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Low-dose quinpirole ontogenically sensitizes to quinpirole-induced yawning in rats

It is known that dopamine (DA) receptors can be sensitized by repeated treatments with quinpirole during postnatal development. This study was undertaken to determine whether low-dose quinpirole treatments might sensitize receptors to quinpirole-induced yawning behavior. Rats were treated with quinpirole HCl (50 micrograms/kg per day) or saline at four different periods of ontogeny: a) the 10th day of gestation to day of birth; b) 1st-11th days after birth; c) 12th-22nd days from birth; or d) 23rd-33rd days from birth. The numbers of yawns occurring in 1 h after a challenge dose of quinpirole HCl (50 micrograms/kg, IP) was determined at 6 weeks. Rats exposed prenatally to quinpirole demonstrated increased numbers of yawns following the third dose of quinpirole (2-day interval between doses). In rats exposed postnatally to quinpirole, there was a 70-300% increase in the yawning response, with the greatest response occurring in the group treated with quinpirole from birth to 11 days from birth. The findings demonstrate that quinpirole receptors are sensitized by a low dose of quinpirole, 60-fold lower than previously shown. It is suggested that sensitized receptors are of the DA D3 subclass.

Nicotine blocks quinpirole-induced behavior in rats: psychiatric implications

Abstractu2002Rationale and objectives: Because of known and imputed roles of dopaminergic and nicotinic cholinergic systems in a variety of neurological and neuropsychiatric disorders, combined neurochemical and behavioral methods assessments were made to study the intermodulatory roles of these neurochemical systems. Methods: Rats were treated daily during postnatal ontogeny with the dopamine D2/D3 agonist, quinpirole (QNP) HCl (1.0 mg/kg/day), for the first 3 weeks from birth. This priming process replicated previous findings of behavioral sensitization, manifested as hyperlocomotion, increased paw treading with jumping, and increased yawning. Results: All effects were partially or totally blocked by acute treatment with nicotine (0.3 mg/kg, i.p.). The effects of nicotine, in turn, were partially or totally blocked by the nicotinic antagonist, mecamylamine (1.0 mg/kg, i.p.). In concert with these behavioral actions, QNP-primed rats displayed greater binding of [3H]cytisine in midbrain and cerebellum and greater [125I]α-bungarotoxin binding in hippocampus and striatum. Conclusions: Accordingly, these selective ligands for α4β2 and α7 nicotinic receptors, respectively, demonstrate that nicotinic receptors are altered by dopamine D2/D3 agonist treatment of rats with primed dopamine receptors. We propose that nicotinic agonists may have a therapeutic benefit in behavioral disorders brought about by central dopaminergic imbalance.

Age-dependence of a 6-hydroxydopamine lesion on SKF 38393- and m-chlorophenylpiperazine-induced oral activity responses of rats

Neonatal 6-hydroxydopamine (6-OHDA) treatment is associated with destruction of dopamine (DA) fibers and subsequent sprouting of serotonin (5-HT) fibers in the striatum of rats. Enhanced oral activity responses to SKF 38393 and m-chlorophenylpiperazine (m-CPP), respective agonists for the DA D1 receptor complex and 5-HT2C receptor complex, ensue. To study the ontogenetic nature of this effect, rats were treated at birth, 3 days, 7 days, 10 days or 14 days with 6-OHDA-HBr (200 micrograms i.c.v.; salt form), following desipramine-HCl pretreatment (20 mg/kg i.p., 1 h; base form). Another group of rats was treated at 35 days and again at 42 days with 6-OHDA-HBr (300 micrograms i.c.v.), following desipramine-HCl (20 mg/kg i.p., 1 h) and pargyline-HCl (50 mg/kg i.p., 30 min). In rats treated from birth to 10 days, 6-OHDA reduced striatal DA content at 5 months by > or = 94%. Striatal 5-HT content was elevated by 28% to 51%, but only in rats treated with 6-OHDA at 7 days from birth or earlier. An enhanced oral activity response to SKF 38393-HCl (0.03 to 1.0 mg/kg i.p.) was absent in rats treated 7 days or later, and the change in SKF 38393 effect was correlated with a change in striatal DA content. An enhanced response to m-CPP.2HCl (0.3 to 6.0 mg/kg i.p.) was absent after treatment at 14 or 35 days, when striatal DA content was reduced only 44% to 63% and 5-HT content was not changed.(ABSTRACT TRUNCATED AT 250 WORDS)

Ontogenetic SKF 38393 treatments sensitize dopamine D1 receptors in neonatal 6-OHDA-lesioned rats

