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.

Valeriana officinalis does not alter the orofacial dyskinesia induced by haloperidol in rats: role of dopamine transporter.

Chronic treatment with classical neuroleptics in humans can produce a serious side effect, known as tardive dyskinesia (TD). Here, we examined the effects of V. officinalis, a medicinal herb widely used as calming and sleep-promoting, in an animal model of orofacial dyskinesia (OD) induced by long-term treatment with haloperidol. Adult male rats were treated during 12 weeks with haloperidol decanoate (38 mg/kg, i.m., each 28 days) and with V. officinalis (in the drinking water). Vacuous chewing movements (VCMs), locomotor activity and plus maze performance were evaluated. Haloperidol treatment produced VCM in 40% of the treated rats and the concomitant treatment with V. officinalis did not alter either prevalence or intensity of VCMs. The treatment with V. officinalis increased the percentage of the time spent on open arm and the number of entries into open arm in the plus maze test. Furthermore, the treatment with haloperidol and/or V. officinalis decreased the locomotor activity in the open field test. We did not find any difference among the groups when oxidative stress parameters were evaluated. Haloperidol treatment significantly decreased [(3)H]-dopamine uptake in striatal slices and V. officinalis was not able to prevent this effect. Taken together, our data suggest a mechanism involving the reduction of dopamine transport in the maintenance of chronic VCMs in rats. Furthermore, chronic treatment with V. officinalis seems not produce any oxidative damage to central nervous system (CNS), but it also seems to be devoid of action to prevent VCM, at least in the dose used in this study.

[Effects of metoclopramide-induced hyperprolactinemia on the murine corneal]. / Efeito da hiperprolactinemia induzida pela metoclopramida na córnea de camundongas.

PURPOSE: To evaluate the morphological changes in murine cornea upon metoclopramide-induced hyperprolactinemia during the proestrous phase or pregnancy. METHODS: Forty adult mice were divided into two groups: (control) CTR1 and (treated with metoclopramide (MET1). After fifty days, half of the mice were sacrificed. The remaining animals were mated, and then labeled as pregnant controls (CTR2). Part of these animals were treated with metoclopramide and constituted the metoclopramide-treated pregnant (MET2) group. The groups CTR2 and MET2 were sacrificed on the 6th day of pregnancy. The hormonal levels were assessed by chemioluminescence and radioimmunoassay methods and the cornea was removed for the histomorphometric study. RESULTS: The epithelial, stromal, endothelial and total thickness in the experimental group was: MET1 and MET2 were higher than one in the control group: CTR1 and CTR2. There was a significant reduction of the hormonal level in the animals that received metoclopramide as compared to controls (CTR1: estradiol = 156.6 +/- 42.2 pg/ml; progesterone = 39.4 +/- 5.1 ng/ml; prolactin = 130.4 +/- 26.2 ng/ml; MET1: estradiol = 108.0 +/- 33.1 pg/ml; progesterone = 28.0 +/- 6.4 ng/ml; prolactin = 551.5 +/- 23.3 ng/ml; CTR2: estradiol = 354.0 +/- 56.0 pg/ml; progesterone = 251.0 +/- 56.0 ng/ml; prolactin = 423.2 +/- 28.1 ng/ml; MET2: estradiol = 293.0 +/- 43.0 pg/ml; progesterone = 184.0 +/- 33.0 ng/ml; prolactin = 823.1 +/- 51.1 ng/ml). CONCLUSION: The metoclopramide-induced hyperprolactinemia may increase corneal layers, mainly in pregnant mice. Possibly, this effect is related to reduction in estrogen and progesterone production.

Efeito da hiperprolactinemia induzida pela metoclopramida na córnea de camundongas / Effects of metoclopramide-induced hyperprolactinemia on the murine corneal

