Effects of Intracerebral Aminophylline Dosing on Catalepsy and Gait in an Animal Model of Parkinson's Disease.

Parkinson's disease (PD) is a progressive disorder characterized by the apoptosis of dopaminergic neurons in the basal ganglia. This study explored the potential effects of aminophylline, a non-selective adenosine A1 and A2A receptor antagonist, on catalepsy and gait in a haloperidol-induced PD model. Sixty adult male Swiss mice were surgically implanted with guide cannulas that targeted the basal ganglia. After seven days, the mice received intraperitoneal injections of either haloperidol (experimental group, PD-induced model) or saline solution (control group, non-PD-induced model), followed by intracerebral infusions of aminophylline. The assessments included catalepsy testing on the bar and gait analysis using the Open Field Maze. A two-way repeated-measures analysis of variance (ANOVA), followed by Tukey's post hoc tests, was employed to evaluate the impact of groups (experimental × control), aminophylline (60 nM × 120 nM × saline/placebo), and interactions. Significance was set at 5%. The results revealed that the systemic administration of haloperidol in the experimental group increased catalepsy and dysfunction of gait that paralleled the observations in PD. Co-treatment with aminophylline at 60 nM and 120 nM reversed catalepsy in the experimental group but did not restore the normal gait pattern of the animals. In the non-PD induced group, which did not present any signs of catalepsy or motor dysfunctions, the intracerebral dose of aminophylline did not exert any interference on reaction time for catalepsy but increased walking distance in the Open Field Maze. Considering the results, this study highlights important adenosine interactions in the basal ganglia of animals with and without signs comparable to those of PD. These findings offer valuable insights into the neurobiology of PD and emphasize the importance of exploring novel therapeutic strategies to improve patient's catalepsy and gait.

Sleep deprivation induces late deleterious effects in a pharmacological model of Parkinsonism.

Parkinson's disease is a degenerative, chronic and progressive disease, characterized by motor dysfunctions. Patients also exhibit non-motor symptoms, such as affective and sleep disorders. Sleep disorders can potentiate clinical and neuropathological features and lead to worse prognosis. The goal of this study was to evaluate the effects of sleep deprivation (SD) in mice submitted to a progressive pharmacological model of Parkinsonism (chronic administration with a low dose of reserpine). Male Swiss mice received 20 injections of reserpine (0.1 mg/kg) or vehicle, on alternate days. SD was applied before or during reserpine treatment and was performed by gentle handling for 6 h per day for 10 consecutive days. Animals were submitted to motor and non-motor behavioral assessments and neurochemical evaluations. Locomotion was increased by SD and decreased by reserpine treatment. SD during treatment delayed the onset of catalepsy, but SD prior to treatment potentiated reserpine-induced catalepsy. Thus, although SD induced an apparent beneficial effect on motor parameters, a delayed deleterious effect on alterations induced by reserpine was found. In the object recognition test, both SD and reserpine treatment produced cognitive deficits. In addition, the association between SD and reserpine induced anhedonic-like behavior. Finally, an increase in oxidative stress was found in hippocampus of mice subjected to SD, and tyrosine hydroxylase immunoreactivity was reduced in substantia nigra of reserpine-treated animals. Results point to a possible late effect of SD, aggravating the deficits in mice submitted to the reserpine progressive model of PD.

Mygalin, an Acanthoscurria gomesiana spider-derived synthetic, modulates haloperidol-induced cataleptic state in mice.

BACKGROUND: Haloperidol (HAL) is an antipsychotic used in the treatment of schizophrenia. However, adverse effects are observed in the extrapyramidal tracts due to its systemic action. Natural compounds are among the treatment alternatives widely available in Brazilian biodiversity. Mygalin (MY), a polyamine that was synthesized from a natural molecule present in the hemolymph of the Acanthoscurria gomesian spider, may present an interesting approach. AIMS: This study aimed to evaluate the effect of MY in mice subjected to HAL-induced catalepsy. METHODS: Male Swiss mice were used. Catalepsy was induced by intraperitoneal administration of HAL (0.5 mg/kg - 1 mL/Kg) diluted in physiological saline. To assess the MY effects on catalepsy, mice were assigned to 4 groups: (1) physiological saline (NaCl 0.9 %); (2) MY at 0.002 mg/Kg; (3) MY at 0.02 mg/Kg; (4) MY at 0.2 mg/Kg. MY or saline was administered intraperitoneally (IP) 10 min b HAL before saline. Catalepsy was evaluated using the bar test at 15, 30, 60, 90, and 120 min after the IP administration of HAL. RESULTS: The latency time in the bar test 15, 30, 60, and 90 min increased (p < 0.05) after IP administration of HAL compared to the control group. Catalepsy was attenuated 15, 30, 90, and 120 min (p < 0.05) after the IP-administration of MY at 0.2 mg/Kg; while MY at 0.02 mg/Kg attenuated catalepsy 15 min after the HAL treatment. Our findings showed that MY attenuates the HAL-induced cataleptic state in mice.

