The role of nigral projections to the thalamus in drug-induced circling behaviour in the rat

Unilateral injection of 6-hydroxydopamine (6-OHDA) into the ascending nigrostriatal pathway caused contraversive circling to apomorphine and ipsiversive circling to amphetamine respectively. An electrolesion of the ventromedial thalamic nucleus on the same side as the 6-OHDA lesion reduced apomorphine-induced circling, but not that to amphetamine. An electrolesion of the ventromedial thalamic nucleus on the side opposite to the 6-OHDA lesion reduced amphetamine circling but not that to apomorphine. Bilateral electrolesions of the ventromedial thalamic nucleus reduced neither apomorphine- nor amphetamine-induced circling. Electrolytic lesions of the parafascicular thalamic nucleus did not reduce apomorphine- or amphetamine-induced circling in animals with a unilateral 6-OHDA lesion of the nigrostriatal pathway. Knife cuts rostral and dorsal to the substantia nigra did not attenuate circling induced by injection of muscimol into the substantia nigra. Circling due to activition of nigral output pathways can be mediated by descending nigro-reticular pathways.     

Drug-induced circling after unilateral 6-hydroxydopamine lesions of the nigro-striatal pathway is mediated via the midbrain periaqueductal grey and adjacent reticular formation (angular complex)

Unilateral 6-hydroxydopamine (6OHDA) lesions of the nigrostriatal pathway resulted in contraversive rotation to apomorphine and ipsiversive rotation to amphetamine. Electrolytic lesioning of the nucleus reticularis gigantocellularis or kainic acid lesions of the nucleus tegmenti pedunculopontis on the same side as the 6OHDA lesion did not reduce apomorphine- or amphetamine-induced circling. An electrolesion of the angular complex (periaqueductal grey and adjacent reticular formation) on the same side as the 6OHDA lesion reduced apomorphine-induced circling and increased amphetamine-induced circling. Bilateral electrolesions of the angular complex reduced both apomorphine- and amphetamine-induced rotation. The decrease in rotation was due to a loss of postural asymmetry while locomotor hyperactivity was maintained. A unilateral kainic acid lesion of the angular complex alone caused weak ipsiversive rotation which was enhanced by apomorphine and amphetamine. When a unilateral kainic acid lesion of the angular complex was made on the same side as a prior 6OHDA lesion, both apomorphine and amphetamine induced ipsiversive rotation. The area of the angular complex is critically involved in the mediation of drug-induced circling in unilaterally 6OHDA lesioned rats and in particular the postural component.     

Cross-tolerance of dopamine metabolism to baclofen, γ-butyrolactone and HA-966 in the striatum and olfactory tubercle of the rat

Rats received 7 daily injections with baclofen (40 mg/kg), GBL (750 mg/kg) or HA-966 (100 mg/kg). Dopamine (DA) was measured in the striatum and olfactory tubercle (OT) of rats, sacrificed 0.5 h or 1 h after the last injection. Marked tolerance and cross-tolerance for the DA-elevating effect of these drugs was seen in the striatum, but not in OT. When on day 7 a unilateral lesion of the nigrostriatal pathway was made, also some tolerance to the DA increase in the striatum on the lesioned side was seen in HA-966-pretreated rats, but it was small compared to the tolerance after an additional drug administration in non-lesioned animals. A low dose of apomorphine (0.25 mg/kg, i.p.) had no effect on DA, dihydroxyphenylacetic acid DOPAC) or homovanillic acid (HVA) levels in the lesioned striata, whether the rats had been pretreated for 6 days with HA-966 or not. However, this dose of apomorphine had a significantly more lowering effect on striatal DOPAC and HVA levels on the unlesioned side of HA-966 pretreated rats. The results show that tolerance develops to the increase of DA synthesis, which is possibly receptor-mediated. This tolerance develops more readily in the striatum than in the olfactory tubercle.     

