Etieli Wendler

The roles of the nucleus accumbens core, dorsomedial striatum, and dorsolateral striatum in learning: performance and extinction of Pavlovian fear conditioned responses and instrumental avoidance responses

This study examined the effects of bilateral excitotoxic lesions of the nucleus accumbens core (NAc-co), dorsomedial striatum (DMS) or dorsolateral striatum (DLS) of rats on the learning and extinction of Pavlovian and instrumental components of conditioned avoidance responses (CARs). None of the lesions caused sensorimotor deficits that could affect locomotion. Lesions of the NAc-co, but not DMS or DLS, decreased unconditioned and conditioned freezing. The NAc-co and DLS lesioned rats learned the 2-way active avoidance task more slowly. These results suggest: (i) CARs depend on both Pavlovian and instrumental learning; (ii) learning the Pavlovian component of CARs depends on the NAc-co; learning the instrumental component of CARs depends on the DLS, NAc and DMS; (iii) although the NAc-co is also needed for learning the instrumental component, it is not clear whether it plays a role in learning the instrumental component per se or if it simply allows learning of the Pavlovian component which is a pre-condition for learning the instrumental component; (iv) we did not find evidence that the DMS and DLS play the same roles in habit and goal-directed aspects of the instrumental component of CARs as observed in appetitive motivated instrumental responding.

Evidence that conditioned avoidance responses are reinforced by positive prediction errors signaled by tonic striatal dopamine.

We conducted an experiment in which hedonia, salience and prediction error hypotheses predicted different patterns of dopamine (DA) release in the striatum during learning of conditioned avoidance responses (CARs). The data strongly favor the latter hypothesis. It predicts that during learning of the 2-way active avoidance CAR task, positive prediction errors generated when rats do not receive an anticipated footshock (which is better than expected) cause DA release that reinforces the instrumental avoidance action. In vivo microdialysis in the rat striatum showed that extracellular DA concentration increased during early CAR learning and decreased throughout training returning to baseline once the response was well learned. In addition, avoidance learning was proportional to the degree of DA release. Critically, exposure of rats to the same stimuli but in an unpredictable, unavoidable, and inescapable manner, did not produce alterations from baseline DA levels as predicted by the prediction error but not hedonic or salience hypotheses. In addition, rats with a partial lesion of substantia nigra DA neurons, which did not show increased DA levels during learning, failed to learn this task. These data represent clear and unambiguous evidence that it was the factor positive prediction error, and not hedonia or salience, which caused increase in the tonic level of striatal DA and which reinforced learning of the instrumental avoidance response.

Quercetin reduces manic-like behavior and brain oxidative stress induced by paradoxical sleep deprivation in mice

Quercetin is a known antioxidant and protein kinase C (PKC) inhibitor. Previous studies have shown that mania involves oxidative stress and an increase in PKC activity. We hypothesized that quercetin affects manic symptoms. In the present study, manic-like behavior (hyperlocomotion) and oxidative stress were induced by 24h paradoxical sleep deprivation (PSD) in male Swiss mice. Both 10 and 40mg/kg quercetin prevented PSD-induced hyperlocomotion. Quercetin reversed the PSD-induced decrease in glutathione (GSH) levels in the prefrontal cortex (PFC) and striatum. Quercetin also reversed the PSD-induced increase in lipid peroxidation (LPO) in the PFC, hippocampus, and striatum. Pearsons correlation analysis revealed a negative correlation between locomotor activity and GSH in the PFC in sleep-deprived mice and a positive correlation between locomotor activity and LPO in the PFC and striatum in sleep-deprived mice. These results suggest that quercetin exerts an antimanic-like effect at doses that do not impair spontaneous locomotor activity, and the antioxidant action of quercetin might contribute to its antimanic-like effects.

Evaluation of 50-kHz ultrasonic vocalizations in animal models of mania: Ketamine and lisdexamfetamine-induced hyperlocomotion in rats

Drug-induced hyperlocomotion in rodents is frequently used as a behavioral model for mania. However, the use of locomotor activity as the single parameter in these animal models of mania may pose some limitations for developing new pharmacological treatments. Thus, alternative behavioral markers are required. Fifty-kHz ultrasonic vocalizations (USV), which are thought to represent positive affect, are increased by the administration of the psychostimulant d-amphetamine, an effect that can be prevented by lithium treatment, the gold standard antimanic drug for treating bipolar disorder. The aim of this study was to evaluate 50-kHz USV in two other pharmacological-induced animal models of mania: ketamine (KET)- and lisdexamfetamine (LDX)-induced hyperlocomotion. After systemic injection of LDX (10mg/kg, ip), racemic-ketamine (25mg/kg, ip) or S-ketamine (25mg/kg, ip), locomotor activity and 50-kHz USV emission were evaluated in rats. Furthermore, the effects of an antimanic treatment, namely lithium carbonate (100mg/kg, ip), on LDX-induced 50-kHz USV and hyperlocomotion were tested. Rats treated with racemic KET and S-KET showed increased locomotor activity, but these drug treatments did not significantly affect 50-kHz USV emission rates. On the other hand, LDX administration increased both locomotor activity and 50-kHz USV with both effects being reversed by lithium administration. The present findings suggest that 50-kHz USV can differentiate between drug-induced models of mania, which may represent different types of manic episodes. Thus, measuring 50-kHz USV might serve as an additional valuable behavioral variable to assess mania-like phenotypes in rat models.