Genetic effects in a progressive model of parkinsonism induced by reserpine.

OBJECTIVE AND METHODS: We investigated the locomotor, emotional, physiological, and neurobiological effects induced by low-dose reserpine repeated treatment (0.1 mg/kg; 14 injections) in males from the Lewis (LEW), Spontaneously Hypertensive Rats (SHR), and SHR.LEW-(D4Rat76-D4Mgh11) (SLA16) isogenic rat strains, which have different genetic backgrounds on chromosome 4. Behavioral responses in the catalepsy, open-field, and oral movements' tests were coupled with blood pressure, body weight, and striatal tyrosine hydroxylase (TH) level assessments to establish neurobiological comparisons between reserpine-induced impairments and genetic backgrounds RESULTS: Results revealed the SHR strain was more sensitive in the catalepsy test and exhibited higher TH immunoreactivity in the dorsal striatum. The SLA16 strain presented more oral movements, suggesting increased susceptibility to develop oral dyskinesia. CONCLUSIONS: Our results showed the efficacy of repeated treatment with a low dose of reserpine and demonstrated, for the first time, the genetic influence of a specific region of chromosome 4 on the expression of these effects.

Aging accentuates decrease in tyrosine hydroxylase immunoreactivity associated with the increase in the motor impairment in a model of reserpine-induced parkinsonism.

Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by progressive dopaminergic neuron loss. Animal models have been used to develop a better understanding of the pathophysiologic mechanisms of PD. However, these models are usually conducted with young animals diverging of the age of PD patients, suggesting a bias in translational science. Thus, the aim of the study was to evaluate the effect of the age on rats in a progressive parkinsonism model induced by reserpine (RES). Adult (6 - 8 month-old) or elderly (18 - 24 month-old) male rats were assigned to six groups: control-elderly (CTL-ELDERLY), reserpine-elderly (RES-ELDERLY), reserpine-elderly withdrawal (RES-ELDERLY WITHDRAWAL), control-adult (CTL-ADULT), reserpine-adult (RES-ADULT), and reserpine-adult withdrawal (RES-ADULT WITHDRAWAL). Animals received 15 injections every other day of RES (0.1 mg / kg) or vehicle during 30 days. Throughout treatment, animals were evaluated in the catalepsy test (every 48 h) and open field test (24 h after the second injection), and weight assessment (every 4 days) was also made. Upon completion of behavioral tests, rat brains were collected for tyrosine hydroxylase (TH) immunohistochemical analysis. Main results demonstrated that RES-treated animals spent more time in the catalepsy bar compared with control groups, moreover the RES-elderly group showed a longer catalepsy time compared with the RES-ADULT group. A shorter time from RES treatment to the development of symptoms was observed in the RES-ADULT group, compared with the RES-ELDERLY group. In addition, RES-induced weight loss in both RES-ELDERLY and RES-ADULT when compared with their corresponding controls. Cessation of RES treatment was followed by weight gain only in the RES-ADULT group. A significant decrease in TH-immunoreactive cells was observed in the substantia nigra pars compacta (SNpc) and dorsal striatum (STR) in the rats in both the RES-ADULT and RES-ELDERLY groups and in the ventral tegmental area in rats in the RES-ADULT group. Furthermore, TH immunoreactivity decrease was not reversible in SNpc and STR in the RES-ELDERLY. These results show that RES has an age-dependent effect in rats, suggesting a greater sensitivity of the dopaminergic pathway to RES with advancing age. These suggest that the RES rat model of parkinsonism can be useful in improving our knowledge on the effect of aging on neurodegeneration.

Haloperidol-induced catalepsy as an animal model for parkinsonism: A systematic review of experimental studies.

Several useful animal models for parkinsonism have been developed so far. Haloperidol-induced catalepsy is often used as a rodent model for the study of motor impairments observed in Parkinson's disease and related disorders and for the screening of potential antiparkinsonian compounds. The objective of this systematic review is to identify publications that used the haloperidol-induced catalepsy model for parkinsonism and to explore the methodological characteristics and the main questions addressed in these studies. A careful systematic search of the literature was carried out by accessing articles in three different databases: Web of Science, PubMed and SCOPUS. The selection and inclusion of studies were performed based on the abstract and, subsequently, on full-text analysis. Data extraction included the objective of the study, study design and outcome of interest. Two hundred and fifty-five articles were included in the review. Publication years ranged from 1981 to 2020. Most studies used the model to explore the effects of potential treatments for parkinsonism. Although the methodological characteristics used are quite varied, most studies used Wistar rats as experimental subjects. The most frequent dose of haloperidol used was 1.0 mg/kg, and the horizontal bar test was the most used to assess catalepsy. The data presented here provide a framework for an evidence-based approach to the design of preclinical research on parkinsonism using the haloperidol-induced catalepsy model. This model has been used routinely and successfully and is likely to continue to play a critical role in the ongoing search for the next generation of therapeutic interventions for parkinsonism.

