Rafael Castro

Increased or decreased locomotor response in rats following repeated administration of apomorphine depends on dosage interval

Administration of drugs that reduce the influence of dopamine at its receptor site can lead to postsynaptic supersensitivity, whereas treatment with dopamine (DA) agonists can cause postsynaptic subsensitivity. Both unaltered and enhanced postsynaptic responses to DA have been shown after pretreatment with DA agonists. In the present manuscript pretreatment with apomorphine, a dopaminergic agonist, is shown to induce either increased or reduced locomotor activity. When a drug-free period between successive injections was allowed, apomorphine induced an enhanced locomotor response, whereas a reduced response occurred when each dose was injected before the previous apomorphine dose had been completely metabolized. Pretreatment with both high (1 and 3 mg/kg) and low (0.05 mg/kg) apomorphine doses enhanced the response. Apomorphine treatment that caused enhanced locomotor responses did not modify the stereotypy response to the drug. Similar enhanced or reduced response were found in rats with partial lesions of the nigrostriatal system. These altered responses to DA agonists may have important clinical consequences. The present data also suggest the existence of a different DA systems for locomotor and stereotypy actions of dopaminergic agonists.

Tyrosine administration to pregnant rats induces persistent behavioral modifications in the male offspring

Pregnant rats were given, by stomach intubation, 1-tyrosine (20 or 500 mg/kg), beginning on day 11 post-coitus. Tyrosine or saline solution administrations were continued on a once-daily basis until day 20 of gestation. When male offspring were seventy days old, the spontaneous locomotor activity, open field test, swim test and motor ability test were performed. The offspring treated with large tyrosine doses showed a marked increase in both spontaneous locomotor activity and open field locomotion as adults. However, activity in the swim test decreased. The number of defecation boluses produced in the open field test and the motor ability in the rotating rod test diminished. The behavior of the rats treated with small doses of tyrosine was similar, in all tests performed, to that of rats treated with saline solution. These findings strongly suggest that a large increase in diet tyrosine during pregnancy modifies the behavior of male offspring.

Apomorphine lowers dopamine synthesis for up to 48 h: implications for drug sensitization.

Previous reports have shown that tolerance or sensitization to apomorphine depends on the dosage interval. The effect of apomorphine on behaviour increases when there is a drug-free period between successive injections. Here we studied the biochemical action of apomorphine during a drug-free period. The experiments showed that dopamine level and dopamine turn-over are persistently inhibited for at least 48 h after apomorphine administration. At 24 h after drug injection, there was a decrease of both DOPAC level and tyrosine hydroxylase activity. The results suggest that apomorphine induces long-lasting dopaminergic inhibition action that increases drug-induced behavioural response, perhaps after development of postsynaptic hypersensitivity.

Fetal brain serotonin synthesis and catabolism is under control by mother intake of tryptophan

Previous morphological studies reported that serotonergic neurons appear in rats in the second half of prenatal life. Initially the biochemical differentiation of these neurons before birth was studied. Both serotonin (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) was detected in the fetal brain on day 15 of gestation. During prenatal development an increase was detected in the brain levels of 5-HT (200% higher on day 19 than on day 15) and 5-HIAA (700% higher on day 19 than on day 15). Oral administration of tryptophan to pregnant rats induced a dose-related increase of tryptophan concentration in different fetal tissues, including brain. The increase in tryptophan tissue concentration was detected for low doses (50 mg/kg) and remained unsaturated after administration of high doses (1000 mg/kg). This observation suggests that the placental barrier is not effective to block the influx of high levels of tryptophan to the fetus. Tryptophan concentration in the brain is 300% higher than in the carcass and 600% higher than in the placenta. These data suggest a mechanism to assume a role in concentrating of tryptophan in the brain. Finally, it was found that an increase in brain tryptophan induced changes in both serotonin and 5-HIAA brain levels, but did not modify tyrosine, dopamine or norepinephrine levels. Thus, under physiological conditions, tryptophan hydroxylase activity in prenatal brain is probably not saturated by its substrate tryptophan.

Conditioning of the early behavioral response to apomorphine in the rotational model of Parkinson's disease

The rotational model of Parkinsons disease has been widely used to investigate the action of dopamine agonists. This animal model involves the production of a unilateral nigrostriatal lesion in rats. The lesion is produced with 6-hydroxydopamine which causes dopamine depletion and subsequent supersensitivity of striatal receptors. Thus, administration of drugs which are therapeutically effective in Parkinsons disease, elicits circling behavior contralateral to the lesioned side. The origin of the paradoxical response and the undrugged rotations observed after saline injections in apomorphine pretreated rats has not been explained. We report here that the undrugged response can be associated with the early rotational response elicited by the drug. Furthermore, we show the effect of inhibitory conditioning on this early response. Our results suggest that pharmacological conditioning plays a significant role in the modification of the therapeutic effectiveness of CNS-active drugs after extended treatments.

