Anton Pekcec

Deficits in spontaneous burrowing behavior in the rat bilateral monosodium iodoacetate model of osteoarthritis: an objective measure of pain-related behavior and analgesic efficacy

OBJECTIVE To characterize deficits in burrowing behavior - an ethologically-relevant rodent behavior - in the monosodium iodoacetate (MIA) rat model of osteoarthritis (OA), and the sensitivity of these deficits to reversal by analgesic drugs of both prototypical and novel mechanisms of action. A second objective was to compare the burrowing assay to a spontaneous locomotor activity (sLA) assay. METHOD Male Wistar Han rats (200-220 g) received intrarticular (i.a.) injections of MIA or saline for sham animals. A deficit in the amount of sand burrowed from steel tubes filled with 2.5 kg of sand was used as a measure of pain-related behavior, and sensitivity to reversal of these deficits by analgesic drugs was assessed in bilaterally MIA-injected rats. RESULTS Bilateral MIA injections induced a significant impairment of burrowing behavior, which was concentration-dependent. The temporal pattern of the deficits was biphasic: a large deficit at 3 days post-injection, resolving by day 14 and returning at the 21 and 28 day time points. At the 3 day time point ibuprofen, celecoxib and an anti-nerve growth factor (NGF) monoclonal antibody (mAb) were able to significantly reinstate burrowing behavior, whereas the fatty acid amide hydrolase (FAAH) inhibitor PF-04457845 and morphine displayed no reversal effect. Morphine impaired burrowing behavior at 3 mg/kg in sham animals. Deficits in rearing frequency in the locomotor activity assay proved irreversible by analgesics. CONCLUSION Burrowing behavior provides an objective, non-reflexive read-out for pain-related behavior in the MIA model that has predictive validity in detecting analgesic efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) and an anti-NGF mAb.

Cross-centre replication of suppressed burrowing behaviour as an ethologically relevant pain outcome measure in the rat: a prospective multicentre study.

Abstract Burrowing, an ethologically relevant rodent behaviour, has been proposed as a novel outcome measure to assess the global impact of pain in rats. In a prospective multicentre study using male rats (Wistar, Sprague-Dawley), replication of suppressed burrowing behaviour in the complete Freund adjuvant (CFA)-induced model of inflammatory pain (unilateral, 1 mg/mL in 100 µL) was evaluated in 11 studies across 8 centres. Following a standard protocol, data from participating centres were collected centrally and analysed with a restricted maximum likelihood-based mixed model for repeated measures. The total population (TP—all animals allocated to treatment; n = 249) and a selected population (SP—TP animals burrowing over 500 g at baseline; n = 200) were analysed separately, assessing the effect of excluding “poor” burrowers. Mean baseline burrowing across studies was 1113 g (95% confidence interval: 1041-1185 g) for TP and 1329 g (1271-1387 g) for SP. Burrowing was significantly suppressed in the majority of studies 24 hours (7 studies/population) and 48 hours (7 TP, 6 SP) after CFA injections. Across all centres, significantly suppressed burrowing peaked 24 hours after CFA injections, with a burrowing deficit of −374 g (−479 to −269 g) for TP and −498 g (−609 to −386 g) for SP. This unique multicentre approach first provided high-quality evidence evaluating suppressed burrowing as robust and reproducible, supporting its use as tool to infer the global effect of pain on rodents. Second, our approach provided important informative value for the use of multicentre studies in the future.

Pharmacological characterization of intraplantar Complete Freund’s Adjuvant-induced burrowing deficits

BACKGROUND It has recently been suggested that non-reflex behavioral readouts, such as burrowing, may be used to evaluate the efficacy of analgesics in rodent models of pain. OBJECTIVE To confirm whether intraplantar Complete Freunds Adjuvant (CFA)-induced pain reliably results in burrowing deficits which can be ameliorated by clinically efficacious analgesics as previously suggested. METHODS Uni- or bilateral intraplantar CFA injections were performed in male Wistar Han rats. The time- and concentration-response of burrowing deficits and the ability of various analgesics to reinstate burrowing performance were studied. An anxiolytic was also tested to evaluate the motivational cue that drives this behavior. RESULTS Burrowing deficits were dependent on the concentration of CFA injected, most pronounced 24h after CFA injections and even more pronounced after bilateral compared with unilateral injections. Celecoxib and ibuprofen reversed CFA-induced burrowing deficits whereas indomethacin failed to significantly reinstate burrowing performance. Morphine and tramadol failed to reinstate burrowing performance, but sedation was observed in control rats at doses thought to be efficacious. An antibody directed against the nerve growth factor significantly improved CFA-induced burrowing deficits. Neither gabapentin nor the anxiolytic diazepam reinstated burrowing performance and the opportunity to find shelter did not modify burrowing performance. CONCLUSION Burrowing is an innate behavior reliably exhibited by rats. It is suppressed in a model of inflammatory pain and differently reinstated by clinically efficacious analgesics that lack motor impairing side effects, but not an anxiolytic, suggesting that this assay is suitable for the assessment of analgesic efficacy of novel drugs.