Coumarin analogue 3-methyl-7H-furo[3,2-g] chromen-7-one as a possible antiparkinsonian agent / El análogo de cumarina 3-metil-7H-furo[3,2-g]cromen-7-ona, un posible agente antiparkinsoniano

INTRODUCTION: Parkinson's disease is the second most common neurodegenerative disease. Monoamine oxidase B inhibitors are used in the treatment of this disease concomitantly with levodopa or as monotherapy. Several substituted coumarins have shown activity as inhibitors of monoamine oxidase B. OBJECTIVE: To evaluate the possible antiparkinsonian effects of the coumarin analogue FCS005 (3-methyl-7H-furo[3,2-g]chromen-7-one) in mouse models, as well as its inhibitory activity towards monoamine oxidases (MAO) and its antioxidant activity. MATERIALS AND METHODS: FCS005 was synthesized and the reversal of hypokinesia was evaluated in the reserpine and levodopa models. Moreover, in the haloperidol model, its anticataleptic effects were evaluated. Additionally, the monoamine oxidase inhibitory activity and antioxidant activity of FCS005 were evaluated using in vitro and ex vivo studies, respectively. RESULTS: FCS005 (100 mg/kg) caused the reversal of hypokinesia in the reserpine and levodopa models. This furocoumarin also presented anti-cataleptic effects at the same dose. Besides, it showed selective inhibitory activity towards the MAO-B isoform and antioxidant activity. CONCLUSION: These results attribute interesting properties to the compound FCS005. It is important to continue research on this molecule considering that it could be a potential antiparkinsonian agent.

Introducción. El segundo trastorno neurodegenerativo más común es la enfermedad de Parkinson. Los inhibidores de la monoamino oxidasa B se emplean en el tratamiento de esta enfermedad en monoterapia o concomitantemente con levodopa. Varios compuestos cumarínicos han mostrado actividad como inhibidores de la monoamino oxidasa B. Objetivo. Evaluar los posibles efectos antiparkinsonianos del análogo de la cumarina FCS005 (3-methyl-7H-furo[3,2-g]chromen-7-one) en modelos de ratones, la actividad inhibitoria frente a las monoamino oxidasas (MAO) y la actividad antioxidante. Materiales y métodos. Se sintetizó la furanocumarina FCS005 y, en los modelos de reserpina y levodopa, se evaluó si producía reversión de la hipocinesia; en el modelo de haloperidol se evaluaron sus efectos anticatalépticos. Además, se evaluó in vitro la actividad inhibidora de MAO y, ex vivo, la actividad antioxidante del compuesto FCS005. Resultados. El compuesto FCS005 en dosis de 100 mg/kg produjo la remisión de la hipocinesia en los modelos de reserpina y de levodopa. Esta furanocumarina presentó efectos anticatalépticos con la misma dosis. Además, mostró tener actividad inhibitoria selectiva sobre la MAO B, así como efectos antioxidantes. Conclusión. Los resultados evidenciaron propiedades interesantes del compuesto FCS005. Es importante continuar investigando esta molécula porque puede ser un potencial agente antiparkinsoniano.

Coumarin analogue 3-methyl-7H-furo[3,2-g]chromen-7-one as a possible antiparkinsonian agent / El análogo de cumarina 3-metil-7H-furo[3,2-g]cromen-7-ona, un posible agente antiparkinsoniano

Abstract Introduction: Parkinson's disease is the second most common neurodegenerative disease. Monoamine oxidase B inhibitors are used in the treatment of this disease concomitantly with levodopa or as monotherapy. Several substituted coumarins have shown activity as inhibitors of monoamine oxidase B. Objective: To evaluate the possible antiparkinsonian effects of the coumarin analogue FCS005 (3-methyl-7H-furo[3,2-g]chromen-7-one) in mouse models, as well as its inhibitory activity towards monoamine oxidases (MAO) and its antioxidant activity. Materials and methods: FCS005 was synthesized and the reversal of hypokinesia was evaluated in the reserpine and levodopa models. Moreover, in the haloperidol model, its anticataleptic effects were evaluated. Additionally, the monoamine oxidase inhibitory activity and antioxidant activity of FCS005 were evaluated using in vitro and ex vivo studies, respectively. Results: FCS005 (100 mg/kg) caused the reversal of hypokinesia in the reserpine and levodopa models. This furocoumarin also presented anti-cataleptic effects at the same dose. Besides, it showed selective inhibitory activity towards the MAO-B isoform and antioxidant activity. Conclusion: These results attribute interesting properties to the compound FCS005. It is important to continue research on this molecule considering that it could be a potential antiparkinsonian agent.

