Alcoholism: Clinical and Experimental Research, 2009
GABAergic neurons play an essential role in pathways signaling both reward, and anxiety. In keepi... more GABAergic neurons play an essential role in pathways signaling both reward, and anxiety. In keeping, human genetic studies have revealed associations between haplotypes of genes encoding individual subunits of GABAA receptors and addictions, especially to alcohol, but also other drugs of abuse. One example is the GABRA2 gene encoding a2 subunits. GABAA receptors expressing a2 subunits are highly expressed in nucleus accumbens, making them potentially important in signaling reward. We have studied the consequences of manipulating the gene encoding a2, on accumbens signalling, and on consumption and self-administration of ethanol. Mice with a2 gene deletion showed a 33% reduction in the amplitude of synaptic GABAA receptor-mediated responses in accumbens medium spiny neurons. In mice with a H101R point mutation in the benzodiazepine binding pocket of a2-containing GABAA receptors, activation of the mutated receptors was facilitated by the atypical benzodiazepine, Ro 15-4513, that in wildtype neurons acted usually to inhibit GABA-induced currents. Consistent with a role for accumbens a2-containing receptors in mediating incentive behaviour, systemic administration of Ro 15- 4513 induced behavioural sensitization in the a2H101R mutant, but not wildtype mice. Nevertheless, a2-/- mice did not differ from wildtype mice in operant self-administration of ethanol/sucrose reinforcers, suggesting a2-containing GABAA receptors are not essential for ethanol reward. Human genetic studies suggest that variations the a2 gene may instead contribute to increased risk of alcoholism by mediating anxiety or stress responses. Consistent with that idea, yohimbine increased selfadministration of ethanol/sucrose mixtures more in a2-/- mice than in wildtype mice. The GABRA2 gene is located on human chromosome 4, close to other GABAA genes encoding a4, b1 and c1 subunits, syntenic with a homologous region on mouse chromosome 5. Human b1 haplotypes have also recently been associated with alcoholism. Heterozygous mice bearing a point mutation of b1subunits, b1L285R that abolishes the ability of mutated receptors to respond to GABA, showed both increased consumption of ethanol in a 2-choice test, and increased instrumental responding for ethanol/sucrose mixtures, despite lower responding for sucrose alone. These observations suggest that GABAA receptors expressing b1, but not those expressing a2 may mediate the incentive properties of ethanol.
Mice were tested in a simple automated Y-maze. Total number of arm entries and alternation behavi... more Mice were tested in a simple automated Y-maze. Total number of arm entries and alternation behaviour were measured. The latter is thought to reflect working memory capacity at a rudimentary level. During an 8 min session, vehicle-treated mice performed 32.4 +/- 7.4 arm entries, 51.0 +/- 12.4% of which were organized in alternations (triplets). The two variables showed a negative correlation. Scopolamine (1.0 mg/kg) significantly enhanced activity, reduced alternation behaviour and diminished the correlation between the two variables. The effects of benzodiazepine receptor inverse agonist, antagonist and agonist beta-carbolines on this spontaneous behaviour and on the effects of scopolamine were examined. The effects of inverse agonists and agonists on locomotor activity were complex in interaction with both vehicle and scopolamine. The scopolamine-induced reduction of alternation behaviour was significantly reversed by the antagonist ZK 93426 but not by inverse agonists; furthermore, partial agonists and agonists showed no effects. It is hypothesized that the interaction of antagonist beta-carbolines with scopolamine is based on a direct GABA-ergic control of cholinergic neurotransmission, and suggests an ability of antagonist beta-carbolines to antagonize amnestic properties of scopolamine.
Deletions of gria1 or gria2 genes encoding alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic-ac... more Deletions of gria1 or gria2 genes encoding alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic-acid-receptor subunits differ in their effects on appetitive conditioning. The authors investigated whether similar differences would occur in an aversive conditioning test. The ability of a discrete stimulus paired with footshock to subsequently inhibit food-maintained operant responding (conditioned emotional response) was examined in mice with deletions of gria1 or gria2 genes. Whereas gria1 knockout (KO) mice performed normally compared with wild-type (WT) controls, gria2 KO mice displayed no reduction in response rates when the shock-paired stimulus was presented. Nevertheless, gria2 KOs displayed evidence of freezing in a footshock-paired context, indicating that aversive learning could occur. In addition, gria1 KO mice showed some evidence of increased anxiety, and gria2 KOs showed reduced anxiety, in the elevated plus-maze.