Effects of acute and chronic quercetin administration on methylphenidate-induced hyperlocomotion and oxidative stress.

Aims: Increases in protein kinase C (PKC) and oxidative stress have been related to mania. Drugs with antioxidant effects or inhibitory actions on PKC may have antimanic effects. The flavonoid quercetin has antioxidant and PKC‐inhibiting effects that resemble those of lithium, the first‐line treatment for mania in bipolar disorder. We hypothesized that quercetin may have antimanic‐like effects in an animal model. Main methods: In the present study, we investigated the effects of acute and chronic treatment with quercetin (2.5, 5, 10, and 40 mg/kg, i.p.) in male Swiss mice that were subjected to methylphenidate (5 mg/kg, i.p.)‐induced hyperlocomotion, an animal model of mania. Lithium (100 mg/kg, i.p.) and diazepam (5 mg/kg, i.p.) were used as positive and negative controls, respectively. We also evaluated the effects of these treatments on methylphenidate‐induced oxidative stress in the brain by measuring reduced glutathione (GSH) and lipid peroxidation (LPO) levels in the prefrontal cortex, hippocampus, and striatum. Key findings: Acute and chronic (21‐day) treatment with lithium and diazepam reduced methylphenidate‐induced hyperlocomotion. Chronic but not acute treatment with quercetin (10 and 40 mg/kg) blocked methylphenidate‐induced hyperlocomotion. These effects of lithium and quercetin occurred at doses that did not alter spontaneous locomotor activity, whereas diazepam reduced spontaneous locomotor activity. Chronic treatment with lithium and quercetin blocked the methylphenidate‐induced increase in LPO levels in the striatum. Significance: These results suggest that chronic quercetin treatment has antimanic‐like and antioxidant effects, thus encouraging further studies of quercetin as a putative new antimanic drug.

Mania-like elevated mood in rats: Enhanced 50-kHz ultrasonic vocalizations after sleep deprivation

Abstract Mania is characterized by elevated drive and mood but animal models of mania have often neglected elevated mood. Ultrasonic vocalizations (USV) of 50‐kHz emitted by rats are thought to index the subjects positive affective state. Fifty‐kHz USV emission is increased by amphetamine, an effect blocked by lithium administration. Sleep deprivation (SD) is an environmental model of mania and the present study evaluated SD effects on behavioral activity and USV emission, together with the impact of lithium treatment. Adult rats were submitted to 24h or 72h SD, and locomotor activity and USV emission were assessed. To test their sensitivity to a standard antimanic drug, these behavioral parameters were also evaluated after acute administration of lithium carbonate (25, 50 or 100 mg/kg, i.p.). Striatal monoamine content was measured post‐mortem. SD (24h and 72h) led to increased locomotor activity, rearing behavior and 50‐kHz USV emission, together with a change in the call profile characterized by an increase in the percentage of frequency‐modulated 50‐kHz USV, which may indicate the mania‐like consequences of SD. Importantly, all SD effects were reverted by lithium administration. SD also led to a decrease in dopamine content in the ventral striatum, while increasing dopamine turnover. In conclusion, SD increased 50‐kHz USV emission, an effect prevented by acute lithium administration. This suggests 50‐kHz USV as a new marker for mania‐like elevated mood, which shows construct validity (associated with increased dopaminergic tone), face validity (reflecting increased positive affect) and predictive validity (high sensitivity to lithium treatment). Highlights50‐kHz Ultrasonic Vocalizations (USV) are proposed as an index of positive affect.Sleep deprivation increased locomotor activity, rearing and 50‐kHz USV.These effects were blocked by lithium pretreatment.50‐kHz USV can be a marker of elevated mood in animal models of mania.

Effects of ketamine on vocal impairment, gait changes, and anhedonia induced by bilateral 6-OHDA infusion into the substantia nigra pars compacta in rats: Therapeutic implications for Parkinson’s disease

GRAPHICAL ABSTRACT Figure. No caption available. &NA; Parkinsons disease is a chronic neurodegenerative disorder characterized by cardinal motor features, such as bradykinesia, but also vocal deficits (e.g. difficulties to articulate words and to keep the tone of voice) and depression. In the present study, rats with bilateral 6‐hydroxydopamine lesion of the substantia nigra pars compacta were evaluated for changes in the emission of 50‐kHz ultrasonic vocalizations, gait impairment (catwalk test), and depressive‐like behaviour (sucrose preference test). Furthermore, we evaluated the effect of repeated treatment (28 days) with ketamine (5, 10, and 15 mg/kg, ip, once per week) or imipramine (15 mg/kg, ip, daily). The lesion had prominent effects on the production of 50‐kHz ultrasonic vocalizations (reduced call numbers, call durations, total calling time, and increased latency to start calling), led to gait impairment (increased run duration and stand of right forelimb) and induced anhedonia (reduced sucrose preference). Also, significant correlations between gait changes, sucrose preference, and ultrasonic calling were found, yet, except for run duration and sucrose preference, these correlations were low indicating that these associations are weak. Importantly, ketamine and imipramine reversed lesion‐induced anhedonia and improved gait impairments, but neither drug improved ultrasonic calling. In conclusion, the substantia nigra lesion with 6‐hydroxydopamine induced subtle motor and non‐motor manifestations, reflecting key features of the wide clinical spectrum of early Parkinsons disease. Furthermore, the present results suggest a potential efficacy of ketamine on depression and gait alterations in Parkinsons disease.