Resumen Introducción. El segundo trastorno neurodegenerativo más común es la enfermedad de Parkinson. Los inhibidores de la monoamino oxidasa B se emplean en el tratamiento de esta enfermedad en monoterapia o concomitantemente con levodopa. Varios compuestos cumarínicos han mostrado actividad como inhibidores de la monoamino oxidasa B. Objetivo. Evaluar los posibles efectos antiparkinsonianos del análogo de la cumarina FCS005 (3-methyl-7H-furo [3,2-g ] chromen-7-one) en modelos de ratones, la actividad inhibitoria frente a las monoamino oxidasas (MAO) y la actividad antioxidante. Materiales y métodos. Se sintetizó la furanocumarina FCS005 y, en los modelos de reserpina y levodopa, se evaluó si producía reversión de la hipocinesia; en el modelo de haloperidol se evaluaron sus efectos anticatalépticos. Además, se evaluó in vitro la actividad inhibidora de MAO y, ex vivo, la actividad antioxidante del compuesto FCS005. Resultados. El compuesto FCS005 en dosis de 100 mg/kg produjo la remisión de la hipocinesia en los modelos de reserpina y de levodopa. Esta furanocumarina presentó efectos anticatalépticos con la misma dosis. Además, mostró tener actividad inhibitoria selectiva sobre la MAO B, así como efectos antioxidantes. Conclusión. Los resultados evidenciaron propiedades interesantes del compuesto FCS005. Es importante continuar investigando esta molécula porque puede ser un potencial agente antiparkinsoniano.

Carvacrol prevents impairments in motor and neurochemical parameters in a model of progressive parkinsonism induced by reserpine.

Parkinson's disease (PD) is a neurodegenerative disease characterized by a progressive degeneration of dopaminergic neurons in the substantia nigra pars compact (SNpc), with consequent depletion of dopamine in the striatum, which gives rise to the characteristic motor symptoms of PD. Although its etiology is unknown, several studies have suggested that oxidative stress plays a critical function in the pathophysiology of PD, and antioxidant agents could be helpful to slown down the dopaminergic neurodegeneration. Carvacrol (CA) is a phenolic monoterpene found in essential oils of many aromatic plants that presents antioxidant and neuroprotective effects. This study aimed to assess the effect of CA in a reserpine (RES)-induced rat model of PD. Male Wistar rats received 15 s.c. injections of 0.1 mg/kg RES or vehicle, every other day, concomitantly to daily i.p. injections of CA (12.5 or 25 mg/kg) or vehicle. Across the treatment, the animals were submitted to behavioral evaluation in the catalepsy test (performed daily), open field test (7th day) and assessment of vacuous chewing movements (12th, 20th and 30th days). Upon completion of behavioral tests, rats were perfused and their brains underwent tyrosine hydroxylase (TH) immunohistochemical analysis. Our results showed that CA (12.5 e 25 mg/kg) prevented the increase in catalepsy behavior and number of vacuous chewing movements, but failed to revert the decreased open-field locomotor activity induced by RES. In addition, CA in both doses prevented the decrease in TH immunostaining induced by RES in the SNpc and dorsal striatum. Taken together, our results suggest that CA shows a protective effect in a rat model of PD, preventing motor and neurochemical impairments induced by RES. Thus, the use of CA as a promising new strategy for the prevention and/or treatment of PD may be considered.

Aluminum exposure for 60days at an equivalent human dietary level promotes peripheral dysfunction in rats.

Aluminum (Al) is a neurotoxic associated with a number of chronic human diseases. We investigated the effects of Al exposure at doses similar to human dietary levels and at a high level exposure to Al on the peripheral nervous system. Wistar male rats were divided into two major groups and received orally: 1) First group - Low level - rats were subdivided and treated for 60days: a) Control - received ultrapure water; b) AlCl3 - received Al at 8.3mg/kg body weight (bw) for 60days; and 2) Second group - High level - rats were subdivided and treated for 42days: C) Control - received ultrapure water through oral gavage; d) AlCl3 - received Al at 100mg/kg bw for 42days. Von Frey hair test, plantar test, the presence of catalepsy and the spontaneous motor activity were investigated. Reactive oxygen species, lipid peroxidation and total antioxidant capacity, immunohistochemistry to investigate the nerve inflammation and, the specific presence of Al in the sciatic nerve fibers were investigated. Al exposure at a representative human dietary level promotes the development of mechanical allodynia, catalepsy, increased inflammation in the sciatic nerve, systemic oxidative stress and, is able to be retained in the sciatic nerve. The effects of low-dose Al were similar to those found in rats exposed to Al at a dose much higher (100mg/kg). Our findings suggest that Al may be considered toxic for the peripheral nervous system, thus inducing peripheral dysfunction.

