Yolanda Peña-Oliver

Exaggerated waiting impulsivity associated with human binge drinking, and high alcohol consumption in mice

There are well-established links between impulsivity and alcohol use in humans and animal models; however, whether exaggerated impulsivity is a premorbid risk factor or a consequence of alcohol intake remains unclear. In a first approach, human young (18–25 years) social binge and non-binge drinkers were tested for motor impulsivity and attentional abilities in a human version of the Five-Choice Serial Reaction Time Task (Sx-5CSRTT), modeled on the rodent 5CSRTT. Participants completed four variants of the Sx-5CSRT, in addition to being screened for impulsive traits (BIS-11 questionnaire) and impulsive behavior (by means of the Delay Discounting Questionnaire, Two-Choice Impulsivity Paradigm (TCIP), Stop Signal Reaction Time, and Time Estimation Task). Using a second approach, we compared one of these impulsivity measures, 5CSRTT performance, in two inbred strains of mice known to differ in alcohol intake. Compared with non-bingers (NBD; n=22), binge drinkers (BD, n=22) showed robust impairments in attention and premature responding when evaluated under increased attentional load, in addition to presenting deficits in decision making using the TCIP. The best predictors for high binge drinking score were premature responding in the Sx-5CSRTT, trait impulsivity in the BIS-11, and decision making in the TCIP. Alcohol-naïve C57BL/6J (B6) mice (alcohol preferring) were more impulsive in the 5CSRTT than DBA2/J (D2) mice (alcohol averse); the degree of impulsivity correlated with subsequent alcohol consumption. Homologous measures in animal and human studies indicate increased premature responding in young social BD and in the ethanol-preferring B6 strain of mice.

Performance Deficits of NK1 Receptor Knockout Mice in the 5-Choice Serial Reaction-Time Task: Effects of d-Amphetamine, Stress and Time of Day

Background The neurochemical status and hyperactivity of mice lacking functional substance P-preferring NK1 receptors (NK1R-/-) resemble abnormalities in Attention Deficit Hyperactivity Disorder (ADHD). Here we tested whether NK1R-/- mice express other core features of ADHD (impulsivity and inattentiveness) and, if so, whether they are diminished by d-amphetamine, as in ADHD. Prompted by evidence that circadian rhythms are disrupted in ADHD, we also compared the performance of mice that were trained and tested in the morning or afternoon. Methods and Results The 5-Choice Serial Reaction-Time Task (5-CSRTT) was used to evaluate the cognitive performance of NK1R-/- mice and their wildtypes. After training, animals were tested using a long (LITI) and a variable (VITI) inter-trial interval: these tests were carried out with, and without, d-amphetamine pretreatment (0.3 or 1 mg/kg i.p.). NK1R-/- mice expressed greater omissions (inattentiveness), perseveration and premature responses (impulsivity) in the 5-CSRTT. In NK1R-/- mice, perseveration in the LITI was increased by injection-stress but reduced by d-amphetamine. Omissions by NK1R-/- mice in the VITI were unaffected by d-amphetamine, but premature responses were exacerbated by this psychostimulant. Omissions in the VITI were higher, overall, in the morning than the afternoon but, in the LITI, premature responses of NK1R-/- mice were higher in the afternoon than the morning. Conclusion In addition to locomotor hyperactivity, NK1R-/- mice express inattentiveness, perseveration and impulsivity in the 5-CSRTT, thereby matching core criteria for a model of ADHD. Because d-amphetamine reduced perseveration in NK1R-/- mice, this action does not require functional NK1R. However, the lack of any improvement of omissions and premature responses in NK1R-/- mice given d-amphetamine suggests that beneficial effects of this psychostimulant in other rodent models, and ADHD patients, need functional NK1R. Finally, our results reveal experimental variables (stimulus parameters, stress and time of day) that could influence translational studies.

Measuring impulsivity in mice: the five-choice serial reaction time task

RationaleMice are useful tools for dissecting genetic and environmental factors in relation to the study of attention and impulsivity. The five-choice serial reaction time task (5CSRTT) paradigm has been well established in rats, but its transferability to mice is less well documented.ObjectivesThis study aims to summarise the main results of the 5CSRTT in mice, with special focus on impulsivity.MethodsThe 5CSRTT can be used to explore aspects of both attentional and inhibitory control mechanisms.ResultsDifferent manipulations of the task parameters can lead to different results; adjusting the protocol as a function of the main variable of interest or the standardisation of the protocol to be applied to a large set of strains will be desirable.ConclusionsThe 5CSRTT has proven to be a useful tool to investigate impulsivity in mice.

