice were tested after the administration of a cocaine priming injection (10 mg/kg i.p.), the presentation of a light cue associated with cocaine administration, or the exposure to a stressful situation (0.21 mA electric footshock). Results Under our experimental conditions the three stimuli successfully reinstated an extinguished cocaine-seeking behavior. Reexposure to cocaine effects by a priming injection was revealed as the strongest stimulus, capable of reinstating cocaine-seeking behavior. Conclusions The effective reinstatement model that we have developed will become a useful tool for future understanding of the neurobiological basis of cocaine addiction and relapse, specifically, with the use of genetically modified mice.
Uploads
Papers by Guadalupe Soria