Withdrawal symptoms are observed upon cessation of cannabis use in humans. Although animal studie... more Withdrawal symptoms are observed upon cessation of cannabis use in humans. Although animal studies have examined withdrawal symptoms following exposure to delta-9-tetrahydrocannabinol (THC), difficulties in obtaining objective measures of spontaneous withdrawal using paradigms that mimic cessation of use in humans have slowed research. The neuromodulator dopamine (DA) is known to be affected by chronic THC treatment and plays a role in many behaviors related to human THC withdrawal symptoms. These symptoms include sleep disturbances that often drive relapse, and emotional behaviors, e.g., irritability and anhedonia. We examined THC withdrawal-induced changes in striatal DA release and the extent to which sleep disruption and behavioral maladaptation manifest during withdrawal in a mouse chronic cannabis exposure model. Using a THC treatment regimen known to produce tolerance we measured electrically elicited DA release in acute brain slices from different striatal subregions during ...
Modafinil is a non-amphetaminic psychostimulant used therapeutically for sleep and psychiatric di... more Modafinil is a non-amphetaminic psychostimulant used therapeutically for sleep and psychiatric disorders. However, some studies indicate that modafinil can have addictive properties. The present study examined whether modafinil can produce behavioral sensitization in mice, an experience and drug-dependent behavioral adaptation, and if individual differences play a role in this process. We further tested context-related factors and cross-sensitization between modafinil and methamphetamine. Important individual differences in the behavioral sensitization of Swiss Albino mice were observed after repeated administration of 50 mg/kg modafinil (Experiment 1), or 1 mg/kg methamphetamine (Experiment 2). Only mice classified as sensitized subgroup developed clear behavioral sensitization to the drugs. After a withdrawal period, mice received challenges of modafinil (Experiment 1), or methamphetamine (Experiment 2) and locomotor activity was evaluated in the activity cages (previous context) and in the open field arena (new context) in order to evaluate the context dependency of behavioral sensitization. The expression of sensitization to modafinil, but not to methamphetamine, was affected by contextual testing conditions, since modafinil-sensitized mice only expressed sensitization in the activity cage, but not in the open field. Subsequently, locomotor cross-sensitization between methamphetamine and modafinil was assessed by challenging modafinil-pretreated mice with 1mg/kg methamphetamine (Experiment 1), and methamphetamine-pretreated mice with 50mg/kg modafinil (Experiment 2). We observed a symmetrical cross-sensitization between the drugs only in those mice that were classified as sensitized subgroup. Our findings indicate that repeated exposure to modafinil induces behavioral sensitization only in some animals by similar neurobiological, but not contextual, mechanisms to those of methamphetamine.
Conditioned place preference (CPP) is a model to study the role of drug conditioning properties. ... more Conditioned place preference (CPP) is a model to study the role of drug conditioning properties. In outbred strains, individual variability may affect some behavioral measures. However, there are few studies focusing on understanding how different phenotypes of ethanol conditioned behavior may influence its extinction, reinstatement, and behavioral adaptation measures. We used male Swiss Webster mice to study different phenotypes related to ethanol conditioning strength, reinstatement and behavioral sensitization. Mice went through a CPP procedure with ethanol (2.2 g/kg, i.p.). After that, one group of mice was submitted to repeated extinction sessions, while another group remained in their home cages without any drug treatment. Mice went through environmental and ethanol priming (1.0 g/kg, i.p.) reinstatement tests. Ethanol priming test reinstated the conditioned behavior only in the animals kept in the home-cage during the abstinence period. Besides, the ethanol conditioned behavi...
In mice there are clear individual differences in the development of behavioral sensitization to ... more In mice there are clear individual differences in the development of behavioral sensitization to ethanol, a progressive potentiation of its psychomotor stimulant effect. Variability in the behavioral responses to ethanol has been associated with alcohol preference. Here we investigated if the functional hyperresponsiveness of D1 receptors observed in ethanol sensitized mice leads to an increased activation of DARPP-32, a central regulatory protein in medium spiny neurons, in the nucleus accumbens -a brain region known to play a role in drug reinforcement. Swiss Webster mice received ethanol (2.2 g/ kg/day) or saline i.p. administrations for 21 days and were weekly evaluated regarding their locomotor activity. From those treated with ethanol, the 33% with the highest levels of locomotor activity were classified as ''sensitized'' and the 33% with the lowest levels as "non-sensitized''. The latter presented similar locomotor levels to those of saline-treated mice. Different subgroups of mice received intra-accumbens administrations of saline and, 48 h later, SKF-38393, D1 receptor agonist 0.1 or 1 mg/side. Indeed, sensitized mice presented functional hyperresponsiveness of D1 receptors in the accumbens. Two weeks following the ethanol treatment, other subgroups received systemic saline or SKF 10 mg/kg, 20 min before the euthanasia. The nucleus accumbens were dissected for the Western Blot analyses of total DARPP-32 and phospho-Thr34-DARPP-32 expression. D1 receptor activation induced higher phospho-Thr34-DARPP-32 expression in sensitized mice than in nonsensitized or saline. The functionally hyperresponsiveness of D1 receptors in the nucleus accumbens is associated with an increased phospho-Thr34-DARPP-32 expression after D1 receptor activation. These data suggest that an enduring increase in the sensitivity of the dopamine D1 receptor intracellular pathway sensitivity represents a neurobiological correlate associated with the development of locomotor sensitization to ethanol.
