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Cocaine use disorder (CUD) is a worldwide public health problem, associated with severe psychosocial and economic impacts. Currently, no FDA-approved treatment is available for CUD. However, an emerging body of evidence from clinical and preclinical studies suggests that biperiden, an M1 muscarinic receptor antagonist, presents potential therapeutic use for CUD. These studies have suggested that biperiden may reduce the reinforcing effects of cocaine. It is well established that rodents emit 50-kHz ultrasonic vocalizations (USV) in response to natural rewards and stimulant drugs, including cocaine. Nonetheless, the effects of biperiden on the cocaine-induced increase of 50-kHz USV remains unknown. Here, we hypothesized that biperiden could antagonize the acute effects of cocaine administration on rat 50-kHz USV. To test this hypothesis, adult male Wistar rats were divided into four experimental groups: saline, 5 mg/kg biperiden, 10 mg/kg cocaine, and biperiden/cocaine (5 and 10 mg/kg, i.p., respectively). USV and locomotor activity were recorded in baseline and test sessions. As expected, cocaine administration significantly increased the number of 50-kHz USV. Biperiden administration effectively antagonized the increase in 50-kHz USV induced by cocaine. Cocaine administration also increased the emission of trill and mixed 50 kHz USV subtypes and this effect was antagonized by biperiden. Additionally, we showed that biperiden did not affect the cocaine-induced increase in locomotor activity, although biperiden administration per se increased locomotor activity. In conclusion, our findings indicate that administering biperiden acutely reduces the positive affective effects of cocaine, as demonstrated by its ability to inhibit the increase in 50-kHz USV., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ultrasonic vocalizations (USV) are emitted by both young pups and adult rats to convey positive or negative emotional states. These USV manifestations are contingent on factors including developmental stage, situational requirements, and individual dispositions. Pups emit 40-kHz USV when separated from their mother and litter, which function to elicit maternal care. Conversely, adult rats can produce 50-kHz USV in response to stimuli that elicit reward-related states, including natural rewards, stimulant drugs, and reward-predictive stimuli. The present study aims to investigate whether pup 40-kHz USV can serve as predictors of behaviors related to positive or negative states in adult rats. Both male and female Wistar pups were initially tested on the 11th postnatal day and subsequently in adulthood. There was no significant difference in the number of 40-kHz ultrasonic vocalizations between male and female pups. However, cocaine elicited more 50-kHz USV and hyperactivity in adult females compared to males. Notably, cocaine increased the proportion of step and trill USV subtypes in both adult males and females. Interestingly, this effect of cocaine was stronger in females that were in the diestrus, compared to the estrus phase. In males, a significant positive correlation was found between pup 40-kHz USV and lower anxiety scores in adult male but not female rats tested on the elevated plus-maze test. Furthermore, no significant correlation was found between pup 40-kHz and adult 50-kHz USV in both males and females, whether in undrugged (saline) or in cocaine-treated rats. It is possible that the 40-kHz USV emitted by pups predicted reduced anxiety-like behavior only for male rats because they could elicit maternal care directed specifically to male pups. These findings suggest that 40-kHz USV can serve as an indicator of the emotional link between the rat mother and male pups. Indeed, this suggests that maternal care exerts a positive influence on the emotional state during adulthood., (Copyright © 2023. Published by Elsevier B.V.)