Neonatal 6-hydroxydopamine (6-OHDA) treatment of rats is associated with supersensitization of the dopamine (DA) D1 agonist induction of stereotyped and locomotor behaviors. The present study was conducted to determine whether ontogenetic treatments of these rats with the DA D1 receptor agonist, SKF 38393, would produce a maximal DA D1 receptor supersensitivity, as measured by locomotor behavior in adulthood. Rat pups were treated daily with SKF 38393-HCl (3.0 mg/kg per day, i.p.) or saline vehicle for 28 consecutive days from birth. These animals were additionally treated at 3 days after birth with 6-OHDA-HBr (100 micrograms, in each lateral ventricle, salt form) or its vehicle. Between 6 and 9 weeks locomotor activity or stereotyped behaviors were observed after weekly challenge doses of SKF 38393-HCl (3.0 mg/kg, i.p.). In the neonatal 6-OHDA group, successive SKF 38393 treatments produced progressively greater locomotor activity. In the group of rats treated during postnatal ontogeny with both 6-OHDA and SKF 38393 daily treatments, the first adult challenge dose of SKF 38393 produced an enhanced locomotor response, greater than that seen in other groups (P < 0.01). Subsequent SKF 38393 treatments of this group produced increasingly greater locomotor responses. SKF 38393-induced stereotyped behavioral effects were greater in the 6-OHDA-lesioned groups, whether or not SKF 38393 was administered ontogenetically. Profound reductions (> 99%) of DA and its metabolites were found in the striatum of neonatal 6-OHDA treated rats, regardless of whether SKF 38393 was co-administered ontogenetically.(ABSTRACT TRUNCATED AT 250 WORDS)

Ontogenetic homologous sensitization to the antinociceptive action of quinpirole in rats

Repeated postnatal treatment of rats with the dopamine receptor agonist, quinpirole results in exaggeration of selected behaviors that are induced by quinpirole in adulthood. To determine whether the antinociceptive response to quinpirole could be similarly enhanced, rats were treated daily from birth with quinpirole HCl (3.0 mg/kg per day i.p. x 28 days) and their response time in the hot plate analgesia test was determined at 4 months. An acute dose of quinpirole HCl (100 or 1000 micrograms/kg i.p.) produced an analgesic response in the neonatally primed rats and in the vehicle controls. More significantly, the effect was substantially greater in the quinpirole-primed group at each of these two doses of quinpirole. This effect of quinpirole was fully attenuated in both groups by treatment with the dopamine receptor antagonist, spiperone HCl (0.30 mg/kg i.p., 1 h before quinpirole). The analgesic effect of morphine sulfate (6.0 mg/kg i.p.) was not greater in the quinpirole-primed group. These findings demonstrate that the ontogenetic sensitization of quinpirole receptors results in enhanced antinociceptive responses to quinpirole in adulthood. This animal model may be useful for studying the involvement of dopamine systems in algesia and analgesia.

Ethanol inhibits cadmium accumulation in brains of offspring of pregnant rats that consume cadmium

The present study was designed to test the effect of ethanol on cadmium accumulation in tissues of pregnant rats and their offspring. Starting 10 days before mating and continuing until parturition, ethanol (10% v/v) was present in the drinking water of half the rats. Cadmium chloride (CdCl2; 50 ppm) was present in the water of half the rats (+/- ethanol) from the fist day after mating until parturition. On the day of parturition cadmium accumulated to a moderate level in bone (7.3 micrograms/g tissue, wet weight; this and other values, P < 0.05 vs. control), liver (12.9 micrograms/g) and kidney (13.0 micrograms/g) of dams, while the brain had only a low level of cadmium (0.45 microgram/g). In offspring at 6 weeks cadmium accumulated in high amounts in the brain (34.0 micrograms/g), bone (15.9 micrograms), kidney (78.2 micrograms/g) and particularly the liver (227.3 micrograms/g). Ethanol, given simultaneously with cadmium, inhibited cadmium accumulation in brain (1.8 micrograms/g), bone (3.28 micrograms/g) and kidney (61.3 micrograms/g), but enhanced cadmium accumulation in liver (408.7 micrograms/g). At 12 weeks there were only residual levels of cadmium in all tissues of offspring. These findings demonstrate an interaction between 2 known teratogenic agents, with ethanol conferring protection of the brain from cadmium accumulation. The nature of this interaction is not known, but is likely to be related to ethanol induction of metallothionein in the liver and placenta.

Mediation of central prostaglandin effects by serotoninergic neurons

Ten days after administration of 5,6-dihydroxytryptamine, which causes degeneration of central serotoninergic neurons, the depressive behavioral effects of PGF2α and PGE2 were evidently inhibited. Central chemical serotoninectomy abolished the hyperthermic and hypertensive effects of PGF2α, but only slightly affected those of PGE2. It is concluded that serotoninergic neurons mediate the depressive behavioral action of both PGF2α and PGE2. They also mediate the hyperthermic and hypertensive action of PGF2α but not of PGE2. This suggests that these prostaglandins have different central modes of action.