Although alcoholism is a worldwide problem resulting in millions of deaths, only a small percenta... more Although alcoholism is a worldwide problem resulting in millions of deaths, only a small percentage of alcohol users become addicted. The specific neural substrates responsible for individual differences in vulnerability to alcohol addiction are not known. In this study, we used rodent models to study behavioral and synaptic correlates related to individual differences in the development of ethanol locomotor sensitization, a form of drug-dependent behavioral plasticity associated with addiction vulnerability. Male Swiss Webster mice were treated daily with saline or 1.8 g/kg ethanol for 21 d. Locomotor activity tests were performed once a week for 15 min immediately after saline or ethanol injections. After at least 11 d of withdrawal, cohorts of saline- or ethanol-treated mice were used to characterize the relationships between locomotor sensitization, ethanol drinking, and glutamatergic synaptic transmission in the nucleus accumbens. Ethanol-treated mice that expressed locomotor sensitization to ethanol drank significantly more ethanol than saline-treated subjects and ethanol-treated animals resilient to this form of behavioral plasticity. Moreover, ethanol-sensitized mice also had reduced accumbal NMDA receptor function and expression, as well as deficits in NMDA receptor-dependent long-term depression in the nucleus accumbens core after a protracted withdrawal. These findings suggest that disruption of accumbal core NMDA receptor-dependent plasticity may represent a synaptic correlate associated with ethanol-induced locomotor sensitization and increased propensity to consume ethanol.
Alcohol abuse and dependence are important medical, social and economical problems, affecting mil... more Alcohol abuse and dependence are important medical, social and economical problems, affecting millions of people. A relatively recent habit among young people is mixing alcohol with energy drinks (ED), in spite of the risks involved may be higher than those associated with alcohol consumption alone. The mixture of alcohol and energy drinks, both with stimulant properties, may alter the perception of intoxication and could lead individuals to believe they are less drunk and can drink more or for longer periods of time. In animals, the repeated administration of ethanol can lead to a progressive increase of the locomotor stimulant effect, known as behavioral sensitization, a drug-dependent behavioral plasticity associated with vulnerability to addiction. As well as for addiction, there are clear individual differences in the level of sensitization to ethanol among species and even among individuals from the same strain. The present study assessed how ED affects the expression of ethanol sensitization. Female mice chronically treated with ethanol (2.4 g/kg) were classified as low-sensitized or high-sensitized. Two days later, different groups of mice were submitted to saline + water, ethanol + water or ethanol + ED systemic challenges. As expected, only the high-sensitized group expressed clear sensitization after ethanol administration. However, the administration of ethanol + ED triggered the sensitization expression in the low-sensitized group. These data indicate that the combined use of ED and ethanol can potentiate the stimulant and, consequently, the reward effects of ethanol in previously treated mice. If a similar process occurs in human beings, the use of ED can increase the risk of developing alcohol abuse or dependence.
In mice, repeated ethanol administration may induce behavioral sensitization - a process of progr... more In mice, repeated ethanol administration may induce behavioral sensitization - a process of progressive potentiation of its stimulant effects, associated with neuroadaptations in the brain reward system. Few studies have directly investigated the subsequent neuroadaptations in the nucleus accumbens (NAc), the central area of the brain reward system, after chronic ethanol administration. The goal of the present study was to analyze the involvement of accumbal glutamate NMDA receptors in the locomotion behavioral response to an NMDA agonist or to an NMDA antagonist in mice previously treated with ethanol. Swiss Albino mice received repeated daily administrations of 2.2 g/kg ethanol or saline for 21 days. According to their locomotor response on the last day of treatment, ethanol-treated mice were classified into sensitized or non-sensitized groups. They were then submitted to a surgical procedure to implement intra-NAc cannulae. After recovery, mice were challenged with intra-NAc administration of saline and, two days later, with NMDA (NMDA agonist) or MK-801 (NMDA antagonist), having their locomotor activity recorded for 1 h. The administration of NMDA induced similar locomotor behavior in all groups. On the other hand, the administration of 3 μg/side MK-801 induced a significant stimulant effect which was more prominent during the first 15 min in the sensitized group than in the non-sensitized or saline groups. Despite no effect of the agonist administration, only in sensitized mice did we observe cross-sensitization between repeated ethanol treatment and the intra-NAc administration of MK-801.