Deletion of alpha-synuclein decreases impulsivity in mice

The presynaptic protein alpha‐synuclein, associated with Parkinsons Disease (PD), plays a role in dopaminergic neurotransmission and is implicated in impulse control disorders (ICDs) such as drug addiction. In this study we investigated a potential causal relationship between alpha‐synuclein and impulsivity, by evaluating differences in motor impulsivity in the 5‐choice serial reaction time task (5‐CSRTT) in strains of mice that differ in the expression of the alpha‐synuclein gene. C57BL/6JOlaHsd mice differ from their C57BL/6J ancestors in possessing a chromosomal deletion resulting in the loss of two genes, snca, encoding alpha‐synuclein, and mmrn1, encoding multimerin‐1. C57BL/6J mice displayed higher impulsivity (more premature responding) than C57BL/6JOlaHsd mice when the pre‐stimulus waiting interval was increased in the 5‐CSRTT. In order to ensure that the reduced impulsivity was indeed related to snca, and not adjacent gene deletion, wild type (WT) and mice with targeted deletion of alpha‐synuclein (KO) were tested in the 5‐CSRTT. Similarly, WT mice were more impulsive than mice with targeted deletion of alpha‐synuclein. Interrogation of our ongoing analysis of impulsivity in BXD recombinant inbred mouse lines revealed an association of impulsive responding with levels of alpha‐synuclein expression in hippocampus. Expression of beta‐ and gamma‐synuclein, members of the synuclein family that may substitute for alpha‐synuclein following its deletion, revealed no differential compensations among the mouse strains. These findings suggest that alpha‐synuclein may contribute to impulsivity and potentially, to ICDs which arise in some PD patients treated with dopaminergic medication.

Lack of involvement of alpha-synuclein in unconditioned anxiety in mice

Alpha-synuclein is implicated in the pathology of Parkinson disease (PD) and is involved in synaptic function, particularly in presynaptic events in dopamine (DA) synapses. Recently, a role for alpha-synuclein in reward and addiction, especially in alcoholism, has been reported. Since PD and alcohol dependence present a strong comorbidity with anxiety disorders, a role for alpha-synuclein in anxiety has been proposed. The aim of the present investigation was to study the involvement of alpha-synuclein in anxiety by testing alpha-synuclein knock out and wild type mice in three different emotionality tests: the open field, the elevated plus maze and the light-dark box. Alpha-synuclein knock out mice and wild type controls displayed consistently similar emotionality profiles in all the tests, suggesting a lack of involvement of alpha-synuclein in unconditioned anxiety in mice.

Alpha-synuclein deletion decreases motor impulsivity but does not affect risky decision making in a mouse Gambling Task

RationaleThere is evidence to support the role of alpha-synuclein in motor impulsivity, but the extrapolation of this finding to other types of impulsivity remains to be elucidated.ObjectiveThis study aims to investigate the role of alpha-synuclein in choice impulsivity/risky decision-making by means of a mouse version of the Iowa Gambling Task (mIGT).MethodsTwo strains of mice that differ in the expression of the alpha-synuclein gene, the C57BL/6JOlaHsd (HA) and C57BL/6J (CR), were tested in the mIGT. HA mice differ from their CR ancestors in possessing a chromosomal deletion resulting in the loss of two genes: snca, encoding alpha-synuclein and mmrn1, encoding multimerin-1. Mice were trained in the mIGT until a stable pattern of responding was achieved and then the acute effects of ethanol and cocaine in choice preference were investigated.ResultsNo differences between the strains were evident in risky decision-making in any of the experiments, but HA mice showed consistently reduced levels of premature responding in comparison with CR mice, confirming the reduced motor impulsivity found in a previous study. Ethanol did not modify the percentage of advantageous choices in either strain, while cocaine increased the risky choice behaviour by increasing the percentage of disadvantageous choices in both strains.ConclusionsWe provide further evidence for the involvement of alpha-synuclein in motor impulsivity and suggest that alpha-synuclein does not play a role in risky decision-making as evaluated in the mIGT.