Catatonia y delirium: síndromes que pueden confluir en el paciente neuropsiquiátrico / Catatonia and Delirium: Syndromes that may Converge in the Neuropsychiatrie Patient

Resumen Introducción: La catatonia y el delírium son 2 síndromes diferentes e independientes. La catatonia es un síndrome psicomotor asociado a una variedad de enfermedades de diferentes causas médicas y está caracterizado por ausencia de actividad, inducción de posturas pasivas contra gravedad, la oposición o ausencia de respuesta ante estímulos externos, flexibilidad cérea, estereotipias, manierismos y ecofenómenos, entre otros. El delirium se caracteriza por alteraciones de la conciencia y cognitivas, principalmente atención y orientación, habitualmente de aparición aguda, que tiende a fluctuar durante el día y con evidencia de que la alteración es una consecuencia fisiológica directa de una enfermedad, una intoxicación o la abstinencia de alguna sustancia. A pesar de las diferencias y que las clasificaciones excluyen la posibilidad de que estos síndromes puedan presentarse juntos, varios reportes de casos y estudios en grupos de pacientes han planteado que pueden darse las 2 condiciones conjuntamente. Material y métodos: En el presente estudio se detectó a 16 pacientes hospitalizados en quienes concomitaban ambos síndromes, identificados mediante la escala Delirium rating scale-R (DRS-98) y la escala de Bush y Francis de Catatonia (BFCRS). Resultados: Se siguió el desenlace durante la hospitalización y su condición clínica al egreso. Estos pacientes en su mayoría tenían diagnósticos neurológicos, tuvieron una hospitalización larga, requirieron tratamiento con antipsicóticos y benzodiacepinas y sufrieron frecuentes complicaciones. Conclusiones: Catatonia y delirium son síndromes que pueden presentarse al mismo tiempo, lo que lleva a que los pacientes tengan peor desenlace y mayor riesgo de complicaciones.

Abstract Introduction: Catatonia and delirium are two different and independent syndromes. Catatonia is a psychomotor syndrome associated with a variety of diseases of different medical causes and is characterised by lack of activity, induction of passive postures against gravity, opposition or absence of response to external stimuli, waxy flexibility, stereotypies, mannerisms and echophenomena. Delirium is characterised by consciousness and cognitive alterations, mainly attention and orientation and usually of acute onset, which tend to fluctuate during the day and with evidence that the alteration is a direct physiological consequence of a disease, intoxication or substance withdrawal. Despite the differences and the fact that the classifications exclude the possibility that these syndromes may manifest together, several case reports and studies in groups of patients have postulated that the two conditions can occur together. Material and methods: In this study we identified 16 hospitalised patients who experienced both syndromes at the same time as confirmed by the Delirium Rating Scale-Revised (DRS-98) and the Bush-Francis Catatonia Rating Scale (BFCRS). Results: Patient outcome was followed during hospitalisation and the patients' clinical condition upon discharge. These patients had mostly neurological diagnoses, long hospital stays, required treatment with antipsychotics and benzodiazepines and had frequent complications. Conclusions: Catatonia and delirium are syndromes that can present at the same time, resulting in worse patient outcome and an increased risk of complications.

Influence of magnesium supplementation on movement side effects related to typical antipsychotic treatment in rats.

Chronic use of typical antipsychotic haloperidolis related to movement disturbances such as parkinsonism, akathisia and tardive dyskinesia which have been related to excitotoxicity in extrapyramidal brain areas, requiring their prevention and treatment. In the current study we evaluated the influence of the magnesium on prevention (for 28days before-), reversion (for 12days after-) and concomitant supplementation on haloperidol-induced movement disorders in rats. Sub-chronic haloperidol was related to orofacial dyskinesia (OD) and catalepsy development, increased generation of reactive species (RS) and levels of protein carbonyl (PC) in cortex, striatum and substantia nigra (SN) in all experimental protocols. When provided preventatively, Mg reduced the increase of OD and catalepsy time 14 and 7days after haloperidol administration, respectively. When supplemented after haloperidol-induced OD establishment, Mg reversed this behavior after 12days, while catalepsy was reversed after 6days of Mg supplementation.When Mg was concomitantly supplemented with haloperidol administration, OD and catalepsy were prevented. Moreover, Mg supplementation was able to prevent the RS generation in both cortex and SN, reducing PC levels in all brain areas evaluated. When supplemented after haloperidol, Mg reversed RS generation in cortex and striatum, decreasing PC levels in SN and striatum.The co-administration of haloperidol and Mg supplementation prevented RS generation in cortex, striatum and SN, and PC levels in the SN.These outcomes indicate that Mg supplementation may be a useful alternative to prevent movement disturbances resulting of classic antipsychotic pharmacotherapy as haloperidol.