Benzodiazepines increase food intake, an effect attributed to their ability to enhance palatabili... more Benzodiazepines increase food intake, an effect attributed to their ability to enhance palatability. We investigated which GABA(A) receptor subtypes may be involved in mediating benzodiazepine-induced hyperphagia. The role of the alpha2 subtype was investigated by observing the effects of midazolam, on the behavioural satiety sequence in mice with targeted deletion of the alpha2 gene (alpha2 knockout). Midazolam (0.125, 0.25 and 0.5mg/kg) increased food intake and the amount of time spent feeding in alpha2 knockout mice, suggesting that BZ-induced hyperphagia does not involve alpha2-containing GABA(A) receptors. We further investigated the roles of alpha1- and alpha3-containing GABA(A) receptors in mediating BZ-induced hyperphagia. We treated alpha2(H101R) mice, in which alpha2-containing receptors are rendered benzodiazepine insensitive, with L-838417, a compound which acts as a partial agonist at alpha2-, alpha3- and alpha5-receptors but is inactive at alpha1-containing receptors. L-838417 (10 and 30 mg/kg) increased food intake and the time spent feeding in both wildtype and alpha2(H101R) mice, demonstrating that benzodiazepine-induced hyperphagia does not require alpha1- and alpha2-containing GABA(A) receptors. These observations, together with evidence against the involvement of alpha5-containing GABA(A) receptors, suggest that alpha3-containing receptors mediate BZ-induced hyperphagia in the mouse.
Within the nucleus accumbens (NAc), synaptic GABAAreceptors (GABAARs) mediate phasic inhibition o... more Within the nucleus accumbens (NAc), synaptic GABAAreceptors (GABAARs) mediate phasic inhibition of medium spiny neurons (MSNs) and influence behavioral responses to cocaine. We demonstrate that both dopamine D1- and D2-receptor-expressing MSNs (D-MSNs) additionally harbor extrasynaptic GABAARs incorporating α4, β, and δ subunits that mediate tonic inhibition, thereby influencing neuronal excitability. Both the selective δ-GABAAR agonist THIP and DS2, a selective positive allosteric modulator, greatly increased the tonic current of all MSNs from wild-type (WT), but not from δ−/−or α4−/−mice. Coupling dopamine and tonic inhibition, the acute activation of D1 receptors (by a selective agonist or indirectly by amphetamine) greatly enhanced tonic inhibition in D1-MSNs but not D2-MSNs. In contrast, prolonged D2 receptor activation modestly reduced the tonic conductance of D2-MSNs. Behaviorally, WT and constitutive α4−/−mice did not differ in their expression of cocaine-conditioned place p...
During rest, brain activity is synchronized between different regions widely distributed througho... more During rest, brain activity is synchronized between different regions widely distributed throughout the brain, forming functional networks. However, the molecular mechanisms supporting functional connectivity remain undefined. We show that functional brain networks defined with resting-state functional magnetic resonance imaging can be recapitulated by using measures of correlated gene expression in a post mortem brain tissue data set. The set of 136 genes we identify is significantly enriched for ion channels. Polymorphisms in this set of genes significantly affect resting-state functional connectivity in a large sample of healthy adolescents. Expression levels of these genes are also significantly associated with axonal connectivity in the mouse. The results provide convergent, multimodal evidence that resting-state functional networks correlate with the orchestrated activity of dozens of genes linked to ion channel activity and synaptic function.
Recent evidence has implicated the opioid system in exaggerated ethanol consumption and impulsivi... more Recent evidence has implicated the opioid system in exaggerated ethanol consumption and impulsivity deficits. The opioid receptor antagonist naltrexone (NTX) has proven efficient in reducing alcohol consumption; however, its role on impulsive behaviour is not fully characterised. The aim of this study was to investigate the effects of NTX on two measures of impulsive behaviour in two inbred mouse strains that differ in ethanol preference and impulsive phenotype. Two separate groups of C57BL/6J (B6, n = 24) and DBA2/J (D2, n = 24) male mice were exposed to intermittent ethanol (IEE; 2 g/kg) during early (PND 30-45, IEE_Early) or late (PND 45-60, IEE_Late) adolescence or the respective saline control. The ability of NTX (10 mg/kg) alone, or co-administered with ethanol (0.5 g/kg), to diminish waiting impulsivity in the five-choice serial reaction time task (5-CSRTT), or improve decision-making in a mouse version of the Iowa Gambling Task (mIGT), was examined in adulthood. In the 5-CSRTT, NTX diminished impulsivity in both strains of mice, irrespective of previous ethanol experience. In the mIGT, NTX failed to alter risky decision-making but decreased perseverative responding. Blocking the actions of endogenous opioids may attenuate waiting impulsivity, in addition to alleviating perseverative responding. In a broader context, μ-opiate antagonism may be of potential interest for impulse-control disorders.