Alcohol-Preferring Rats Show Goal Oriented Behaviour to Food Incentives but Are Neither Sign-Trackers Nor Impulsive

Drug addiction is often associated with impulsivity and altered behavioural responses to both primary and conditioned rewards. Here we investigated whether selectively bred alcohol-preferring (P) and alcohol-nonpreferring (NP) rats show differential levels of impulsivity and conditioned behavioural responses to food incentives. P and NP rats were assessed for impulsivity in the 5-choice serial reaction time task (5-CSRTT), a widely used translational task in humans and other animals, as well as Pavlovian conditioned approach to measure sign- and goal-tracking behaviour. Drug-naïve P and NP rats showed similar levels of impulsivity on the 5-CSRTT, assessed by the number of premature, anticipatory responses, even when the waiting interval to respond was increased. However, unlike NP rats, P rats were faster to enter the food magazine and spent more time in this area. In addition, P rats showed higher levels of goal-tracking responses than NP rats, as measured by the number of magazine nose-pokes during the presentation of a food conditioned stimulus. By contrast, NP showed higher levels of sign-tracking behaviour than P rats. Following a 4-week exposure to intermittent alcohol we confirmed that P rats had a marked preference for, and consumed more alcohol than, NP rats, but were not more impulsive when re-tested in the 5-CSRTT. These findings indicate that high alcohol preferring and drinking P rats are neither intrinsically impulsive nor do they exhibit impulsivity after exposure to alcohol. However, P rats do show increased goal-directed behaviour to food incentives and this may be associated with their strong preference for alcohol.

Mouse and Human Genetic Analyses Associate Kalirin with Ventral Striatal Activation during Impulsivity and with Alcohol Misuse

Impulsivity is associated with a spectrum of psychiatric disorders including drug addiction. To investigate genetic associations with impulsivity and initiation of drug taking, we took a two-step approach. First, we identified genes whose expression level in prefrontal cortex, striatum and accumbens were associated with impulsive behavior in the 5-choice serial reaction time task across 10 BXD recombinant inbred (BXD RI) mouse strains and their progenitor C57BL/6J and DBA2/J strains. Behavioral data were correlated with regional gene expression using GeneNetwork (www.genenetwork.org), to identify 44 genes whose probability of association with impulsivity exceeded a false discovery rate of < 0.05. We then interrogated the IMAGEN database of 1423 adolescents for potential associations of SNPs in human homologs of those genes identified in the mouse study, with brain activation during impulsive performance in the Monetary Incentive Delay task, and with novelty seeking scores from the Temperament and Character Inventory, as well as alcohol experience. There was a significant overall association between the human homologs of impulsivity-related genes and percentage of premature responses in the MID task and with fMRI BOLD-response in ventral striatum (VS) during reward anticipation. In contrast, no significant association was found between the polygenic scores and anterior cingulate cortex activation. Univariate association analyses revealed that the G allele (major) of the intronic SNP rs6438839 in the KALRN gene was significantly associated with increased VS activation. Additionally, the A-allele (minor) of KALRN intronic SNP rs4634050, belonging to the same haplotype block, was associated with increased frequency of binge drinking.

The influence of test experience and NK1 receptor antagonists on the performance of NK1R-/- and wild type mice in the 5-Choice Serial Reaction-Time Task

Genetically-altered mice, lacking functional NK1 receptors (NK1R-/-), express abnormal behaviours that are prominent in Attention Deficit Hyperactivity Disorder: namely, inattentiveness and impulsivity (indicated by their greater % omissions and premature responses in the 5-Choice Serial Reaction-Time Task (5-CSRTT) and locomotor hyperactivity. We investigated how behaviour in the 5-CSRTT is affected by repeated testing and whether the abnormalities expressed by NK1R-/- mice are mimicked by treating wild type mice with a NK1R antagonist (L 733060 or RP 67580; 5 or 10 mg/kg). Repeated testing with a variable (VITI) or fixed, prolonged (LITI) intertrial interval reduced % omissions. Premature responses also declined, but only in NK1R-/- mice, in the VITI test. By contrast, perseveration increased in both genotypes. RP 67580 (10 mg/kg) increased the % omissions in both genotypes in the VITI, an action which cannot be attributed to NK1R antagonism. Neither drug affected perseveration. However, for premature responses, the response profile suggested that the low and high doses of RP 67580 (VITI) and L 733060 (LITI) had opposing effects on this behaviour. We infer that the effect of NK1R antagonists in the 5-CSRTT is confounded by animals’ test experience and non-specific drug effects at sites other than NK1R, possibly L-type Ca2+v channels.