Trends in Neuroscience and Education, Mar 14, 2014
The use of neuroscience to improve education has been considered by researchers and practitioners... more The use of neuroscience to improve education has been considered by researchers and practitioners alike. However, workable solutions that lead to improvements in research and practice are yet to emerge. As newly qualified educational neuroscientists, our experiences dictate that the progress in this field relies upon ‘Educational Neuroscience’ being recognised as a distinct discipline. We therefore present a four-stage practical approach that concretely describes the role of the educational neuroscientist and details how neuroscientific knowledge can be practically assessed in the classroom. Using this approach, junior scientists will become empowered to replace the ‘bridge’ between education and neuroscience with a stronger, distinct Educational Neuroscience highway that is built in parallel to the existing paths.
Behavioral sensitization to the stimulating effect of ethanol (EtOH) or other drugs, which can be... more Behavioral sensitization to the stimulating effect of ethanol (EtOH) or other drugs, which can be observed in mice as an increase in locomotor activity after repeated administration, has been associated with neuroadaptations within the dopaminergic mesolimbic pathway. In the nucleus accumbens (NAc), an afferent region of the mesolimbic pathway, dopamine (DA) release can be modulated by serotonergic 2C receptors (5-HT2CR). The aim of the present study was to evaluate the function of 5-HT2CR in the expression of EtOH-induced behavioral sensitization in Albino Swiss mice with various levels of sensitization to EtOH. In the four experiments that we performed, the mice were given saline or 2.2 g/kg EtOH daily for 21 days. Based on their locomotion on day 21, the EtOH-pretreated mice were assigned to one of two groups, highly sensitized or weakly sensitized to the stimulating effect of EtOH. In each experiment, 2 weeks after the 21-day treatment (withdrawal period), the mice were submitted to four pharmacological challenges of two drug treatments each. The mice in experiments 1 and 2 received two i.p. injections, whereas the mice in experiments 3 and 4 received an intra-NAc administration followed by an i.p. injection. The challenges were: saline+saline; saline+EtOH; SB-242084 (a 5-HT2CR antagonist; 0.5, 1.0 or 2.0 mg/kg i.p. or 1.0 or 2.0 μg/side intra-NAc)+EtOH; and SB-242084 (0.5, 1.0 or 2.0 mg/kg i.p. or 1.0 or 2.0 μg/side intra-NAc)+saline. At all tested doses, i.p. administration of SB-242084 did not affect the stimulating effect of EtOH in the highly sensitized mice. However, when delivered by intra-NAc administration, SB-242084 reduced (at 1.0 μg/side) or completely blocked (at 2.0 μg/side) the expression of EtOH-induced behavioral sensitization in the highly sensitized mice. These findings suggest that the expression of behavioral sensitization to the stimulating effect of EtOH depends on accumbal 5-HT2CR activity.▶Some mice treated 3 weeks with EtOH developed high sensitization to its stimulant effect. ▶Other mice under the same treatment (2.2 g/kg EtOH) developed weak sensitization. ▶SB-242084 intra-NAc reduced sensitization expression only in highly sensitized mice. ▶SB-242084 i.p. did not affect the expression of EtOH-induced sensitization. ▶Expression of behavioral sensitization to EtOH depends on accumbal 5-HT2CR activity.