Gender differences in the discriminative stimulus properties of drugs of abuse have sometimes bee... more Gender differences in the discriminative stimulus properties of drugs of abuse have sometimes been reported, although we have previously found no differences in subjective or discriminative responses in human subjects acquiring an alcohol discrimination. The aim of the present work was to determine if there were gender differences in the effects of lorazepam, a benzodiazepine-receptor agonist which substituted for the alcohol stimulus in trained social drinkers. Volunteers who had already acquired an alcohol (0.2g/kg) placebo discrimination were administered (double-blind) either placebo (nine females, nine males) or lorazepam 2mg (six females, six males). They then sampled a series of five drinks and rated each one for likeness to the training stimulus (the generalization response). In addition they completed rating scales for subjective effects and the Digit Symbol Substitution Test (DSST). Lorazepam substituted for the alcohol stimulus equally in both sexes and increased associat...
Reward is a concept fundamental to discussions of drug abuse and addiction. The idea that altered... more Reward is a concept fundamental to discussions of drug abuse and addiction. The idea that altered sensitivity to either drug-reward, or to rewards in general, contributes to, or results from, drug-taking is a common theme in several theories of addiction. However, the concept of reward is problematic in that it is used to refer to apparently different behavioural phenomena, and even to diverse neurobiological processes (reward pathways). Whether these different phenomena are different behavioural expressions of a common underlying process is not established, and much research suggests that there may be only loose relationships among different aspects of reward. Measures of rewarding effects of drugs in humans often depend upon subjective reports. In animal studies, such insights are not available, and behavioural measures must be relied upon to infer rewarding effects of drugs or other events. In such animal studies, but also in many human methods established to objectify measures of reward, many other factors contribute to the behaviour being studied. For that reason, studying the biological (including genetic) bases of performance of tasks that ostensibly measure reward cannot provide unequivocal answers. The current overview outlines the strengths and weaknesses of current approaches that hinder the conciliation of cross-species studies of the genetics of reward sensitivity and the dysregulation of reward processes by drugs of abuse. Some suggestions are made as to how human and animal studies may be made to address more closely homologous behaviours, even if those processes are only partly able to isolate 'reward' from other factors contributing to behavioural output.
Proceedings of the National Academy of Sciences of the United States of America, Jan 21, 2016
Dysfunctional reward processing is implicated in various mental disorders, including attention de... more Dysfunctional reward processing is implicated in various mental disorders, including attention deficit hyperactivity disorder (ADHD) and addictions. Such impairments might involve different components of the reward process, including brain activity during reward anticipation. We examined brain nodes engaged by reward anticipation in 1,544 adolescents and identified a network containing a core striatal node and cortical nodes facilitating outcome prediction and response preparation. Distinct nodes and functional connections were preferentially associated with either adolescent hyperactivity or alcohol consumption, thus conveying specificity of reward processing to clinically relevant behavior. We observed associations between the striatal node, hyperactivity, and thevacuolar protein sorting-associated protein 4A(VPS4A) gene in humans, and the causal role ofVps4for hyperactivity was validated inDrosophila Our data provide a neurobehavioral model explaining the heterogeneity of reward-...
Over the last decade there have been further developments in our knowledge of the risks and benef... more Over the last decade there have been further developments in our knowledge of the risks and benefits of benzodiazepines, and of the risks and benefits of alternatives to benzodiazepines. Representatives drawn from the Psychopharmacology Special Interest Group of the Royal College of Psychiatrists and the British Association for Psychopharmacology together examined these developments, and have provided this joint statement with recommendations for clinical practice. The working group was mindful of widespread concerns about benzodiazepines and related anxiolytic and hypnotic drugs. The group believes that whenever benzodiazepines are prescribed, the potential for dependence or other harmful effects must be considered. However, the group also believes that the risks of dependence associated with long-term use should be balanced against the benefits that in many cases follow from the short or intermittent use of benzodiazepines and the risk of the underlying conditions for which treatm...