Undrugged rotational response in nigro-striatal system-lesioned rats is related to the previous early response to apomorphine when repeatedly administered

Development and time-course characteristics of undrugged rotational response weeks or months after repeated apomorphine administration in 6-hydroxydopamine-lesioned rats were explored. In one series of experiments, all groups received several drug doses two-three weeks post-lesion and remained undrugged at different intervals from the last drug injection. Weeks or months later, they were injected with saline in the same environment where they previously had received apomorphine. In this way we studied acquisition, time-course and extinction of the rotational response after saline. Furthermore, we related this undrugged response which does not fully develop until two weeks after treatment, and which previously had not been related to a specific parameter of the rotational response to the drug, to a critical point of the time-course response to the drug, i.e., the early rotational response in the first minute after injection. This early response is a learning phenomenon based on the environmental cues where drug has been repeatedly administered. Finally, we state the concept of pharmacological conditioning using this animal model of Parkinsons disease, in agreement with our own results and the previous results of Silverman and Ho (1981).

Different roles of intrahypothalamic and nigrostriatal dopaminergic systems in thermoregulatory responses of the rat

Classically, two neurotransmitters in the brain have been implicated in thermoregulation: 5-hydroxytryptamine and norepinephrine. A dopamine action is less well-known and usually has been studied by means of pharmacological rather than physiological procedures. In the present work using a physiological approach to the problem, the role of different central dopaminergic systems in the thermoregulatory response of rats exposed to cold (4 degrees C) or warm (45 degrees C) environments has been studied. Rostral incertohypothalamic neurons in the medial preoptic area synthesized and released more dopamine in response to a warm but not to a cold environment. On the other hand DA and DOPAC levels in nigrostriatal systems were decreased by cold but not warm environments. The dopaminergic neurons projecting to nucleus accumbens or hypothalamus do not appear to be related to the thermoregulatory response in the rat.

The degeneration and replacement of dopamine cells in Parkinson's disease: the role of aging

Available data show marked similarities for the degeneration of dopamine cells in Parkinson’s disease (PD) and aging. The etio-pathogenic agents involved are very similar in both cases, and include free radicals, different mitochondrial disturbances, alterations of the mitophagy and the ubiquitin-proteasome system. Proteins involved in PD such as α-synuclein, UCH-L1, PINK1 or DJ-1, are also involved in aging. The anomalous behavior of astrocytes, microglia and stem cells of the subventricular zone (SVZ) also changes similarly in aging brains and PD. Present data suggest that PD could be the expression of aging on a cell population with high vulnerability to aging. The future knowledge of mechanisms involved in aging could be critical for both understanding the etiology of PD and developing etiologic treatments to prevent the onset of this neurodegenerative illness and to control its progression.

Prenatal haloperidol treatment decreases nerve growth factor receptor and mRNA in neonate rat forebrain

Pregnant rats were treated daily with haloperidol (2 mg/kg) for 11 days until 1 day before birth. The levels of nerve growth factor (NGF), its receptor (NGFR) and NGFR-mRNA were measured in forebrain of 2-day old postnatal rats. Using Northern blot analysis, we observed a decrease in NGFR-mRNA. Furthermore, in binding studies, Kd and Bmax of treated rats were lower than in controls, but only in the low affinity binding sites. However NGF and its mRNA did not change after haloperidol treatment. In conclusion, our results suggest that prenatal haloperidol treatment can modify the development of forebrain cells, by changing NGFR expression.

Tyrosine availability and brain noradrenaline synthesis in the fetus: control by maternal tyrosine ingestion

In spite of substantial evidence that tyrosine availability modulates catecholamine synthesis, under a variety of conditions, in adult brains, its possible influence during brain development has received little attention. In the present paper, the effect of tyrosine when administered to pregnant rats on tyrosine and noradrenaline brain levels in the fetus was investigated. In the first experiment noradrenaline (NA) was detected in the fetal brain by day 13 of development. NA levels increased from days 13 to 19. Administration of tyrosine to the mother raises both tyrosine and NA levels in the fetal brain. The increase in tyrosine was similar on days 13, 15, 17 and 19 of pregnancy. However, the increase of NA was more pronounced on days 17 and 19 than on days 13 or 15. Tyrosine and NA enhancement was detected 30 min after tyrosine administration, persisted for at least 2 h and disappeared completely 6 h after its administration. Both tyrosine and NA increase are tyrosine dose-related. The present studies suggest that there are no important barriers for tyrosine transport between the maternal blood and the fetal brain. Furthermore, during prenatal life the rate of NA synthesis is regulated by tyrosine brain concentration and therefore maternal intake of tyrosine is an important factor for noradrenaline synthesis regulation in the fetal brain. The possible functional significance of noradrenaline brain increase after tyrosine administration are unknown. However, the NA modification could be the cause of the persistent behavioral modification that we have found in adult rats whose mothers were treated with tyrosine during pregnancy.