Striatal dopamine D2 receptors have been implicated in the development of behavioral sensitizatio... more Striatal dopamine D2 receptors have been implicated in the development of behavioral sensitization after repeated exposure to drugs of abuse. There are clear individual differences in the level of sensitization to ethanol among species and even among individuals from the same strain. Albino Swiss mice treated with ethanol (2.2 g/kg) have been shown to present clear variations in the development of sensitization. While some mice developed ethanol (EtOH) induced sensitization, others did not. This variability was associated with differences in D2 dopaminergic receptor binding. In the present study, we evaluated the functional relevance of dopamine D2 receptor by measuring, in sensitized and non-sensitized mice, the locomotor response to a D2 receptor agonist (quinpirole, 0.5 and 2.0 mg/kg i.p. or 0.01 and 0.2 μg/side intra-accumbens) or antagonist (sulpiride, 10 or 50 mg/kg i.p. or 0.02 μg/side intra-accumbens + ethanol i.p.). Whereas the systemic administration of quinpirole decreased locomotor activity in a similar way in all the groups, intra-nucleus accumbens (NAc) administration induced significantly higher locomotor stimulation in the sensitized group alone. Our data show that functionally hyperresponsive D2 receptors are present in the NAcs of sensitized but not non-sensitized mice, suggesting that this could be a biomarker of behavioral sensitization. Furthermore, i.p. administration of sulpiride blocked the expression of sensitization in the sensitized group, and intra-NAc administration attenuated it, indicating that the activation of accumbal D2 receptors is essential for the expression of EtOH behavioral sensitization.This article is part of a Special Issue entitled ‘Post-Traumatic Stress Disorder’.► There is significant individual variability in the development of ethanol sensitization. ► D2 receptor hyperfunctionality in the NAc is associated with ethanol sensitization. ► Activation of NAc D2 receptors is important for the expression of ethanol sensitization. ► Individual variations in susceptibility to ethanol sensitization are related to differences in accumbal D2 receptor function.
International Journal of Neuropsychopharmacology, Jan 1, 2010
... system, promoting increased dop-amine concentrations in the NAc (Di Chiara, 1999; Diana et al... more ... system, promoting increased dop-amine concentrations in the NAc (Di Chiara, 1999; Diana et al. ... Inset: Locomotor activity (mean+S.E.M.) for 15 min of naive animals (n=5 ... observation of changes in dopamine D1R function after sensitization to psychostimulants (Capper-Loup et ...
Behavioral sensitization to ethanol is characterized by an increased locomotor activity after rep... more Behavioral sensitization to ethanol is characterized by an increased locomotor activity after repeated exposure. A great variability exists among species and strains in the development of sensitization. There is a growing amount of evidence to indicate that the opioid system is involved in alcoholism; it is possible, therefore, that this system also modulates the sensitization to ethanol. In this study we evaluated the role of the opioid system in determining the variability of the sensitized response to ethanol. Mice received repeated administrations of ethanol (2.2 g/kg) or saline every other day for 10 days. According to their locomotor response on the last day of treatment, ethanol-treated animals were classified into two groups: sensitized or non-sensitized mice. After the treatment, mice were submitted to four challenges 48 h apart. In experiments 1 and 2, mice were challenged, respectively, with i.p. administration of opioid antagonists (naloxone or naltrexone) or an opioid agonist (morphine), followed immediately by 2.2 g/kg ethanol. In experiment 3, animals received morphine by i.c.v., followed by 2.2 g/kg of ethanol (i.p.). Pretreatment with opioid antagonists (naloxone or naltrexone) did not block the expression of ethanol sensitization; however pretreatment with morphine attenuated the increased locomotor activity after ethanol administration in sensitized mice. In experiment 4, after the ethanol or saline treatment, mice brains were processed and brain mu opioid binding was assessed by autoradiography using [3H]D-Ala2,N-mePhe4, Gly-ol5-enkephalin ([3H]DAMGO). No differences were seen between any of the groups of mice, so the agonist effect is not likely to be mediated by differences in binding to mu opioid receptors.
Repeated administration of drugs may induce adaptations which affect the behavioral responses to ... more Repeated administration of drugs may induce adaptations which affect the behavioral responses to the drug itself or to other drugs. Whether individual characteristics to repeated drug administration predict sensitivity to the effects of another drug is not clear. We evaluated whether or not mice that present higher vs. lower locomotor response after repeated treatment with ethanol display increased or decreased locomotor responses when challenged with methamphetamine or morphine, and vice versa. Mice received daily i.p. 2.2 g/kg ethanol (21 days), 1.0 mg/kg methamphetamine or 10 mg/kg morphine (10 days). According to the response presented during repeated drug treatment, mice were classified as HIGH or LOW activity groups. Locomotor activity was monitored after mice were challenged with saline, and 48 h later with a drug. Ethanol-treated mice were challenged with methamphetamine or morphine, methamphetamine- and morphine-treated animals were challenged with ethanol. After repeated treatment with ethanol or methamphetamine, locomotor sensitization was observed only in HIGH mice, not LOW mice. Ethanol-treated mice with HIGH activity showed sensitized, increased locomotor responses to methamphetamine (p < 0.05), but not to morphine. Locomotor responses to ethanol were not affected by a previous history of methamphetamine treatment. Although repeated administration of morphine failed to induce sensitization, morphine-treated mice with HIGH activity presented sensitized locomotor responses after an ethanol challenge. The current experiments confirm important individual differences in response to repeated administration of ethanol, methamphetamine and morphine, which in some cases affected the locomotor response to a second drug challenge, in an asymmetrical pattern.