Selective and interactive effects of D2 receptor antagonism and positive allosteric mGluR4 modulation on waiting impulsivity

Background: Metabotropic glutamate receptor 4 (mGluR4) and dopamine D2 receptors are specifically expressed within the indirect pathway neurons of the striato‐pallidal‐subthalamic pathway. This unique expression profile suggests that mGluR4 and D2 receptors may play a cooperative role in the regulation and inhibitory control of behaviour. We investigated this possibility by testing the effects of a functionally‐characterised positive allosteric mGluR4 modulator, 4‐((E)‐styryl)‐pyrimidin‐2‐ylamine (Cpd11), both alone and in combination with the D2 receptor antagonist eticlopride, on two distinct forms of impulsivity. Methods: Rats were trained on the five‐choice serial reaction time task (5‐CSRTT) of sustained visual attention and segregated according to low, mid, and high levels of motor impulsivity (LI, MI and HI, respectively), with unscreened rats used as an additional control group. A separate group of rats was trained on a delay discounting task (DDT) to assess choice impulsivity. Results: Systemic administration of Cpd11 dose‐dependently increased motor impulsivity and impaired attentional accuracy on the 5‐CSRTT in all groups tested. Eticlopride selectively attenuated the increase in impulsivity induced by Cpd11, but not the accompanying attentional impairment, at doses that had no significant effect on behavioural performance when administered alone. Cpd11 also decreased choice impulsivity on the DDT (i.e. increased preference for the large, delayed reward) and decreased locomotor activity. Conclusions: These findings demonstrate that mGluR4s, in conjunction with D2 receptors, affect motor‐ and choice‐based measures of impulsivity, and therefore may be novel targets to modulate impulsive behaviour associated with a number of neuropsychiatric syndromes. HighlightsPositive allosteric mGluR4 modulation increases motor impulsivity and impairs aspects of visual attention.Positive allosteric mGluR4 modulation decreases choice impulsivity as well as indices of motor function.Blocking D2 receptors selectively attenuates the effect of positive allosteric mGluR4 modulation on motor impulsivity.

Ventral Striatal D2/3 Receptor Availability Is Associated with Impulsive Choice Behavior As Well As Limbic Corticostriatal Connectivity

Abstract Background Low dopamine D2/3 receptor availability in the nucleus accumbens shell is associated with highly impulsive behavior in rats as measured by premature responses in a cued attentional task. However, it is unclear whether dopamine D2/3 receptor availability in the nucleus accumbens is equally linked to intolerance for delayed rewards, a related form of impulsivity. Methods We investigated the relationship between D2/3 receptor availability in the nucleus accumbens and impulsivity in a delay-discounting task where animals must choose between immediate, small-magnitude rewards and delayed, larger-magnitude rewards. Corticostriatal D2/3 receptor availability was measured in rats stratified for high and low impulsivity using in vivo [18F]fallypride positron emission tomography and ex vivo [3H]raclopride autoradiography. Resting-state functional connectivity in limbic corticostriatal networks was also assessed using fMRI. Results Delay-discounting task impulsivity was inversely related to D2/3 receptor availability in the nucleus accumbens core but not the dorsal striatum, with higher D2/3 binding in the nucleus accumbens shell of high-impulsive rats compared with low-impulsive rats. D2/3 receptor availability was associated with stronger connectivity between the cingulate cortex and hippocampus of high- vs low-impulsive rats. Conclusions We conclude that delay-discounting task impulsivity is associated with low D2/3 receptor binding in the nucleus accumbens core. Thus, two related forms of waiting impulsivity—premature responding and delay intolerance in a delay-of-reward task—implicate an involvement of D2/3 receptor availability in the nucleus accumbens shell and core, respectively. This dissociation may be causal or consequential to enhanced functional connectivity of limbic brain circuitry and hold relevance for attention-deficit/hyperactivity disorder, drug addiction, and other psychiatric disorders.

Differences in trait impulsivity do not bias the response to pharmacological drug challenge in the rat five-choice serial reaction time task

RationaleMaladaptive impulsivity is symptomatic of several neuropsychiatric disorders including schizophrenia, attention-deficit hyperactivity disorder (ADHD), and substance abuse disorders; paradigms designed to assess the underlying neurobiology of this behavior are essential for the discovery of novel therapeutic agents. Various models may be used to assess impulsivity as measured by the five-choice serial reaction time task (5-CSRTT), including variable inter-trial interval (ITI) sessions, the selection of extreme high and low impulsivity phenotypes from a large outbred population of rats, as well as pharmacological challenges.ObjectivesThe aim of this study is to evaluate if pharmacological challenge models for impulsivity are biased by underlying differences in impulsivity phenotype.MethodsExtreme high and low impulsivity phenotypes were selected in the 5-CSRTT, and dose-dependent effects of various pharmacological challenges, namely MK-801, yohimbine, and cocaine, were evaluated on task performance, specifically accuracy and premature responses.ResultsAll three compounds increased premature responding, while a decrease in attentional performance occurred following MK-801 and yohimbine administration. No differences in drug-induced impulsivity between rats selected for high or low impulsivity or in parameters indicative of attentional performance could be determined.ConclusionsOur findings indicate that different pharmacological challenges increase impulsivity on the 5-CSRTT, with modest effects on attention. These effects were not influenced by underlying differences in impulsivity phenotype, which is an important prerequisite to reliably use these challenge models to screen and profile compounds with putative anti-impulsive characteristics.

Targeting the dopamine D1 receptor or its downstream signalling by inhibiting phosphodiesterase‐1 improves cognitive performance

Insufficient prefrontal dopamine 1 (D1) receptor signalling has been linked to cognitive dysfunction in several psychiatric conditions. Because the PDE1 isoform B (PDE1B) is postulated to regulate D1 receptor‐dependent signal transduction, in this study we aimed to elucidate the role of PDE1 in cognitive processes reliant on D1 receptor function.