Margarita Moreno

Modulation of high impulsivity and attentional performance in rats by selective direct and indirect dopaminergic and noradrenergic receptor agonists

RationaleImpulsivity is associated with a number of psychiatric disorders, most notably attention deficit/hyperactivity disorder (ADHD). Drugs that augment catecholamine function (e.g. methylphenidate and the selective noradrenaline reuptake inhibitor atomoxetine) have clinical efficacy in ADHD, but their precise mechanism of action is unclear.ObjectiveThe objective of this study is to investigate the relative contribution of dopamine (DA) and noradrenaline (NA) to the therapeutic effects of clinically effective drugs in ADHD using rats selected for high impulsivity on the five-choice serial reaction time task (5CSRTT).MethodsWe examined the effects of direct and indirect DA and NA receptor agonists and selective DA and NA reuptake inhibitors in rats showing high and low levels of impulsivity on the 5CSRTT (designated high impulsive ‘HI’ and low impulsive ‘LI’, respectively). Drugs were administered by systemic injection in a randomized, counterbalanced manner.ResultsLow doses of quinpirole (a D2/D3 agonist) and sumanirole (a D2 agonist) selectively reduced impulsivity on the 5CSRTT, whilst higher doses resulted in increased omissions and slower response latencies. The NA reuptake inhibitor, atomoxetine, and the alpha-2 adrenoreceptor agonist, guanfacine, dose dependently decreased premature responding. The dopaminergic reuptake inhibitor GBR-12909 increased impulsivity, whereas the nonselective DA and NA reuptake inhibitor methylphenidate had no significant effect on impulsive responses in HI and LI rats.ConclusionsThese findings indicate that high impulsivity can be ameliorated in rats by drugs that mimic the effects of DA and NA, just as in ADHD, and that activation of D2/3 receptors selectively decreases high impulsivity on the 5CSRTT.

Impulsivity Characterization in the Roman High- and Low-Avoidance Rat Strains: Behavioral and Neurochemical Differences

The selective breeding of Roman high- (RHA) and low-avoidance (RLA) rats for rapid vs extremely poor acquisition of active avoidance behavior in a shuttle-box has generated two phenotypes with different emotional and motivational profiles. The phenotypic traits of the Roman rat lines/strains (outbred or inbred, respectively) include differences in sensation/novelty seeking, anxiety/fearfulness, stress responsivity, and susceptibility to addictive substances. We designed this study to characterize differences between the inbred RHA-I and RLA-I strains in the impulsivity trait by evaluating different aspects of the multifaceted nature of impulsive behaviors using two different models of impulsivity, the delay-discounting task and five-choice serial reaction time (5-CSRT) task. Previously, rats were evaluated on a schedule-induced polydipsia (SIP) task that has been suggested as a model of obsessive-compulsive disorder. RHA-I rats showed an increased acquisition of the SIP task, higher choice impulsivity in the delay-discounting task, and poor inhibitory control as shown by increased premature responses in the 5-CSRT task. Therefore, RHA-I rats manifested an increased impulsivity phenotype compared with RLA-I rats. Moreover, these differences in impulsivity were associated with basal neurochemical differences in striatum and nucleus accumbens monoamines found between the two strains. These findings characterize the Roman rat strains as a valid model for studying the different aspects of impulsive behavior and for analyzing the mechanisms involved in individual predisposition to impulsivity and its related psychopathologies.

Impulsivity differences in recreational cannabis users and binge drinkers in a university population

BACKGROUND Recreational cannabis use and alcohol binge drinking are the most common drug consumption patterns in young adults. Impulsivity and several psychopathological signs are increased in chronic drug users, but the implications of recreational use are still poorly understood. METHODS We evaluated impulsivity, sensation-seeking traits, impulsive decision-making, inhibitory control and possible symptoms of depression, anxiety and psychosis in three groups of young university adults: recreational cannabis users (N=20), alcohol binge drinkers (N=22) and non-drug users (N=26). RESULTS The cannabis and binge drinking groups had increased scores for impulsivity and sensation-seeking traits. Both groups also exhibited increased impulsive decision-making on the two-choice task and the Iowa gambling task; however, only the cannabis group was significantly different from the non-drug group regarding inhibitory control (go/no-go and stop tasks). The cannabis and binge drinking groups did not show differences in the psychopathological symptoms evaluated. CONCLUSIONS Our observations of this population of non-dependent drug users are consistent with the increased impulsivity traits and behaviors that have been described previously in chronic drug abusers. In this study, compared to no drug use, the recreational use of cannabis was associated with a major dysfunction of the different facets of impulsive behaviors. However, alcohol binge drinking was related only to impulsive decision-making. These results suggest that impulsivity traits and behaviors are present not only in chronic drug abusers but also in recreational drug users. Future work should continue to investigate the long-term effects of these common consumption patterns on various impulsive behaviors and psychopathological symptoms.

Long-term monoamine changes in the striatum and nucleus accumbens after acute chlorpyrifos exposure.