Withdrawal symptoms are observed upon cessation of cannabis use in humans. Although animal studie... more Withdrawal symptoms are observed upon cessation of cannabis use in humans. Although animal studies have examined withdrawal symptoms following exposure to delta-9-tetrahydrocannabinol (THC), difficulties in obtaining objective measures of spontaneous withdrawal using paradigms that mimic cessation of use in humans have slowed research. The neuromodulator dopamine (DA) is known to be affected by chronic THC treatment and plays a role in many behaviors related to human THC withdrawal symptoms. These symptoms include sleep disturbances that often drive relapse, and emotional behaviors, e.g., irritability and anhedonia. We examined THC withdrawal-induced changes in striatal DA release and the extent to which sleep disruption and behavioral maladaptation manifest during withdrawal in a mouse chronic cannabis exposure model. Using a THC treatment regimen known to produce tolerance we measured electrically elicited DA release in acute brain slices from different striatal subregions during ...
Modafinil is a non-amphetaminic psychostimulant used therapeutically for sleep and psychiatric di... more Modafinil is a non-amphetaminic psychostimulant used therapeutically for sleep and psychiatric disorders. However, some studies indicate that modafinil can have addictive properties. The present study examined whether modafinil can produce behavioral sensitization in mice, an experience and drug-dependent behavioral adaptation, and if individual differences play a role in this process. We further tested context-related factors and cross-sensitization between modafinil and methamphetamine. Important individual differences in the behavioral sensitization of Swiss Albino mice were observed after repeated administration of 50 mg/kg modafinil (Experiment 1), or 1 mg/kg methamphetamine (Experiment 2). Only mice classified as sensitized subgroup developed clear behavioral sensitization to the drugs. After a withdrawal period, mice received challenges of modafinil (Experiment 1), or methamphetamine (Experiment 2) and locomotor activity was evaluated in the activity cages (previous context) and in the open field arena (new context) in order to evaluate the context dependency of behavioral sensitization. The expression of sensitization to modafinil, but not to methamphetamine, was affected by contextual testing conditions, since modafinil-sensitized mice only expressed sensitization in the activity cage, but not in the open field. Subsequently, locomotor cross-sensitization between methamphetamine and modafinil was assessed by challenging modafinil-pretreated mice with 1mg/kg methamphetamine (Experiment 1), and methamphetamine-pretreated mice with 50mg/kg modafinil (Experiment 2). We observed a symmetrical cross-sensitization between the drugs only in those mice that were classified as sensitized subgroup. Our findings indicate that repeated exposure to modafinil induces behavioral sensitization only in some animals by similar neurobiological, but not contextual, mechanisms to those of methamphetamine.
Conditioned place preference (CPP) is a model to study the role of drug conditioning properties. ... more Conditioned place preference (CPP) is a model to study the role of drug conditioning properties. In outbred strains, individual variability may affect some behavioral measures. However, there are few studies focusing on understanding how different phenotypes of ethanol conditioned behavior may influence its extinction, reinstatement, and behavioral adaptation measures. We used male Swiss Webster mice to study different phenotypes related to ethanol conditioning strength, reinstatement and behavioral sensitization. Mice went through a CPP procedure with ethanol (2.2 g/kg, i.p.). After that, one group of mice was submitted to repeated extinction sessions, while another group remained in their home cages without any drug treatment. Mice went through environmental and ethanol priming (1.0 g/kg, i.p.) reinstatement tests. Ethanol priming test reinstated the conditioned behavior only in the animals kept in the home-cage during the abstinence period. Besides, the ethanol conditioned behavi...
In mice there are clear individual differences in the development of behavioral sensitization to ... more In mice there are clear individual differences in the development of behavioral sensitization to ethanol, a progressive potentiation of its psychomotor stimulant effect. Variability in the behavioral responses to ethanol has been associated with alcohol preference. Here we investigated if the functional hyperresponsiveness of D1 receptors observed in ethanol sensitized mice leads to an increased activation of DARPP-32, a central regulatory protein in medium spiny neurons, in the nucleus accumbens -a brain region known to play a role in drug reinforcement. Swiss Webster mice received ethanol (2.2 g/ kg/day) or saline i.p. administrations for 21 days and were weekly evaluated regarding their locomotor activity. From those treated with ethanol, the 33% with the highest levels of locomotor activity were classified as ''sensitized'' and the 33% with the lowest levels as "non-sensitized''. The latter presented similar locomotor levels to those of saline-treated mice. Different subgroups of mice received intra-accumbens administrations of saline and, 48 h later, SKF-38393, D1 receptor agonist 0.1 or 1 mg/side. Indeed, sensitized mice presented functional hyperresponsiveness of D1 receptors in the accumbens. Two weeks following the ethanol treatment, other subgroups received systemic saline or SKF 10 mg/kg, 20 min before the euthanasia. The nucleus accumbens were dissected for the Western Blot analyses of total DARPP-32 and phospho-Thr34-DARPP-32 expression. D1 receptor activation induced higher phospho-Thr34-DARPP-32 expression in sensitized mice than in nonsensitized or saline. The functionally hyperresponsiveness of D1 receptors in the nucleus accumbens is associated with an increased phospho-Thr34-DARPP-32 expression after D1 receptor activation. These data suggest that an enduring increase in the sensitivity of the dopamine D1 receptor intracellular pathway sensitivity represents a neurobiological correlate associated with the development of locomotor sensitization to ethanol.