Egg white hydrolysate promotes neuroprotection for neuropathic disorders induced by chronic exposure to low concentrations of mercury.

This study aims to investigate whether the egg white hydrolysate (EWH) acts on the neuropathic disorders associated with long-term Mercury (Hg) exposure in rats. 8- week-old male Wistar rats were treated for 60 days with: a) Control - saline solution (i.m.); b) Mercury - HgCl2 (1st dose 4.6µg/kg, subsequent doses 0.07µg/kg/day, i.m.); c) Hydrolysate - EWH (1g/kg/day, gavage); d) Mercury and Hydrolysate. Mechanical allodynia was assessed using Von Frey Hairs test; heat hyperalgesia by the plantar test; catalepsy by a modification of the "ring test" and spontaneous locomotor activity by a photocell activity chambers. Analyses were performed at 0, 30 and 60 days of treatment. Brain and plasma MDA, plasma NPSH and TNF-α determination and skin immunohistochemistry were performed at 60 days. Hg induced a reduction in mechanical sensitivity threshold at 30 and 60 days and in thermal sensitivity threshold at 60 days. At the end of treatment catalepsy was developed, but there was not significant alteration in spontaneous locomotor activity. Hg also increased brain and plasma MDA, plasma NPSH and TNF-α levels and the number of Merkel cell-neurite complex in the skin. EWH prevented the development of mechanical allodynia, thermal hyperalgesia and catalepsy induced by Hg and the increase in MDA concentration in brain and plasma and in the number of Merkel cell-neurite complex in the skin. In conclusion, EWH promotes neuroprotection against the toxic effects caused by Hg, demonstrating a beneficial therapeutic potential.

Post-trial dopaminergic modulation of conditioned catalepsy: A single apomorphine induced increase/decrease in dopaminergic activation immediately following a conditioned catalepsy response can reverse/enhance a haloperidol conditioned and sensitized catalepsy response.

Haloperidol can induce catalepsy and this drug effect can be conditioned as well as sensitized to contextual cues. We used a paired/unpaired Pavlovian conditioning protocol to establish haloperidol catalepsy conditioned and sensitized responses. Groups of rats were given 10 daily catalepsy tests following administration of vehicle (n=24) or haloperidol (1.0mg/kg) either paired (n=18) or unpaired (n=18) to testing. Subsequently, testing for conditioning was conducted and conditioning and sensitization of catalepsy were observed selectively in the paired group. Immediately following a second test for catalepsy conditioning, the groups were subdivided into 4 vehicle groups, 3 unpaired haloperidol groups and 3 paired haloperidol groups and were given one of three post-trial treatments (vehicle, 0.05mg/kg or 2.0mg/kg apomorphine). One day later the conditioned catalepsy test 3 was carried out and on the next day, a haloperidol challenge test was performed. The post-trial apomorphine treatments had major effects on the paired groups upon both conditioning and the haloperidol challenge test. The low dose apomorphine post-trial treatment enhanced both the conditioned and the haloperidol sensitized catalepsy responses. The high dose apomorphine post-trial treatment eliminated conditioned catalepsy and eliminated the initial acute catalepsy response to haloperidol that was induced in the vehicle control groups. These results demonstrate the sensitivity of conditioned drug cues to modification by increases/decreases in activity of the dopamine system in the immediate post-trial interval after a conditioning trial. This demonstration that post-trial dopaminergic drug treatments can modify conditioned drug behavior has broad implications for conditioned drug effects.

Prenatal exposure to integerrimine N-oxide enriched butanolic residue from Senecio brasiliensis affects behavior and striatal neurotransmitter levels of rats in adulthood.

Pyrrolizidine alkaloids (PAs) are toxins that are exclusively biosynthesized by plants and are commonly present in foods and herbs. PAs are usually associated with poisoning events in livestock and human beings. The aim of the present study was to evaluate the behavioral and neurochemical effects of prenatal exposure to PA integerrimine N-oxide of rats in adulthood. Pregnant Wistar rats received integerrimine N-oxide from the butanolic residue of Senecio brasiliensis by gavage on gestational days 6-20 at doses of 3, 6 and 9 mg/kg. During adulthood of the offspring, the following behavioral tests were performed: open-field, plus-maze, forced swimming, catalepsy and stereotypy. Histological analyses and monoamine levels were measured. Male offspring from dams that were exposed to 9 mg/kg showed an increase in locomotion in the open-field test, an increased frequency of entries and time spent in open arms in elevated plus-maze test, as well as decreased swimming time. In the female offspring from dams that were exposed to 9 mg/kg, there was an increased time of climbing in forced swimming and intensity of stereotyped behavior. The histological study indicates an increase in the number of multinucleated cells in the liver (6 and 9 mg/kg). In neurotransmitter analysis, specifically in the striatum, we observed change in dopamine and serotonin levels in the middle dose. Thus, our results indicate that prenatal exposure to integerrimine N-oxide changed behavior in adulthood and neurotransmitter levels in the striatum. Our results agree with previous studies, which showed that integerrimine N-oxide impaired physical and neurobehavioral development in childhood that can persist until adulthood.