Alcoholism: Clinical and Experimental Research, 2009
GABAergic neurons play an essential role in pathways signaling both reward, and anxiety. In keepi... more GABAergic neurons play an essential role in pathways signaling both reward, and anxiety. In keeping, human genetic studies have revealed associations between haplotypes of genes encoding individual subunits of GABAA receptors and addictions, especially to alcohol, but also other drugs of abuse. One example is the GABRA2 gene encoding a2 subunits. GABAA receptors expressing a2 subunits are highly expressed in nucleus accumbens, making them potentially important in signaling reward. We have studied the consequences of manipulating the gene encoding a2, on accumbens signalling, and on consumption and self-administration of ethanol. Mice with a2 gene deletion showed a 33% reduction in the amplitude of synaptic GABAA receptor-mediated responses in accumbens medium spiny neurons. In mice with a H101R point mutation in the benzodiazepine binding pocket of a2-containing GABAA receptors, activation of the mutated receptors was facilitated by the atypical benzodiazepine, Ro 15-4513, that in wildtype neurons acted usually to inhibit GABA-induced currents. Consistent with a role for accumbens a2-containing receptors in mediating incentive behaviour, systemic administration of Ro 15- 4513 induced behavioural sensitization in the a2H101R mutant, but not wildtype mice. Nevertheless, a2-/- mice did not differ from wildtype mice in operant self-administration of ethanol/sucrose reinforcers, suggesting a2-containing GABAA receptors are not essential for ethanol reward. Human genetic studies suggest that variations the a2 gene may instead contribute to increased risk of alcoholism by mediating anxiety or stress responses. Consistent with that idea, yohimbine increased selfadministration of ethanol/sucrose mixtures more in a2-/- mice than in wildtype mice. The GABRA2 gene is located on human chromosome 4, close to other GABAA genes encoding a4, b1 and c1 subunits, syntenic with a homologous region on mouse chromosome 5. Human b1 haplotypes have also recently been associated with alcoholism. Heterozygous mice bearing a point mutation of b1subunits, b1L285R that abolishes the ability of mutated receptors to respond to GABA, showed both increased consumption of ethanol in a 2-choice test, and increased instrumental responding for ethanol/sucrose mixtures, despite lower responding for sucrose alone. These observations suggest that GABAA receptors expressing b1, but not those expressing a2 may mediate the incentive properties of ethanol.
Mice were tested in a simple automated Y-maze. Total number of arm entries and alternation behavi... more Mice were tested in a simple automated Y-maze. Total number of arm entries and alternation behaviour were measured. The latter is thought to reflect working memory capacity at a rudimentary level. During an 8 min session, vehicle-treated mice performed 32.4 +/- 7.4 arm entries, 51.0 +/- 12.4% of which were organized in alternations (triplets). The two variables showed a negative correlation. Scopolamine (1.0 mg/kg) significantly enhanced activity, reduced alternation behaviour and diminished the correlation between the two variables. The effects of benzodiazepine receptor inverse agonist, antagonist and agonist beta-carbolines on this spontaneous behaviour and on the effects of scopolamine were examined. The effects of inverse agonists and agonists on locomotor activity were complex in interaction with both vehicle and scopolamine. The scopolamine-induced reduction of alternation behaviour was significantly reversed by the antagonist ZK 93426 but not by inverse agonists; furthermore, partial agonists and agonists showed no effects. It is hypothesized that the interaction of antagonist beta-carbolines with scopolamine is based on a direct GABA-ergic control of cholinergic neurotransmission, and suggests an ability of antagonist beta-carbolines to antagonize amnestic properties of scopolamine.
Deletions of gria1 or gria2 genes encoding alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic-ac... more Deletions of gria1 or gria2 genes encoding alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic-acid-receptor subunits differ in their effects on appetitive conditioning. The authors investigated whether similar differences would occur in an aversive conditioning test. The ability of a discrete stimulus paired with footshock to subsequently inhibit food-maintained operant responding (conditioned emotional response) was examined in mice with deletions of gria1 or gria2 genes. Whereas gria1 knockout (KO) mice performed normally compared with wild-type (WT) controls, gria2 KO mice displayed no reduction in response rates when the shock-paired stimulus was presented. Nevertheless, gria2 KOs displayed evidence of freezing in a footshock-paired context, indicating that aversive learning could occur. In addition, gria1 KO mice showed some evidence of increased anxiety, and gria2 KOs showed reduced anxiety, in the elevated plus-maze.