Effects of unilateral intracerebroventricular microinjections of cholecystokinin (CCK) on circling behavior of rats

Unilateral intracerebroventricular (ICV) injections of a high dose of CCK₇ have been reported to elicit barrel rotations accompanied by contralateral postural asymmetry; there was no spontaneous locomotor activity other than barrel rolling. The aim of the present study was to investigate the effects of lower doses of CCK-peptides on circling behavior; it was reasoned that if ambulation was present following unilateral ICV administrations of lower doses of CCK, then the contralateral postural asymmetry previously reported might be expressed as contraversive circling. In the present study, spontaneous locomotor activity was observed following ICV injections of lower doses of CCK sulfated octapeptide (CCK₈), desulfated CCK octapeptide (dCCK₈) and CCK tetrapeptide (CCK₄). As postulated, contraversive circling was induced by CCK₈ (0.5–5000 ng, ICV); the two other CCK fragments, dCCK₈ and CCK₄, were inactive in this respect. In addition, the contraversive circling bias induced by CCK₈ (5.0 ng, ICV) was attenuated by co-injections of the CCK antagonist proglumide (10 and 100 ng) and by intraperitoneal injections of the dopamine (DA) antagonist haloperidol (0.05 and 0.1 mg/kg, 45 min prior to ICV CCK₈). These data suggest that the effect is mediated by CCK receptors and through a facilitatory influence on central DA function.     

Effect of Acute and Chronic Administration of l-Tyrosine on Nerve Growth Factor Levels in Rat Brain

Most inborn errors of tyrosine catabolism produce hypertyrosinemia. Neurological manifestations are variable and some patients are developmentally normal, while others show different degrees of developmental retardation. Considering that current data do not eliminate the possibility that elevated levels of tyrosine and/or its derivatives may have noxious effects on central nervous system development in some patients, the present study evaluated nerve growth factor (NGF) levels in hippocampus, striatum and posterior cortex of young rats. In our acute protocol, Wistar rats (10 and 30 days old) were killed 1 h after a single intraperitoneal administration of l-tyrosine (500 mg/kg) or saline. Chronic administration consisted of l-tyrosine (500 mg/kg) or saline injections 12 h apart for 24 days in Wistar rats (7 days old); the rats were killed 12 h after the last injection. NGF levels were then evaluated. Our findings showed that acute administration of l-tyrosine decreased NGF levels in striatum of 10-day-old rats. In the 30-day-old rats, NGF levels were decreased in hippocampus and posterior cortex. On the other hand, chronic administration of l-tyrosine increased NGF levels in posterior cortex. Decreased NGF may impair growth, differentiation, survival and maintenance of neurons.     

GABA in the entopeduncular nucleus and the subthalamic nucleus participates in mediating dopaminergic striatal output functions

The bilateral intracerebral injection of the specific GABA agonists muscimol (25, 100 ng) and THIP (500 ng) into the pallido-entopeduncular nucleus (EP) and the subthalamic nucleus (STN) of rats induced a behavioural stimulation closely resembling the syndrome evoked by direct stimulation of dopamine receptors in the striatum or by the systemic injection of dopamine agonists. The rats showed strong locomotor and rearing activity followed by characteristic stereotyped behaviour consisting of sniffing and gnawing activity. The stimulation induced by muscimol (25 ng) was found independent of dopamine, since the dopamine antagonist haloperidol (1 mg/kg s.c.) induced no blockade. Injection of the GABA antogonist picrotoxin (100 ng) into the EP or STN induced sedation and catalepsy. The unilateral injection of muscimol and picrotoxin provoked contraversive and ipsiversive postural changes. Related behavioral effects were induced by GABAergic drugs injected in substantia nigra, zona reticulata (SNR). These data provide support for the new hypothesis that GABA in the EP, SNR and STN is important for the expression of behavior related to stimulation of dopamine receptors in the striatum. The effects may be induced by a dopamine activation of the descending striato-EP, striato-SNR GABAergic pathways and possibly also the pallido-STN GABAergic pathway. The findings suggest that in addition to a pathology of the dopamine system there may also be a GABAergic dysfunction in the efferent system of the basal ganglia localized to the EP, SNR and STN in diseases, such as parkinsonism, Huntington's chorea and possibly schizophrenia.     