Although alcoholism is a worldwide problem resulting in millions of deaths, only a small percenta... more Although alcoholism is a worldwide problem resulting in millions of deaths, only a small percentage of alcohol users become addicted. The specific neural substrates responsible for individual differences in vulnerability to alcohol addiction are not known. In this study, we used rodent models to study behavioral and synaptic correlates related to individual differences in the development of ethanol locomotor sensitization, a form of drug-dependent behavioral plasticity associated with addiction vulnerability. Male Swiss Webster mice were treated daily with saline or 1.8 g/kg ethanol for 21 d. Locomotor activity tests were performed once a week for 15 min immediately after saline or ethanol injections. After at least 11 d of withdrawal, cohorts of saline- or ethanol-treated mice were used to characterize the relationships between locomotor sensitization, ethanol drinking, and glutamatergic synaptic transmission in the nucleus accumbens. Ethanol-treated mice that expressed locomotor sensitization to ethanol drank significantly more ethanol than saline-treated subjects and ethanol-treated animals resilient to this form of behavioral plasticity. Moreover, ethanol-sensitized mice also had reduced accumbal NMDA receptor function and expression, as well as deficits in NMDA receptor-dependent long-term depression in the nucleus accumbens core after a protracted withdrawal. These findings suggest that disruption of accumbal core NMDA receptor-dependent plasticity may represent a synaptic correlate associated with ethanol-induced locomotor sensitization and increased propensity to consume ethanol.
Alcohol abuse and dependence are important medical, social and economical problems, affecting mil... more Alcohol abuse and dependence are important medical, social and economical problems, affecting millions of people. A relatively recent habit among young people is mixing alcohol with energy drinks (ED), in spite of the risks involved may be higher than those associated with alcohol consumption alone. The mixture of alcohol and energy drinks, both with stimulant properties, may alter the perception of intoxication and could lead individuals to believe they are less drunk and can drink more or for longer periods of time. In animals, the repeated administration of ethanol can lead to a progressive increase of the locomotor stimulant effect, known as behavioral sensitization, a drug-dependent behavioral plasticity associated with vulnerability to addiction. As well as for addiction, there are clear individual differences in the level of sensitization to ethanol among species and even among individuals from the same strain. The present study assessed how ED affects the expression of ethanol sensitization. Female mice chronically treated with ethanol (2.4 g/kg) were classified as low-sensitized or high-sensitized. Two days later, different groups of mice were submitted to saline + water, ethanol + water or ethanol + ED systemic challenges. As expected, only the high-sensitized group expressed clear sensitization after ethanol administration. However, the administration of ethanol + ED triggered the sensitization expression in the low-sensitized group. These data indicate that the combined use of ED and ethanol can potentiate the stimulant and, consequently, the reward effects of ethanol in previously treated mice. If a similar process occurs in human beings, the use of ED can increase the risk of developing alcohol abuse or dependence.
In mice, repeated ethanol administration may induce behavioral sensitization - a process of progr... more In mice, repeated ethanol administration may induce behavioral sensitization - a process of progressive potentiation of its stimulant effects, associated with neuroadaptations in the brain reward system. Few studies have directly investigated the subsequent neuroadaptations in the nucleus accumbens (NAc), the central area of the brain reward system, after chronic ethanol administration. The goal of the present study was to analyze the involvement of accumbal glutamate NMDA receptors in the locomotion behavioral response to an NMDA agonist or to an NMDA antagonist in mice previously treated with ethanol. Swiss Albino mice received repeated daily administrations of 2.2 g/kg ethanol or saline for 21 days. According to their locomotor response on the last day of treatment, ethanol-treated mice were classified into sensitized or non-sensitized groups. They were then submitted to a surgical procedure to implement intra-NAc cannulae. After recovery, mice were challenged with intra-NAc administration of saline and, two days later, with NMDA (NMDA agonist) or MK-801 (NMDA antagonist), having their locomotor activity recorded for 1 h. The administration of NMDA induced similar locomotor behavior in all groups. On the other hand, the administration of 3 μg/side MK-801 induced a significant stimulant effect which was more prominent during the first 15 min in the sensitized group than in the non-sensitized or saline groups. Despite no effect of the agonist administration, only in sensitized mice did we observe cross-sensitization between repeated ethanol treatment and the intra-NAc administration of MK-801.