Benzodiazepines increase food intake, an effect attributed to their ability to enhance palatabili... more Benzodiazepines increase food intake, an effect attributed to their ability to enhance palatability. We investigated which GABA(A) receptor subtypes may be involved in mediating benzodiazepine-induced hyperphagia. The role of the alpha2 subtype was investigated by observing the effects of midazolam, on the behavioural satiety sequence in mice with targeted deletion of the alpha2 gene (alpha2 knockout). Midazolam (0.125, 0.25 and 0.5mg/kg) increased food intake and the amount of time spent feeding in alpha2 knockout mice, suggesting that BZ-induced hyperphagia does not involve alpha2-containing GABA(A) receptors. We further investigated the roles of alpha1- and alpha3-containing GABA(A) receptors in mediating BZ-induced hyperphagia. We treated alpha2(H101R) mice, in which alpha2-containing receptors are rendered benzodiazepine insensitive, with L-838417, a compound which acts as a partial agonist at alpha2-, alpha3- and alpha5-receptors but is inactive at alpha1-containing receptors. L-838417 (10 and 30 mg/kg) increased food intake and the time spent feeding in both wildtype and alpha2(H101R) mice, demonstrating that benzodiazepine-induced hyperphagia does not require alpha1- and alpha2-containing GABA(A) receptors. These observations, together with evidence against the involvement of alpha5-containing GABA(A) receptors, suggest that alpha3-containing receptors mediate BZ-induced hyperphagia in the mouse.
Within the nucleus accumbens (NAc), synaptic GABAAreceptors (GABAARs) mediate phasic inhibition o... more Within the nucleus accumbens (NAc), synaptic GABAAreceptors (GABAARs) mediate phasic inhibition of medium spiny neurons (MSNs) and influence behavioral responses to cocaine. We demonstrate that both dopamine D1- and D2-receptor-expressing MSNs (D-MSNs) additionally harbor extrasynaptic GABAARs incorporating α4, β, and δ subunits that mediate tonic inhibition, thereby influencing neuronal excitability. Both the selective δ-GABAAR agonist THIP and DS2, a selective positive allosteric modulator, greatly increased the tonic current of all MSNs from wild-type (WT), but not from δ−/−or α4−/−mice. Coupling dopamine and tonic inhibition, the acute activation of D1 receptors (by a selective agonist or indirectly by amphetamine) greatly enhanced tonic inhibition in D1-MSNs but not D2-MSNs. In contrast, prolonged D2 receptor activation modestly reduced the tonic conductance of D2-MSNs. Behaviorally, WT and constitutive α4−/−mice did not differ in their expression of cocaine-conditioned place p...
During rest, brain activity is synchronized between different regions widely distributed througho... more During rest, brain activity is synchronized between different regions widely distributed throughout the brain, forming functional networks. However, the molecular mechanisms supporting functional connectivity remain undefined. We show that functional brain networks defined with resting-state functional magnetic resonance imaging can be recapitulated by using measures of correlated gene expression in a post mortem brain tissue data set. The set of 136 genes we identify is significantly enriched for ion channels. Polymorphisms in this set of genes significantly affect resting-state functional connectivity in a large sample of healthy adolescents. Expression levels of these genes are also significantly associated with axonal connectivity in the mouse. The results provide convergent, multimodal evidence that resting-state functional networks correlate with the orchestrated activity of dozens of genes linked to ion channel activity and synaptic function.
Recent evidence has implicated the opioid system in exaggerated ethanol consumption and impulsivi... more Recent evidence has implicated the opioid system in exaggerated ethanol consumption and impulsivity deficits. The opioid receptor antagonist naltrexone (NTX) has proven efficient in reducing alcohol consumption; however, its role on impulsive behaviour is not fully characterised. The aim of this study was to investigate the effects of NTX on two measures of impulsive behaviour in two inbred mouse strains that differ in ethanol preference and impulsive phenotype. Two separate groups of C57BL/6J (B6, n = 24) and DBA2/J (D2, n = 24) male mice were exposed to intermittent ethanol (IEE; 2 g/kg) during early (PND 30-45, IEE_Early) or late (PND 45-60, IEE_Late) adolescence or the respective saline control. The ability of NTX (10 mg/kg) alone, or co-administered with ethanol (0.5 g/kg), to diminish waiting impulsivity in the five-choice serial reaction time task (5-CSRTT), or improve decision-making in a mouse version of the Iowa Gambling Task (mIGT), was examined in adulthood. In the 5-CSRTT, NTX diminished impulsivity in both strains of mice, irrespective of previous ethanol experience. In the mIGT, NTX failed to alter risky decision-making but decreased perseverative responding. Blocking the actions of endogenous opioids may attenuate waiting impulsivity, in addition to alleviating perseverative responding. In a broader context, μ-opiate antagonism may be of potential interest for impulse-control disorders.