The flavonoid myricitrin showed an antidepressant-like effect in the tail suspension test and increased hippocampal neurogenesis, as well as demonstrating anti-inflammatory effects. Interestingly, inflammation has been linked to depression, and anti-inflammatory drugs showed promising results as antidepressant-like drugs. Thus, the present study evaluated the effects of myricitrin in the chronic mild stress (CMS) model, a translational and valid animal model of depression, using the mini-experiment design to improve the reproducibility of the findings. The sucrose preference test (SPT), forced swim test (FST), and tail suspension test (TST) were the readouts of depressive-like phenotypes induced by CMS. Relative adrenal weight was employed as an index of the hypothalamus-pituitary-adrenal (HPA) axis activation. Interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha levels were measured in the hippocampus. Myricitrin (10 mg/kg, intraperitoneally, for 14 days) reversed depressive-like behaviors induced by CMS (increased immobility in the FST, the TST and anhedonia), as well as decreased adrenal hypertrophy and hippocampal levels of IL-6 in stressed mice. Similar results were observed by imipramine (20 mg/kg, intraperitoneally, for 14 days), a serotonin and norepinephrine reuptake inhibitor (positive control). A significant correlation was observed between immobility time in the TST, and hippocampal IL-6 levels. Hippocampal TNF-α levels were not affected by CMS or drug treatment. In conclusion, myricitrin exhibited an antidepressant-like profile in CMS, and this effect may be associated with its anti-inflammatory activity., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The present study investigated the pharmacological mechanisms of the antidepressant-like effects of amantadine in mice and their influence on hippocampal neurogenesis. To improve the translational validity of preclinical results, reproducibility across laboratories and replication in other animal models and species are crucial. Single amantadine administration at doses of 50 and 75 mg/kg resulted in antidepressant-like effects in mice in the tail suspension test (TST), reflected by an increase in immobility time. The effects of amantadine were seen at doses that did not alter locomotor activity. The tyrosine hydroxylase inhibitor α-methyl-ρ-tyrosine did not influence the anti-immobility effect of amantadine in the TST. Pretreatment with the α 1 adrenergic receptor antagonist prazosin, β adrenergic receptor antagonist propranolol, α 2 adrenergic receptor antagonist yohimbine, and α 2 adrenergic receptor agonist clonidine did not alter the antidepressant-like effect of amantadine. However, amantadine's effect was blocked by the dopamine D 2 receptor antagonist haloperidol and glutamate receptor agonist N-methyl-D-aspartate (NMDA). Repeated amantadine administration (50 mg/kg) also exerted an antidepressant-like effect, paralleled by an increase in hippocampal neurogenesis. The present results demonstrate that the antidepressant-like effects of amantadine may be mediated by its actions on D 2 and NMDA receptors and likely involve hippocampal neurogenesis., (Copyright © 2021. Published by Elsevier B.V.)

Parkinson's 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 Parkinson's disease. Furthermore, the present results suggest a potential efficacy of ketamine on depression and gait alterations in Parkinson's disease., (Copyright © 2018 Elsevier B.V. All rights reserved.)

There is an urgent need to understand the pathophysiological mechanisms related to anxiety associated with diabetes, seeking more effective alternative treatments to treat it. For that, the effect of a preventive and prolonged treatment with fish oil (FO), a source of omega-3 polyunsaturated fatty acid, was tested in streptozotocin-diabetic (DBT) rats submitted to the anxiety tests. Additionally, an immunohistochemistry for neuronal NO synthase (nNOS) was performed in brain areas related to anxiety, such as lateral amygdala (AMY), hippocampus (HIP) and dorsolateral periaqueductal gray (dlPAG). Lastly, the effect of NO precursor L-arginine (L-Arg) or nNOS inhibitor 7-nitroindazole (7-NI) was tested in DBT animals treated with vehicle (VEH) or FO. Our data demonstrated that vehicle-treated DBT animals exhibited a more pronounced anxiogenic-like response and also presented high nNOS levels in the AMY, HIP and rostral dlPAG, what were both significantly prevented by FO treatment. This treatment was able to prevent the impairment in locomotor activity besides improving the high glycemic levels in DBT rats. Interestingly, while injection of 7-NI or L-Arg in VEH-treated DBT animals induced an anxiogenic-like and anxiolytic-like effect, respectively; the previous treatment with both L-Arg and 7-NI in FO-DBT animals abolished the anxiolytic-like effect induced by FO treatment. Altogether, our data support the hypothesis that a dysregulation in the NO production in brain areas as AMY, HIP and dlPAG may contribute to the mechanisms that link anxiety and diabetes, and the prevention of nNOS brain expression changes induced by a prolonged treatment with FO may be an important mechanism related to its anxiolytic-like effect., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Myricitrin (MYR) is a natural flavonoid that inhibits nitric oxide (NO) transmission and has an atypical antipsychotic-like profile in animal models. Considering that several NO inhibitors exert antidepressant-like effects, the present study evaluated the antidepressant-like