Trends in Neuroscience and Education, Mar 14, 2014
The use of neuroscience to improve education has been considered by researchers and practitioners... more The use of neuroscience to improve education has been considered by researchers and practitioners alike. However, workable solutions that lead to improvements in research and practice are yet to emerge. As newly qualified educational neuroscientists, our experiences dictate that the progress in this field relies upon ‘Educational Neuroscience’ being recognised as a distinct discipline. We therefore present a four-stage practical approach that concretely describes the role of the educational neuroscientist and details how neuroscientific knowledge can be practically assessed in the classroom. Using this approach, junior scientists will become empowered to replace the ‘bridge’ between education and neuroscience with a stronger, distinct Educational Neuroscience highway that is built in parallel to the existing paths.
Behavioral sensitization to the stimulating effect of ethanol (EtOH) or other drugs, which can be... more Behavioral sensitization to the stimulating effect of ethanol (EtOH) or other drugs, which can be observed in mice as an increase in locomotor activity after repeated administration, has been associated with neuroadaptations within the dopaminergic mesolimbic pathway. In the nucleus accumbens (NAc), an afferent region of the mesolimbic pathway, dopamine (DA) release can be modulated by serotonergic 2C receptors (5-HT2CR). The aim of the present study was to evaluate the function of 5-HT2CR in the expression of EtOH-induced behavioral sensitization in Albino Swiss mice with various levels of sensitization to EtOH. In the four experiments that we performed, the mice were given saline or 2.2 g/kg EtOH daily for 21 days. Based on their locomotion on day 21, the EtOH-pretreated mice were assigned to one of two groups, highly sensitized or weakly sensitized to the stimulating effect of EtOH. In each experiment, 2 weeks after the 21-day treatment (withdrawal period), the mice were submitted to four pharmacological challenges of two drug treatments each. The mice in experiments 1 and 2 received two i.p. injections, whereas the mice in experiments 3 and 4 received an intra-NAc administration followed by an i.p. injection. The challenges were: saline+saline; saline+EtOH; SB-242084 (a 5-HT2CR antagonist; 0.5, 1.0 or 2.0 mg/kg i.p. or 1.0 or 2.0 μg/side intra-NAc)+EtOH; and SB-242084 (0.5, 1.0 or 2.0 mg/kg i.p. or 1.0 or 2.0 μg/side intra-NAc)+saline. At all tested doses, i.p. administration of SB-242084 did not affect the stimulating effect of EtOH in the highly sensitized mice. However, when delivered by intra-NAc administration, SB-242084 reduced (at 1.0 μg/side) or completely blocked (at 2.0 μg/side) the expression of EtOH-induced behavioral sensitization in the highly sensitized mice. These findings suggest that the expression of behavioral sensitization to the stimulating effect of EtOH depends on accumbal 5-HT2CR activity.▶Some mice treated 3 weeks with EtOH developed high sensitization to its stimulant effect. ▶Other mice under the same treatment (2.2 g/kg EtOH) developed weak sensitization. ▶SB-242084 intra-NAc reduced sensitization expression only in highly sensitized mice. ▶SB-242084 i.p. did not affect the expression of EtOH-induced sensitization. ▶Expression of behavioral sensitization to EtOH depends on accumbal 5-HT2CR activity.
Striatal dopamine D2 receptors have been implicated in the development of behavioral sensitizatio... more Striatal dopamine D2 receptors have been implicated in the development of behavioral sensitization after repeated exposure to drugs of abuse. There are clear individual differences in the level of sensitization to ethanol among species and even among individuals from the same strain. Albino Swiss mice treated with ethanol (2.2 g/kg) have been shown to present clear variations in the development of sensitization. While some mice developed ethanol (EtOH) induced sensitization, others did not. This variability was associated with differences in D2 dopaminergic receptor binding. In the present study, we evaluated the functional relevance of dopamine D2 receptor by measuring, in sensitized and non-sensitized mice, the locomotor response to a D2 receptor agonist (quinpirole, 0.5 and 2.0 mg/kg i.p. or 0.01 and 0.2 μg/side intra-accumbens) or antagonist (sulpiride, 10 or 50 mg/kg i.p. or 0.02 μg/side intra-accumbens + ethanol i.p.). Whereas the systemic administration of quinpirole decreased locomotor activity in a similar way in all the groups, intra-nucleus accumbens (NAc) administration induced significantly higher locomotor stimulation in the sensitized group alone. Our data show that functionally hyperresponsive D2 receptors are present in the NAcs of sensitized but not non-sensitized mice, suggesting that this could be a biomarker of behavioral sensitization. Furthermore, i.p. administration of sulpiride blocked the expression of sensitization in the sensitized group, and intra-NAc administration attenuated it, indicating that the activation of accumbal D2 receptors is essential for the expression of EtOH behavioral sensitization.This article is part of a Special Issue entitled ‘Post-Traumatic Stress Disorder’.► There is significant individual variability in the development of ethanol sensitization. ► D2 receptor hyperfunctionality in the NAc is associated with ethanol sensitization. ► Activation of NAc D2 receptors is important for the expression of ethanol sensitization. ► Individual variations in susceptibility to ethanol sensitization are related to differences in accumbal D2 receptor function.