Gender differences in the discriminative stimulus properties of drugs of abuse have sometimes bee... more Gender differences in the discriminative stimulus properties of drugs of abuse have sometimes been reported, although we have previously found no differences in subjective or discriminative responses in human subjects acquiring an alcohol discrimination. The aim of the present work was to determine if there were gender differences in the effects of lorazepam, a benzodiazepine-receptor agonist which substituted for the alcohol stimulus in trained social drinkers. Volunteers who had already acquired an alcohol (0.2g/kg) placebo discrimination were administered (double-blind) either placebo (nine females, nine males) or lorazepam 2mg (six females, six males). They then sampled a series of five drinks and rated each one for likeness to the training stimulus (the generalization response). In addition they completed rating scales for subjective effects and the Digit Symbol Substitution Test (DSST). Lorazepam substituted for the alcohol stimulus equally in both sexes and increased associat...
Reward is a concept fundamental to discussions of drug abuse and addiction. The idea that altered... more Reward is a concept fundamental to discussions of drug abuse and addiction. The idea that altered sensitivity to either drug-reward, or to rewards in general, contributes to, or results from, drug-taking is a common theme in several theories of addiction. However, the concept of reward is problematic in that it is used to refer to apparently different behavioural phenomena, and even to diverse neurobiological processes (reward pathways). Whether these different phenomena are different behavioural expressions of a common underlying process is not established, and much research suggests that there may be only loose relationships among different aspects of reward. Measures of rewarding effects of drugs in humans often depend upon subjective reports. In animal studies, such insights are not available, and behavioural measures must be relied upon to infer rewarding effects of drugs or other events. In such animal studies, but also in many human methods established to objectify measures of reward, many other factors contribute to the behaviour being studied. For that reason, studying the biological (including genetic) bases of performance of tasks that ostensibly measure reward cannot provide unequivocal answers. The current overview outlines the strengths and weaknesses of current approaches that hinder the conciliation of cross-species studies of the genetics of reward sensitivity and the dysregulation of reward processes by drugs of abuse. Some suggestions are made as to how human and animal studies may be made to address more closely homologous behaviours, even if those processes are only partly able to isolate 'reward' from other factors contributing to behavioural output.
Proceedings of the National Academy of Sciences of the United States of America, Jan 21, 2016
Dysfunctional reward processing is implicated in various mental disorders, including attention de... more Dysfunctional reward processing is implicated in various mental disorders, including attention deficit hyperactivity disorder (ADHD) and addictions. Such impairments might involve different components of the reward process, including brain activity during reward anticipation. We examined brain nodes engaged by reward anticipation in 1,544 adolescents and identified a network containing a core striatal node and cortical nodes facilitating outcome prediction and response preparation. Distinct nodes and functional connections were preferentially associated with either adolescent hyperactivity or alcohol consumption, thus conveying specificity of reward processing to clinically relevant behavior. We observed associations between the striatal node, hyperactivity, and thevacuolar protein sorting-associated protein 4A(VPS4A) gene in humans, and the causal role ofVps4for hyperactivity was validated inDrosophila Our data provide a neurobehavioral model explaining the heterogeneity of reward-...
Over the last decade there have been further developments in our knowledge of the risks and benef... more Over the last decade there have been further developments in our knowledge of the risks and benefits of benzodiazepines, and of the risks and benefits of alternatives to benzodiazepines. Representatives drawn from the Psychopharmacology Special Interest Group of the Royal College of Psychiatrists and the British Association for Psychopharmacology together examined these developments, and have provided this joint statement with recommendations for clinical practice. The working group was mindful of widespread concerns about benzodiazepines and related anxiolytic and hypnotic drugs. The group believes that whenever benzodiazepines are prescribed, the potential for dependence or other harmful effects must be considered. However, the group also believes that the risks of dependence associated with long-term use should be balanced against the benefits that in many cases follow from the short or intermittent use of benzodiazepines and the risk of the underlying conditions for which treatm...
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