effect of MYR (3-30mg/kg) in the tail suspension test (TST). Because of the putative relationship between adult neurogenesis and antidepressant activity, we also assessed cell proliferation, survival, and differentiation in adult neurogenic niches, including the subgranular zone (SGZ) and subventricular zone (SVZ). Similar to the positive control imipramine (IMI; 10mg/kg), repeated treatment with 10mg/kg MIR but not acute treatment reduced immobility time in the TST, indicating an antidepressant-like effect. No effect on general motor activity was observed. Myricitrin also facilitated cell proliferation in the SGZ of the hippocampal dentate gyrus and SVZ. In the SGZ, MYR increased the number of doublecortin- and 5-bromo-2'-deoxyuridine/neuronal nuclei-positive cells. Our results suggest that MYR facilitates hippocampal neurogenesis, which might contribute to its antidepressant-like effect and atypical antipsychotic-like profile., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Systemically administered antipsychotics bind to dopamine (DA) D2 receptors expressed in both pre- and postsynaptic neurons of different striatal sites and present an amnestic effect on learning and memory of conditioned avoidance responses (CAR). The aim of this study was to test whether blockade of the pre- or post-synaptic D2 receptors of the dorsolateral striatum of rats is the mechanism by which systemically administered antipsychotics present this amnestic effect. CAR learning and memory was evaluated in rats that received i.p. administrations of pre- or postsynaptic doses of the antipsychotic sulpiride combined with intra-DLS infusion of the D2 agonist quinpirole. Intra-DLS quinpirole itself was not amnestic and this effect was prevented by co-administration of presynaptic dose of sulpiride. However, sulpiride was amnestic when administered systemically in a post- but not presynaptic dose. This amnestic effect of sulpiride was prevented by the co-administration of quinpirole into the DLS. These results show that a blockade of postsynaptic D2 receptors in the DLS is necessary and sufficient to produce the amnestic effect of neuroleptics on CARs., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Among the non-motor phenomena of Parkinson's disease (PD) are depressive symptoms, with a prevalence of 40-70%. The reason for this high prevalence is not yet clear. The basal ganglia receives dopamine (DA) inputs from the substantia nigra pars compacta (SNpc), which is known to be impaired in PD patients. The neurotransmitter deficiency hypothesis of PD considers that low serotonin (5-hydroxytryptamine [5-HT]) activity in the brain in PD patients is a risk factor for depression. We investigated whether DA depletion promoted by the neurotoxin 6-hydroxydopamine (6-OHDA) is able to induce depressive-like behavior and neurotransmitter alterations that are similar to those observed in PD. To test this hypothesis, we performed intranigral injections of 6-OHDA in male Wistar rats and conducted motor behavior, depressive-like behavior, histological, and neurochemical tests. After the motor recovery period, 6-OHDA was able to produce anhedonia and behavioral despair 7, 14, and 21 days after neurotoxin infusion. These altered behavioral responses were accompanied by reductions of striatal DA. Additionally, decreases in hippocampal 5-HT content were detected in the 6-OHDA group. Notably, correlations were found between 5-HT and DA levels and swimming, immobility, and sucrose preference. Our results indicate that 6-OHDA produced depressive-like behavior accompanied by striatal DA and hippocampal 5-HT reductions. Moreover, DA and 5-HT levels were strongly correlated with "emotional" impairments, suggesting the important participation of these neurotransmitters in anhedonia and behavioral despair after 6-OHDA-induced nigral lesions., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Depression is a common comorbid in diabetic patients. The pathophysiologic mechanisms that relate this comorbidity is not completely elucidated yet, although several lines of evidence point out that increased oxidative stress resulting from hyperglycemia may have a crucial role. Thus, the effect of prolonged treatment with insulin (INS), the antioxidant vitamin E (VIT E) or the antidepressant imipramine (IMI) was evaluated in animals submitted to forced swimming test. Oxidative stress parameters (lipid peroxidation product levels, reduced gluthatione levels and catalase and superoxide dismutase activities) were also evaluated in brain areas related to depression, prefrontal cortex (PFC) and hippocampus (HIP). Our data show that treatment of streptozotocin-induced diabetic (DBT) rats with INS (6 UI/day, s.c.) prevented the blood glucose increase, reduced the immobility time, an antidepressant-like behavior, and normalized the reduced weight gain. Although the VIT E treatment (300 mg/kg, p.o.) had not altered the blood glucose levels, this treatment was able to reduce the immobility time and to reestablish the reduced weight gain in DBT rats. Differently, treatment with IMI (15 mg/kg, i.p.) induced antidepressant-like behavior in normoglycemic besides DBT animals. While VIT E and IMI treatments restored only specific oxidative stress parameters, INS was able to prevent all changed parameters evaluated in both PFC and HIP from DBT animals. Therefore, our data provide further evidence of the importance of oxidative stress in PFC and HIP in the pathophysiology of depression related to diabetes., (Copyright © 2013. Published by Elsevier B.V.)