OBJETIVO: Avaliar as alterações morfológicas promovidas pela hiperprolactinemia induzida pela metoclopramida na córnea de camundongas durante a fase de proestro e na gestação. MÉTODOS: Quarenta camundongas adultas foram divididas, aleatoriamente, em dois grupos, a saber: controle (CTR1) e metoclopramida (MET1). Após 50 dias metade dos animais de cada grupo foram sacrificados. O restante dos animais foi acasalado, constituindo dois grupos: controle prenhe (CTR2) e o metoclopramida prenhe (MET2), que foi sacrificado no 6° dia de gestação. Após decapitação dos animais coletou-se sangue para dosagens de estradiol, progesterona e prolactina, em seguida removidos os globos oculares para estudo histomorfométrico da córnea. RESULTADOS: As espessuras do epitélio, estroma, endotélio e a espessura total das córneas dos grupos experimentais: MET1 e MET2 mostraram-se mais espessados quando comparados com os grupos controles: CTR1 e CTR2, respectivamente. Houve redução dos níveis hormonais do estrogênio e da progesterona nos animais que receberam metoclopramida em comparação com os respectivos controles (CTR1: estradiol = 156,6±42,2 pg/ml; progesterona = 39,4±5,1 ng/ml; prolactina = 130,4±26,2 ng/ml; MET1: estradiol = 108,0±33,1 pg/ml; progesterona = 28,0±6,4 ng/ml; prolactina = 551,5± 23,3 ng/ml; CTR2: estradiol = 354,0±56,0 pg/ml; progesterona = 251,0± 56,0 ng/ml; prolactina = 423,2±28,1 ng/ml; MET2: estradiol = 293,0± 43,0 pg/ml; progesterona = 184,0±33,0 ng/ml; prolactina = 823,1±51,1 ng/ml). CONCLUSÃO: A hiperprolactinemia induzida pela metoclopramida produziu espessamento da córnea, sobretudo, em camundongas prenhes. Possivelmente este efeito está relacionado com a redução da produção hormonal de estrogênio e de progesterona.

PURPOSE: To evaluate the morphological changes in murine cornea upon metoclopramide-induced hyperprolactinemia during the proestrous phase or pregnancy. METHODS: Forty adult mice were divided into two groups: (control) CTR1 and (treated with metoclopramide (MET1). After fifty days, half of the mice were sacrificed. The remaining animals were mated, and then labeled as pregnant controls (CTR2). Part of these animals were treated with metoclopramide and constituted the metoclopramide-treated pregnant (MET2) group. The groups CTR2 and MET2 were sacrificed on the 6th day of pregnancy. The hormonal levels were assessed by chemioluminescence and radioimmunoassay methods and the cornea was removed for the histomorphometric study. RESULTS: The epithelial, stromal, endothelial and total thickness in the experimental group was: MET1 and MET2 were higher than one in the control group: CTR1 and CTR2. There was a significant reduction of the hormonal level in the animals that received metoclopramide as compared to controls (CTR1: estradiol = 156.6±42.2 pg/ml; progesterone = 39.4±5.1 ng/ml; prolactin = 130.4±26.2 ng/ml; MET1: estradiol = 108.0±33.1 pg/ml; progesterone = 28.0±6.4 ng/ml; prolactin = 551.5±23.3 ng/ml; CTR2: estradiol = 354.0±56.0 pg/ml; progesterone = 251.0±56.0 ng/ml; prolactin = 423.2±28.1 ng/ml; MET2: estradiol = 293.0±43.0 pg/ml; progesterone = 184.0±33.0 ng/ml; prolactin = 823.1±51.1 ng/ml). CONCLUSION: The metoclopramide-induced hyperprolactinemia may increase corneal layers, mainly in pregnant mice. Possibly, this effect is related to reduction in estrogen and progesterone production.

Postnatal haloperidol eliminates the deficit in circling behavior produced by prenatal exposure to the same drug.

Up to 35% of pregnant women take psychotropic drugs at least once during gestation [Austin and Mitchell, 1998]. From concurrent animal and human evidence, it has been proposed that exposure to several psychoactive medications in utero or during lactation increases the risk for permanent brain disorders. Present preventive or therapy practices applied on humans for this type of long-lasting behavioral alterations are mainly based on empirical results. Here, we test an experimental approach designed to counteract a circling performance deficit that appears in Sprague-Dawley rats at puberty on exposure to the dopaminergic blocker haloperidol (HAL) during gestation [J.L. Brusés, J.M. Azcurra, The circling training: A behavioral paradigm for functional teratology testing, in: P.M. Conn (Ed.), Paradigms for the study of behavior, Acad. Press, New York, 1993, pp. 166-179. Method Neurosci. 14]. Gestational exposure to HAL (GD 5-18, 2.5 mg/kg/day ip) induced the expected circling activity decrease in the offspring at the fifth week of life. When prenatal exposure to HAL was continued through lactation (PD5-21, 1.5 mg/kg/day ip), rats otherwise showed a control-like circling performance. No difference was yet found between lactation-only, HAL-exposed pups and saline (SAL)-treated controls (n=8 each group). We further performed saturating (3H)-spiroperidol (SPI) binding assays on striatal P2 membrane fractions 2 months later. The dopamine-type D2-specific binding results suggested that above circling behavior findings could be partially explained by enduring HAL-induced neurochemical changes. The role of critical periods of sensitivity as transient windows for opportunistic therapies for behavioral teratology is discussed.

Effects of Ipomoea carnea aqueous fraction intake by dams during pregnancy on the physical and neurobehavioral development of rat offspring.