International Journal of Neuropsychopharmacology, Jan 1, 2010
... system, promoting increased dop-amine concentrations in the NAc (Di Chiara, 1999; Diana et al... more ... system, promoting increased dop-amine concentrations in the NAc (Di Chiara, 1999; Diana et al. ... Inset: Locomotor activity (mean+S.E.M.) for 15 min of naive animals (n=5 ... observation of changes in dopamine D1R function after sensitization to psychostimulants (Capper-Loup et ...
Behavioral sensitization to ethanol is characterized by an increased locomotor activity after rep... more Behavioral sensitization to ethanol is characterized by an increased locomotor activity after repeated exposure. A great variability exists among species and strains in the development of sensitization. There is a growing amount of evidence to indicate that the opioid system is involved in alcoholism; it is possible, therefore, that this system also modulates the sensitization to ethanol. In this study we evaluated the role of the opioid system in determining the variability of the sensitized response to ethanol. Mice received repeated administrations of ethanol (2.2 g/kg) or saline every other day for 10 days. According to their locomotor response on the last day of treatment, ethanol-treated animals were classified into two groups: sensitized or non-sensitized mice. After the treatment, mice were submitted to four challenges 48 h apart. In experiments 1 and 2, mice were challenged, respectively, with i.p. administration of opioid antagonists (naloxone or naltrexone) or an opioid agonist (morphine), followed immediately by 2.2 g/kg ethanol. In experiment 3, animals received morphine by i.c.v., followed by 2.2 g/kg of ethanol (i.p.). Pretreatment with opioid antagonists (naloxone or naltrexone) did not block the expression of ethanol sensitization; however pretreatment with morphine attenuated the increased locomotor activity after ethanol administration in sensitized mice. In experiment 4, after the ethanol or saline treatment, mice brains were processed and brain mu opioid binding was assessed by autoradiography using [3H]D-Ala2,N-mePhe4, Gly-ol5-enkephalin ([3H]DAMGO). No differences were seen between any of the groups of mice, so the agonist effect is not likely to be mediated by differences in binding to mu opioid receptors.
Repeated administration of drugs may induce adaptations which affect the behavioral responses to ... more Repeated administration of drugs may induce adaptations which affect the behavioral responses to the drug itself or to other drugs. Whether individual characteristics to repeated drug administration predict sensitivity to the effects of another drug is not clear. We evaluated whether or not mice that present higher vs. lower locomotor response after repeated treatment with ethanol display increased or decreased locomotor responses when challenged with methamphetamine or morphine, and vice versa. Mice received daily i.p. 2.2 g/kg ethanol (21 days), 1.0 mg/kg methamphetamine or 10 mg/kg morphine (10 days). According to the response presented during repeated drug treatment, mice were classified as HIGH or LOW activity groups. Locomotor activity was monitored after mice were challenged with saline, and 48 h later with a drug. Ethanol-treated mice were challenged with methamphetamine or morphine, methamphetamine- and morphine-treated animals were challenged with ethanol. After repeated treatment with ethanol or methamphetamine, locomotor sensitization was observed only in HIGH mice, not LOW mice. Ethanol-treated mice with HIGH activity showed sensitized, increased locomotor responses to methamphetamine (p < 0.05), but not to morphine. Locomotor responses to ethanol were not affected by a previous history of methamphetamine treatment. Although repeated administration of morphine failed to induce sensitization, morphine-treated mice with HIGH activity presented sensitized locomotor responses after an ethanol challenge. The current experiments confirm important individual differences in response to repeated administration of ethanol, methamphetamine and morphine, which in some cases affected the locomotor response to a second drug challenge, in an asymmetrical pattern.
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Papers by Karina Abrahao