This study examined the time-course effects (2, 7, 14 and 30 days) of acute chlorpyrifos (CPF) intoxication (250 mg/kg, s.c.) on monoamine systems and acetylcholinesterase (AChE) activity in the striatum and nucleus accumbens of adult male rats. We show that CPF produced significant long-term inhibition of AChE activity in the striatum and nucleus accumbens. In the striatum, CPF intoxication resulted in changes in dopamine (DA) metabolism after 2 days and changes in serotonin (5-HT) turnover after 7 and 15 days. Significant decreases in monoamine content including norepinephrine (NE), DA, 5-HT and their metabolites were found in the nucleus accumbens 30 days after CPF intoxication. These results suggest that acute exposure to CPF induces long-term changes in the monoamine systems (NE, DA and 5-HT) in adult animals. The lack of correlation between regional AChE activity and neurochemical outcomes points to independent mechanisms.

Schedule-induced polydipsia as a model of compulsive behavior: neuropharmacological and neuroendocrine bases

BackgroundSchedule-induced polydipsia (SIP), characterized by the development of excessive drinking under intermittent food-reinforcement schedules, has been proposed as a successful model for obsessive–compulsive disorder (OCD), schizophrenia, and alcohol abuse.ObjectivesThe purpose of this study was to review the main findings and current thinking regarding the use of SIP for compulsivity assessment and evaluate its contribution to improving our knowledge of the neurobehavioral mechanisms underlying the excessive behavior manifested in SIP relevant to compulsive behavior disorders.MethodsThe literature reviews SIP procedure and surveys main findings about its neurobehavioral basis and pharmacology relevant to its possible status as a model for compulsive disorders. Specifically, we reviewed effects of antipsychotics and serotoninergic drugs used in the treatment of OCD and schizophrenia. We also considered individual differences in SIP and its relevance as a possible compulsivity endophenotype.ConclusionsSIP represents an animal model of non-regulatory and excessive drinking that may be valid for studying the psychopharmacology of the compulsive phenotype and modeling different psychopathologies from compulsivity spectrum disorders.

5-HT2A and mGlu2 receptor binding levels are related to differences in impulsive behavior in the Roman Low- (RLA) and High- (RHA) avoidance rat strains

The Roman Low- and High-Avoidance rat strains (RLA-I vs RHA-I) have been bidirectionally selected and bred according to their performance in the two-way active avoidance response in the shuttle-box test. Numerous studies have reported a pronounced divergence in emotionality between the two rat strains including differences in novelty seeking, anxiety, stress coping, and susceptibility to addictive substances. However, the underlying molecular mechanisms behind these divergent phenotypes are not known. Here, we determined impulsivity using the 5-choice serial reaction time task and levels of serotonin transporter (SERT), 5-HT(2A) and 5-HT(1A) receptor binding using highly specific radioligands ((3)H-escitalopram, (3)H-MDL100907 and (3)H-WAY100635) and mGlu2/3 receptor binding ((3)H-LY341495) using receptor autoradiography in fronto-cortical sections from RLA-I (n=8) and RHA-I (n=8) male rats. In the more impulsive RHA-I rats, 5-HT(2A), 5-HT(1A) and SERT binding in the frontal cortex was significantly higher compared to RLA-I rats. In contrast, mGlu2/3 receptor binding was decreased by 40% in RHA-I rats compared to RLA-I rats. To differentiate between mGlu2 and mGlu3 receptor protein levels, these were further studied using western blotting, which showed non-detectable levels of mGlu2 receptor protein in RHA rats, while no differences were observed for mGlu3 receptor protein levels. Collectively, these data show general congenital differences in the serotonergic system and a pronounced difference in mGlu2 receptor protein levels. We suggest that the differences in the serotonergic system may mediate some of the phenotypic characteristics in this strain such as hyper-impulsivity and susceptibility to drug addiction.

Individual differences in schedule-induced polydipsia: Neuroanatomical dopamine divergences

Autoradiography analysis of D1 and D2 dopamine receptors and c-Fos activity were performed in brain of rats classified as low drinkers (LD) and high drinkers (HD) according to schedule-induced polydipsia (SIP) performance. Previous studies have shown that groups selected according to their rate of drinking in SIP differ in behavioral response to dopaminergic drugs. This study reports differences between LD and HD rats in dopamine D1 and D2 receptor binding through different mesocorticolimbic brain areas. LD and HD rats showed opposite patterns of binding in dopamine D1 and D2 receptors in the nucleus accumbens, medial prefrontal cortex, amygdala, ventral tegmental area and substantia nigra. Whereas LD rats showed higher binding than HD rats for D1 receptors, HD rats showed higher binding than LD rats for D2 receptors (except in substantia nigra that were roughly similar). These neuroanatomical differences in dopamine receptor binding were also associated with an elevated c-Fos count in the medial prefrontal cortex of HD rats. In tandem with previous evidence, our results suggest a different dopaminergic function between LD and HD, and points to SIP as a behavioral model for distinguishing populations possibly vulnerable to dopaminergic function disorders.

Attentional performance, impulsivity, and related neurotransmitter systems in apoE2, apoE3, and apoE4 female transgenic mice.