Behaviour of rats and biogenic amine level in brain after 6-hydroxy-dopamine

Male, Wistar rats were injected into the right lateral ventricle of the brain with 250 μg of 6-hydroxy-dopamine (6-OHDA). The behaviour of animals and the level of noradrenaline (NA), dopamine (DA) and 5-hydroxytryptamine (5-HT) were measured after different periods of time. During the first hour after 6-OHDA injection the behaviour of rats was similar to that observed after reserpine or a benzoquinolizine derivative; 6 h after the drug injection signs of sedation occurred. 24 and 48 h after 6-OHDA treatment locomotor activity of rats was similar to the activity of untreated animals. 68 h after 6-OHDA application a decrease of exploratory activity was noted. 7 h after 6-OHDA treatment a decrease of NA level was observed in the cortex, mesencephalon, thalamus and hypothalamus but an increase of NA content in the striatum. 3 days after 6-OHDA injection a decrease of the NA content in the cortex, thalamus and hypothalamus was seen. The DA level increased in most of the examined areas 7 h after 6-OHDA application; 3 days after the drug injection the DA level decreased in hypothalamus, thalamus and striatum and did not change in other brain areas. The 5-HT level increased in the pons and medulla oblongata and decreased in the mesencephalon 7 h after 6-OHDA injection and was unchanged in all examined structures 3 days after 6-OHDA application. These biochemical changes in the brain were not correlated with the behavioural changes of rats.

Influence of 6-hydroxydopamine on the behavioral effects induced by apomorphine or clonidine in rats.

The aim of this paper is to examine if central chemical sympathectomy induced by two injections of 6-hydroxydopamine (6-OHDA) in a dose of 250 μg intracerebroventricularly (k.c.v.) affects behavioral phenomena elicited by apomorphine (AP) (1 or 1.2 mg/kg i.p.) or clonidine (CL) (0.1 mg/kg, 5 or 1 μg/kg i.p.).Experiments were carried out on male Wistar rats. The time of duration of several components of behavior and the degree of irritability of rats were measured. Moreover, open field and hole test were performed. The lower dose of AP did not affected behavior of rats. The higher dose increased the locomotor and exploratory activity of animals. 6-OHDA potentiated these effects of AP. CL (0.1 mg/kg) had a depressive effect on the rats behavior, which was potentiated by 6-OHDA. CL (5 μg/kg) had no effect on the rats behavior, but in a dose of 1 μg/kg caused excitatory behavior. This type of behavior was abolished by 6-OHDA. In conclusion, central chemical sympathectomy caused increased sensitivity of the central nervous system on AP. Excitatory behavioral effects of CL in low dosage may be connected with stimulation of central adrenergic receptors. Depressive behavioral effect of CL in high dosage is unspecific. Central chemical sympathectomy affects by different methods the reactivity of dopaminergic and noradrenergic neurons.

Noradrenergic fiber sprouting in the cerebellum

Abstract In order to attain a better understanding of the sprouting response of noradrenergic fibers in the central nervous system (CNS), noradrenergic innervation to the cerebellum was observed by the glyoxylic acid method after a variety of manipulations and in a genetic variant of mouse classified as “Purkinje cell degeneration” (pcd/pcd). It has been found that a midbrain lesion in rats at birth will result in a collateral sprouting response of noradrenergic fibers in the cerebellum at 8 weeks, as indicated by the increased number of histofluorescent fibers observed in the molecular layer of the cerebellar cortex. Another procedure, treatment of neonatal rats with nerve growth factor alone appears to produce a temporary stimulation of noradrenergic fiber growth in the cerebellum, as observed by the histofluorescent method, although the innervation at 6 weeks or later is ultimately unchanged from the control group. In contrast, NGF (500 units) given to rats in combination with 6-hydroxydopa (6-OHDOPA) (60 μg/g IP) at 3 days postbirth produces a hyperinnervation of the cerebellum by noradrenergic fibers by 2 weeks of age and until at least 8 weeks of age. A third procedure, locus coeruleus implantation, was generally unsuccessful using the procedures described, since the implant was usually non-viable after several days. In a few instances where histofluorescent nuclei were found within the implant, there was an abundance of histofluorescent fibers within and adjacent to the implant, with fibers appearing to grow into host cerebellum. In the final procedure, it was noted that the density of noradrenergic input to the molecular layer of the cerebellar cortex was markedly increased in a genetic mutant mouse, classified as “Purkinje cell degeneration” (pcd/pcd), which is characterized by the absence of Purkinje cells of the cerebellum in adulthood. However, because of the tissue shrinkage that occurs after loss of Purkinje cells during postnatal development, it is unclear as to whether this observation represents hyperinnervation or a normal complement of fibers in a smaller brain space. The above procedures demonstrate the plasticity of noradrenergic fibers in neonatal cerebellum, a brain region that undergoes considerable postnatal development. The cerebellum is thought to be a good site for studying development/ regeneration/sprouting of noradrenergic fibers in particular, and central axonal processes in general.