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

RATIONALE: Impulsivity 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. OBJECTIVE: The 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). METHODS: We 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. RESULTS: Low 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. CONCLUSIONS: These 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

Electrode placements and behavioural data.

<p>A) Representative histology of silicon probe placement in the medial prefrontal cortex and nucleus accumbens. B) Reconstructed placements of all electrode contacts in prelimbic and infralimbic prefrontal cortex and nucleus accumbens core and shell. C) Scheme of 5-Choice Serial Reaction Time Task (5-CSRTT). Trials start with a nose-poke in the food magazine. After a 5 second delay a 0.5 second light stimulus is presented pseudorandomly in one of 5 nose-poke ports. A response to the illuminated hole within 5 seconds is rewarded with a food pellet. Responses during the waiting period, to the wrong hole, or the absence of a response within 5 seconds of stimulus presentation are punished with a 5 second lights-off timeout. D) Distribution of behavioural latencies for rats to move from entering the food magazine, starting a new trial, to leaving the magazine to start waiting, split by the outcome of the previous trial (either ending in a correct response, and being rewarded, or ending in an incorrect or premature error response). Boxes show the range from 1^st to 3^rd quartile of responses, black lines show the median, and whiskers extend to the furthest value from the hinge within 1.5 times the inter-quartile range. Values outside this range are represented as black dots.</p

Predicting upcoming impulsive responses.

<p>A) Stacked distribution of premature and non-premature (i.e. correct and incorrect) responses as a function of latency of rats to move to wait-start, divided into trials where the previous trials was rewarded (+), or non-rewarded (−). Time zero is the start of the trial, a vertical grey line represents the time of stimulus light presentation (or in the case of premature responses, the time the stimulus light would have been presented). B) Distribution of premature and non-premature responses as depicted in A, represented as a proportion of all responses. C) Receiver-operator characteristic curve for models predicting upcoming premature responses based on leave-one-out cross-validation results. The diagonal grey line represents an uninformative classifier. D) Plot of model accuracy ([number of true positives] + [number of true negatives]/[number of true positives] + [number of false positives] + [number of true negatives] + [number of false negatives]) against threshold predicted probability value. E) Distribution of predicted probabilities for true premature and non-premature trials from the full (behaviour plus LFP) model. The area under each curve is equal to the total number of trials.</p

Relationship of 5-CSRTT LFP correlates to phenotypic impulsivity.

<p>A) Scree plot of the proportion of variance explained by principal components extracted from LFP variables derived from peri-event LFP variables (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0111300#pone.0111300.s007" target="_blank">Table S15 in File S1</a>). Grey line shows the cumulative proportion of variance explained. Four components were sufficient to explain >95% of variance in the LFP data. B) Scatter plots of the relationship between individual rat's impulsivity screening score and their score on principal components 1–4 for 11 rats meeting the criterion for high impulsivity. Grey line represents the least-squares regression line. The 95% confidence interval is shown by the shaded blue area.</p

Corticostriatal gamma60-delta PAC during 5-CSRTT performance.

<p>A) Example of raw and filtered LFP data showing PAC. Vertical dashed purple lines indicate local gamma60 power maxima; vertical green lines indicate local delta peaks and troughs. B) Phase-amplitude coupling between low (phase giving) and high frequency (amplitude giving) oscillations in PFC and NAcb calculated over whole 30 minute recordings. PAC peaked between gamma60 oscillations and a 2–3 Hz delta oscillation, and was weaker in PRL than other regions. Note that PAC was calculated with amplitude and phase data taken from the same electrode. C) PAC between 30–80 Hz high frequency oscillations and a 2.75 Hz delta oscillation around wait-start for all correct, previously rewarded trials recorded from NAcbC electrodes. D) PAC between 30–80 Hz and 2.75 Hz delta oscillations around nose-poking for all correct, previously rewarded trials recorded from the NAcbC. E) Gamma60-delta PAC around wait-start. Solid lines represent the mean of all trials. Shaded areas represent the SEM. F) Model statistics for the effect of upcoming trial outcome, previous reward, velocity and brain region on instantaneous gamma60-delta PAC around the wait-start alignment event. G) Gamma60-delta PAC around nose-poking. Solid lines represent the mean of all trials. Shaded areas represent the SEM. H) Model statistics for the effect of upcoming trial outcome, previous reward, velocity, and brain region on instantaneous gamma60-delta PAC around nose-poking.</p

Genome-wide association study meta-analysis of chronic widespread pain: Evidence for involvement of the 5p15.2 region

BACKGROUND AND OBJECTIVES: Chronic widespread pain (CWP) is a common disorder affecting ∼10% of the general population and has an estimated heritability of 48–52%. In the first large-scale genome-wide association study (GWAS) meta-analysis, we aimed to identify common genetic variants associated with CWP. METHODS: We conducted a GWAS meta-analysis in 1308 female CWP cases and 5791 controls of European descent, and replicated the effects of the genetic variants with suggestive evidence for association in 1480 CWP cases and 7989 controls. Subsequently, we studied gene expression levels of the nearest genes in two chronic inflammatory pain mouse models, and examined 92 genetic variants previously described associated with pain. RESULTS: The minor C-allele of rs13361160 on chromosome 5p15.2, located upstream of chaperonin-containing-TCP1-complex-5 gene (CCT5) and downstream of FAM173B, was found to be associated with a 30% higher risk of CWP (minor allele frequency=43%; OR=1.30, 95% CI 1.19 to 1.42, p=1.2×10(−8)). Combined with the replication, we observed a slightly attenuated OR of 1.17 (95% CI 1.10 to 1.24, p=4.7×10(−7)) with moderate heterogeneity (I2=28.4%). However, in a sensitivity analysis that only allowed studies with joint-specific pain, the combined association was genome-wide significant (OR=1.23, 95% CI 1.14 to 1.32, p=3.4×10(−8), I2=0%). Expression levels of Cct5 and Fam173b in mice with inflammatory pain were higher in the lumbar spinal cord, not in the lumbar dorsal root ganglions, compared to mice without pain. None of the 92 genetic variants previously described were significantly associated with pain (p>7.7×10(−4)). CONCLUSIONS: We identified a common genetic variant on chromosome 5p15.2 associated with joint-specific CWP in humans. This work suggests that CCT5 and FAM173B are promising targets in the regulation of pain