The effects of daily prenatal exposure to 0.0, 0.7, 3.0 and 15.0 mg/kg of the aqueous extract (AQE) of Ipomoea carnea dried leaves on gestational days 5-21 were studied in rat pups and adult offspring. The physical and reflex developmental parameters, open-field, plus-maze, social interaction, forced swimming, catalepsy and stereotyped behaviors, as well as striatal, cortical and hypothalamic monoamine levels (at 140 days of age) were measured. Maternal and offspring body weights were unaffected by exposure to the different doses of the AQE. High postnatal mortality, smaller size at Day 1 of life, reversible hyperflexion of the carpal joints and delay in the opening of both ears and in negative geotaxis were observed in the offspring exposed to the higher dose of AQE. At 60 and 90 days of age, open-field locomotion frequency was quite different between 0.0 and animals treated with 0.7 and 3.0 mg/kg AQE. No changes were observed in the plus-maze, social interaction, forced swimming, catalepsy, stereotyped behavior and central nervous system monoamines concentrations. Dams treated with the higher AQE dose showed severe cytoplasmic vacuolation in liver, kidney, pancreas and thyroid tissues, in contrast to the mild vacuolation observed in the other experimental groups. No alterations were observed in the histopathological study of the offspring of all experimental groups at 140 days of age. During adulthood, behavior was not modified in offspring exposed to the higher dose of AQE as well as no changes occurred in central nervous system neurotransmitters. The present data show that the offspring development alterations were not severe enough to produce behavioral and central monoamine level changes.

Undernutrition during suckling changes the sensitivity to haloperidol and chlorpromazine in two behavioural measures in weaning rats.

Undernutrition during critical periods of development may cause changes in the behavioural responses of rats to centrally acting drugs. In the present study, the effects of undernutrition during suckling on the behavioural responses of 21-days-old rats to chlorpromazine (0, 2.5, 5, 10 and 20 mg/kg) or haloperidol (0, 0.125, 0.25, 0.5, 1 or 2 mg/kg) were examined. Locomotion was assessed at 1 hr 30 min., 4 hr 30 min., 7 hr 30 min, and 10 hr 30 min., and catalepsy was scored at 3 hr, 6 hr and 9 hr after drug administration. Drug was injected on two consecutive days. On day 1, saline-treated undernourished rats showed significantly greater locomotion activity than did normal rats. The neuroleptic-induced inhibition of locomotor activity in undernourished rats was significantly less than that observed in normal rats from 4 hr 30 min. to 10 hr 30 min. (chlorpromazine) or from 7 hr 30 min. to 10 hr 30 min. (haloperidol). On day 2, a similar trend was observed but only in rats injected with 5 mg/kg chlorpromazine or 0.5, 1, and 2 mg/kg haloperidol. On day 1, the catalepsy scores at 3 hr revealed no significant difference between nutritional groups, but at 6 hr undernourished rats responded significantly less to chlorpromazine or haloperidol. On day 2, undernourished rats were less responsive to neuroleptics than normal rats, but the effect was not so evident as observed on day 1. The present results suggest that the behavioural effects of chlorpromazine and haloperidol are less persistent in undernourished rats, possibly due to differences in drug distribution and elimination, when compared to well-nourished rats.

Metabolic effects of trifluoperazine in the liver and the influence of calcium.

The effects of trifluoperazine on hepatic cell metabolism were investigated using isolated perfused rat liver. The following effects of trifluoperazine were found: (1) trifluoperazine inhibited oxygen uptake, the site of action being the mitochondria. Half-maximal inhibition occurred at concentrations around 50 microM; with 100 microM trifluoperazine the effect was already maximal. When Ca2+ was withdrawn from the perfusion medium and the intracellular Ca2+ pools were exhausted, the inhibitory action on respiration was no longer observable. The reintroduction of Ca2+ restored inhibition. (2) Glycogenolysis and glycolysis were not significantly affected during the infusion of trifluoperazine. After stopping trifluoperazine infusion, however, glycogenolysis (glucose release) experienced a transitory stimulation. (3) Gluconeogenesis from lactate as the carbon source was inhibited by trifluoperazine. This inhibition was approximately proportional to the inhibition of oxygen uptake. Withdrawal of Ca2+ diminished, but it did not eliminate, inhibition of gluconeogenesis. (4) Ketogenesis was also inhibited in parallel with the inhibition of oxygen uptake. Withdrawal of Ca2+ from the perfusion fluid also abolished this action. (5) The effects of trifluoperazine were reverted very slowly when its infusion was stopped. The recovery of oxygen uptake at 50 min after cessation of the infusion was only 30%. Uptake of the substance was very fast. Absence of Ca2+ did not affect uptake. It was concluded that inhibition of mitochondrial energy metabolism is one of the most prominent effects of trifluoperazine in the liver. The fact that this inhibition depends on Ca2+ is unique.