Depressive episodes are associated with disturbances in circadian rhythms, and constant illumination has been reported to induce depressive-like behavior in rodents. Rats kept in constant darkness express the endogenous circadian rhythm, and most animals under constant light conditions lose circadian locomotor rhythmicity. Exposure to constant light in rats during lactation was reported to prevent this loss of circadian rhythm in adulthood. Thus, the aim of the present study was to verify whether exposure to constant light during lactation prevents anhedonia-like behavior induced by constant light in adult rats. In experiment 1, we replicated the anhedonia-like effects of constant light in adult male rats. We showed that this effect is reversed by imipramine treatment in the drinking water. In experiment 2, we subjected rats to constant darkness (neonatal-DD), constant light (neonatal-LL) or to normal light/dark cycle (neonatal-LD) during the neonatal phase and evaluated them after constant light exposure in adulthood. The group exposed to constant light during the neonatal phase did not reduce their sucrose preference and exhibited greater locomotor activity than the other groups. The neonatal-DD group exhibited decreased sucrose preference earlier than controls and had higher serum corticosterone concentrations. Prevention of arrhythymicity might protect neonatal-LL rats from anhedonia-like behavior induced by constant light, whereas constant darkness during the neonatal phase rendered the neonatal-DD group more susceptible to depressive-like behavior. These results corroborate with the literature data indicating that circadian disruption may contribute in mood disorders and that early life stress can influence stress responsivity in adulthood., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The present study investigated the neurochemical, motor and cognitive effects of pioglitazone in a rat model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In the first experiment, we administered MPTP, and 1h later administered a single oral dose of pioglitazone (5, 15 and 30 mg/kg). The following day, we performed the open-field test and neurochemical dose response curve. We demonstrated that 30 mg/kg of pioglitazone was capable of restoring striatal dopamine (DA) concentrations and motor behaviors. A second experiment was conducted to test the effects of two protocols (acute and chronic) of pioglitazone (30 mg/kg) administration in the open-field test, two-way active avoidance task and in the DA and metabolites levels. The acute protocol consisted of a single oral administration 1 h after MPTP, whereas the chronic protocol was performed with daily administrations starting 1 h after MPTP and ending 22 days after that. Results showed that neither protocol was able to reverse the cognitive impairment promoted by MPTP. We also demonstrated that acute treatment generated some level of neuroprotection, as confirmed by the absence of DA reduction in the group treated with pioglitazone in comparison to the sham group. By contrast, chronic treatment leaded to a reduction of striatal DA, close to MPTP administration alone. These findings suggest that acute administration of pioglitazone (30 mg/kg) was more efficient in generating beneficial effects on motor behaviors and in striatal DA levels. Nevertheless, we failed to demonstrate that pioglitazone administration improved performance on a dopamine-related cognitive task after MPTP., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Intra-nigral administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) caused a lesion in the substantia nigra, compact part (SNc) and a specific loss of dopamine and its metabolites in the striatum of rats. The animals were then tested in the two-way active avoidance task. MPTP-treated animals presented lower learning scores in the training and test sessions, an effect that was not caused by motor impairment or by a decreased sensitivity to footshock since their reaction time to the footshock (unconditioned stimulus - UCS) was not reduced. These lower scores were also not attributable to lower acoustic sensitivity or to a slowing in the association of the sound cue (conditioned stimulus - CS) with the UCS since the reaction time to the CS in the active avoidance response did not differ between MPTP-treated and control groups. Therefore, these results are more properly attributable to an impairment of the memory acquisition and retention processes. In addition, this study is presented as a model of early Parkinson's Disease amnesia and is discussed in terms of the importance of the nigrostriatal pathway to memory acquisition and storage processes.