The local application of a flavonoid, (-)-epicatechin, increases the spiking of globus pallidus neurons in a dose-dependent manner and diminishes the catalepsy induced by haloperidol.

Flavonoids are natural substances obtained from plants. Most flavonoids cross the blood-brain barrier and exert a wide range of effects on the central nervous system. These actions have been attributed to the modulation of GABA-A receptors. Although motor systems in the central nervous system express a high density of GABA-A receptors, physiological studies about the effects of flavonoids on motor nuclei are scarce. Among the nuclei of the basal ganglia, the globus pallidus is potentially important for the processing of information related to movement. The electrical activity of globus pallidus neurons depends on the GABAergic fibers coming from the striatum and recurrent collateral fibers. It is known that the basal activity of the globus pallidus is modified by blocking dopaminergic receptors. In the present work, we analyzed the effects of the local application of a flavonoid, (-)-epicatechin, on the spiking of globus pallidus neurons in chloral hydrate-anesthetized rats and determined whether (-)-epicatechin applied bilaterally to the globus pallidus can modify the catalepsy induced by systemic administration of haloperidol. The results showed that (-)-epicatechin increased the basal firing of globus pallidus neurons in a dose-dependent manner and antagonized the inhibitory effect of GABA. Bilateral infusion of (-)-epicatechin to the globus pallidus diminished the catalepsy induced by haloperidol.

Glutamatergic neurotransmission in the inferior colliculus influences intrastriatal haloperidol-induced catalepsy.

The inferior colliculus (IC) is an important midbrain relay station for the integration of descending and ascending auditory information. In addition, it has also been implicated in the processing of acoustic information of aversive nature, as well as in sensory-motor gating. There is evidence that glutamate-mediated mechanisms at the IC level influence haloperidol-induced catalepsy. The present study investigated the influence of glutamate-mediated mechanisms in the IC on catalepsy induced by intrastriatal microinjection of haloperidol (10 µg/0.5 µl). Male Wistar rats received bilateral intracollicular microinjections of the glutamate receptor agonist NMDA (10 or 20 nmol/0.5 µl), the NMDA receptor antagonists MK-801 (15 or 30 nmol/0.5 µl) or physiological saline (0.5 µl), followed by bilateral microinjections of haloperidol (10 µg/0.5 µl) or vehicle (0.5 µl) into the dorso-rostral or ventro-rostral striatum. The catalepsy test was performed positioning both forepaws of the rats on an elevated horizontal wooden bar and recording the time during which the animal remained in this position. The results showed that the administration of physiological saline in the IC followed by the microinjection of haloperidol in the dorso-rostral region of the striatum was not able to induce catalepsy. However, when the bilateral administration of NMDA into the IC was followed by microinjection of haloperidol into the dorso-rostral striatum, catalepsy was observed. The microinjection of haloperidol into the ventro-rostral striatum induced catalepsy, counteracted by previous administration of MK-801 into the IC. These findings suggest that glutamate-mediated mechanisms in the IC can influence the intrastriatal haloperidol-induced catalepsy and that the IC plays an important role as a sensorimotor interface.

The potency and efficacy of anticholinergics to inhibit haloperidol-induced catalepsy in rats correlates with their rank order of affinities for the muscarinic receptor subtypes.

Extrapyramidal syndromes (EPS) caused by antipsychotic therapy are currently treated with anticholinergics that lack selectivity for the five muscarinic receptor subtypes. Since these receptors are heterogeneously expressed among the different classes of striatal neurons and their afferents, it can be expected that their simultaneous blockade will cause distinct, sometimes opposed, effects within the striatal circuitry. In order to test the hypothesis that the differential blockade of the muscarinic receptor subtypes would influence their potency and efficacy to prevent EPS, here we tested four anticholinergics with varying order of affinities for the muscarinic receptor subtypes, and compared their dose-response curves to inhibit haloperidol-induced catalepsy in male rats. Drugs were applied into the lateral ventricle 15 min before haloperidol (2 mg/kg, s.c.). Catalepsy was measured in the bar test at 15 min intervals during 5 h. The preferential M1/M4 antagonist pirenzepine (3, 10, 30, 100, and 300 nmol) caused a dose-dependent inhibition of catalepsy intensity: ED50 = 5.6 nmol [95% CI, 3.9-8.1], and latency: ED50 = 5.6 nmol [95% CI, 3.7-8.6]. Pirenzepine had the steepest dose-response curve, producing maximal inhibition (84 ± 5%) at the dose of 10 nmol, while its effect tended to reverse at higher doses (62 ± 11%). The purported M1/M3 antagonist 4-DAMP (30, 100, and 300 nmol) also caused a dose-dependent inhibition of catalepsy intensity: ED50 = 29.5 nmol [95% CI, 7.0 to 123.0], and latency: ED50 = 28.5 nmol [95% CI, 2.2 to 362.0]. However, the curve for 4-DAMP had a less pronounced slope, reaching its maximal effect (63 ± 14%) at the dose of 300 nmol. The M2/M4 antagonist AF-DX 116 (10, 30, and 300 nmol) only caused a partial inhibition of catalepsy (30 ± 11%) at the dose of 30 nmol, but this changed to a non-significant increment (15 ± 10%) at the dose of 100 nmol. The alleged M4 antagonist tropicamide (30, 100, 300, and 600 nmol) produced a partial inhibition of catalepsy (36 ± 12%) at the dose of 300 nmol, but lacked effect at higher or lower doses. Concurrent treatment with pirenzepine (10 nmol) and tropicamide (300 nmol) produced an effect similar to that of tropicamide alone. The greater potency and efficacy of pirenzepine for catalepsy inhibition could be due to its higher affinity for M1 receptors and, to a lesser extent, for M4 receptors. It is suggested that selective M1 antagonists would be more effective than M2, M3 or M4 antagonists to prevent EPS caused by antipsychotic drugs.