RationaleThe apolipoprotein E (apoE) genotype influences cognitive performance in humans depending on age and sex. While the detrimental role of the apoE4 isoform on spatial learning and memory has been well-established in humans and rodents, less is known on its impact on the executive functions.ObjectivesWe aimed to evaluate the effect of apoE isoforms (apoE2, apoE3, apoE4) on visuospatial attention and inhibitory control performance in female transgenic mice, and to determine the neurochemical and neuropharmacological basis of this potential relationship.MethodsFemale mice carrying apoE2, apoE3, and apoE4 were trained in the five-choice serial reaction time task (5-CSRTT). Upon a stable performance, we manipulated the inter-trial interval and the stimulus duration to elicit impulsive responding and engage attention respectively. We further performed a pharmacological challenge by administering cholinergic and GABAergic agents. Finally, we analyzed the levels of brain amino acids and monoamines by using reversed phase high-performance liquid chromatography (HPLC).ResultsApoE4 mice showed a deficient inhibitory control as revealed by increased perseveration and premature responding. When attention was challenged, apoE4 mice also showed a higher drop in accuracy. The adverse effect of scopolamine on the task was attenuated in apoE4 mice compared to apoE2 and apoE3. Furthermore, apoE4 mice showed less dopamine in the frontal cortex than apoE2 mice.ConclusionsWe confirmed that the apoE genotype influences attention and inhibitory control in female transgenic mice. The influence of apoE isoforms in the brain neuromodulatory system may explain the cognitive and behavioral differences attributable to the genotype.

Activation of serotonin 5-HT2A receptors inhibits high compulsive drinking on schedule-induced polydipsia

RationaleSchedule-induced polydipsia (SIP) is an established model for studying compulsive behaviour in rats. Serotoninergic drugs effectively reduce compulsive drinking on SIP, and high compulsive drinker rats selected by SIP have shown differences in serotoninergic brain activity. However, the specific serotoninergic receptors that modulate compulsive SIP remain unclear.ObjectiveWe investigated the functional role of serotonin 5-hydroxytryptamine 2A or C (5-HT2A/C) receptors in compulsive SIP behaviour.MethodsRats were selected for low (LD) versus high drinking (HD) behaviour on SIP. The effects of the systemic administration of the selective serotonin reuptake inhibitor citalopram, selective norepinephrine reuptake inhibitor atomoxetine, serotonin 5-HT2A/C receptor agonist DOI hydrochloride ((±)-2,5-dimethoxy-4-iodoamphetamine), serotonin 5-HT2C receptor antagonist SB242084, serotonin 5-HT2A receptor antagonist ketanserin and M100907 were assessed on SIP. Subsequently, the effects of DOI were tested after the pre-administration of SB242084, ketanserin and M100907 on SIP.ResultsCitalopram and DOI reduced compulsive drinking in HD compared with LD rats on SIP. In contrast, SB242084 increased compulsive drinking in HD compared with LD rats on SIP. Atomoxetine, ketanserin and M100907 had no effect on SIP. The reduction in water intake produced by DOI was blocked by ketanserin and M100907, but not by SB242084 administration, in HD rats.ConclusionsThese findings highlight the contribution of serotoninergic 5-HT2A/C receptors compared with noradrenergic mechanisms on SIP and reveal the “therapeutic” activation of serotonin 5-HT2A in the inhibition of the compulsive drinking behaviour in HD rats. Thus, it may represent a potentially new marker of vulnerability and provides additional insight for potential treatments on compulsive behaviours in neuropsychiatric populations.

Long term compulsivity on the 5-choice serial reaction time task after acute Chlorpyrifos exposure.

Pesticide exposure has been associated with neuropsychological and psychiatric impairments and neurodegenerative disorders. Pesticide exposure commonly causes a deficit in inhibitory control behaviours. In the present study, we investigated whether acute exposure to organophosphate (OP) chlorpyrifos (CPF) is related to long-term lack of inhibitory control; we also examined the possible neurochemical basis of this association. Lister Hooded rats were exposed to an acute dose of CPF (250 mg/kg). Seven months later, we tested inhibitory control with the 5-choice serial reaction time task (5-CSRTT). We manipulated the baseline conditions of this task and also systemically pre-administered d-amphetamine, quinpirole, dizocilpine (MK-801) or ketanserin. We also analysed the post-mortem baseline levels of monoamines and amino acids in different brain regions. On the 5-CSRT task, CPF-exposed rats showed elevated perseverative responses that persisted across manipulation of baseline conditions of the task and under most of the pharmacological challenges tested. Only D-amphetamine induced a dose-dependent amelioration of the increased perseverative responses in the CPF group. The CPF group also exhibited increased levels of dopamine metabolism in the hippocampus and decreased levels of gamma-aminobutyric acid (GABA) and glutamate in the striatum compared to the vehicle group. These findings suggest that CPF induced a long-term compulsivity that was apparent in the 5-CSRT task and associated with changes in monoaminergic and amino acid brain systems of inhibitory control function. Exposure to high doses of OP should be taken into account in studies of environmental causes for neurodegenerative, neuropsychological and neuropsychiatric disorders.