Distinct effects of haloperidol in the mediation of conditioned fear in the mesolimbic system and processing of unconditioned aversive information in the inferior colliculus.

Chemical and electrical stimulation of the inferior colliculus (IC) causes defensive behavior. Electrical stimulation of the IC at the escape threshold enhances dopamine (DA) release in the prefrontal cortex. Intra-ventral tegmental area injections of quinpirole at doses that act presynaptically reduce the release of DA in the terminal fields of the mesolimbic system and clearly reduce conditioned fear in several animal models of anxiety. However, little is known about the involvement of DA in the mediation of unconditioned fear, such as the reactivity to acute stressors. The present study investigated the neural substrates mediated by DA transmission associated with emotional changes triggered by the activation or inhibition of D2 receptors during conditioned and unconditioned fear. We examined the effects of systemic or local injections of the DA-receptor antagonist and agonist haloperidol and quinpirole, respectively, into the IC in rats subjected to fear-potentiated startle, a Pavlovian paradigm that uses loud sounds as the unconditioned stimulus and light previously paired with footshock as the conditioned stimulus. We also assessed auditory-evoked potentials (AEPs) recorded from electrodes implanted in the IC. Intraperitoneal haloperidol administration dose-dependently enhanced AEPs induced by loud tones and inhibited fear-potentiated startle. Intra-IC injections of quinpirole left AEPs unchanged, suggesting that an optimal level of postsynaptic D2 receptors in the IC may regulate the transmission of aversive information through the midbrain tectum. These findings provide evidence of opposing DA-mediated mechanisms in fear/anxiety processes that depend on the area under study. The activity of the neural substrates of conditioned fear was attenuated by haloperidol, whereas midbrain neural substrates of unconditioned fear were enhanced. Thus, DA appears to regulate unconditioned fear at the midbrain level, likely by reducing the sensory gating of aversive events and reducing conditioned fear by acting at more rostral levels of the brain.

Dopaminergic mechanisms underlying catalepsy, fear and anxiety: do they interact?

Haloperidol is a dopamine D2 receptor antagonist that induces catalepsy when systemically administered to rodents. The haloperidol-induced catalepsy is a state of akinesia and rigidity very similar to that seen in Parkinson's disease. There exists great interest in knowing whether or not some degree of emotionality underlies catalepsy. If so, what kind of emotional distress would permeate such motor disturbance? This study is an attempt to shed some light on this issue through an analysis of ultrasound vocalizations (USVs) of 22 kHz, open-field test, and contextual conditioned fear in rats with some degree of catalepsy induced by haloperidol. Systemic administration of haloperidol caused catalepsy and decreased exploratory activity in the open-field. There was no difference in the emission of USVs between groups during the catalepsy or the exploratory behavior in the open-field test. In the contextual conditioned fear, when administered before training session, haloperidol did not change the emission of USVs or the freezing response. When administered before testing session, haloperidol enhanced the freezing response and decreased the emission of USVs on the test day. These findings suggest that the involvement of dopaminergic mechanisms in threatening situations depends on the nature of the aversive stimulus. Activation of D2 receptors occurs in the setting up of adaptive responses to conditioned fear stimuli so that these mechanisms seem to be important for the emission of 22 kHz USVs during the testing phase of the contextual conditioned fear, but not during the training session or the open-field test (unconditioned fear stimuli). Catalepsy, on the other hand, is the result of the blockage of D2 receptors in neural circuits associated to motor behavior that appears to be dissociated from those directly linked to dopamine-mediated neural mechanisms associated to fear.