Effect of cyclo(Leu-Gly) on the supersensitivity of dopamine receptors in spontaneously hypertensive rats

Spontaneously hypertensive rats exhibited dopamine receptor supersensitivity as evidenced by a greater hypothermic response to apomorphine in comparision with normotensive Wistar-Kyoto rats. A single injection of cyclo(Leu-Gly) given prior to apomorphine administration did no alter apomorphine induced hypothermia in either the normotensive or the hypertensive rats. Chronic administration of cyclo(Leu-Gly) for 7 days did not affect apomorphine response in normotensive rats, but blocked the exaggerated response to apomorphine in the hypertensive rats. These studies suggest that cyclo(Leu-Gly) interacts with the dopamine receptors and that the central dopamine receptors may play a role in the pathophysiology of hypertension.     

单侧帕金森病猴模型的行为、神经递质、多巴胺受体、病理及局部脑血流研究

经右侧颈总动脉注射甲基-苯基-四氢吡啶(MPTP)使猴产生左侧肢体动作减少、行动迟缓、震颤及向右侧缓慢旋转。应用美多巴和阿朴吗啡显著地改善单侧帕金森病(PD)症状,同时引起向左侧快速旋转,并呈明显的剂量依赖性;应用苯丙胺引起向右侧快速旋转。连续应用美多巴诱致单侧PD猴产生舞蹈手足徐动症。高效液相色谱测定显示右侧壳核、尾状核和黑质多巴胺(DA)含量显著降低。光镜发现右侧黑质神经元变性。SPECT活体显像发现病损侧纹状体D_2DA受体活性在病损初期无改变,病损严重时超敏,以及病损侧脑血流灌注减低。实验表明MPTP可建成理想的能形象地模拟人类PD的单侧PD猴模型。SPECT是活体研究PD病理生理的有效检测手段。     

Inactivation of neuronal forebrain A2A receptors protects dopaminergic neurons in a mouse model of Parkinson’s disease

Adenosine A_2A receptors antagonists produce neuroprotective effects in animal models of Parkinson’s disease (PD). As neuroinflammation is involved in PD pathogenesis, both neuronal and glial A_2A receptors might participate to neuroprotection. We employed complementary pharmacologic and genetic approaches to A_2A receptor inactivation, in a multiple MPTP mouse model of PD, to investigate the cellular basis of neuroprotection by A_2A antagonism. MPTP·HCl (20 mg/kg daily for 4 days) was administered in mice treated with the A_2A antagonist SCH58261, or in conditional knockout mice lacking A_2A receptors on forebrain neurons (fbnA_2AKO mice). MPTP‐induced partial loss of dopamine neurons in substantia nigra pars compacta (SNc) and striatum (Str), associated with increased astroglial and microglial immunoreactivity in these areas. Astroglia was similarly activated 1, 3, and 7 days after MPTP administration, whereas maximal microglial reactivity was detected on day 1, returning to baseline 7 days after MPTP administration. SCH58261 attenuated dopamine cell loss and gliosis in SNc and Str. Selective depletion of A_2A receptors in fbnA_2AKO mice completely prevented MPTP‐induced dopamine neuron degeneration and gliosis in SNc, and partially counteracted gliosis in Str. Results provide evidence of a primary role played by neuronal A_2A receptors in neuroprotective effects of A_2A antagonists in a multiple MPTP injections model of PD. With the symptomatic antiparkinsonian potential of several A_2A receptor antagonists being pursued in clinical trials, this study adds to the rationale for broader clinical benefit and use of these drugs early in the treatment of PD.     

Effects of an LHRH agonist and gonadotropins on testicular prolactin receptors

Effects of administration of the LHRH agonist D-Leu6-LHRH ethylamide (LHRH-A), gonadotropin (PMS), and their interaction on testicular prolactin (PRL) receptor levels were investigated in rats. LHRH-A (2 micrograms/100 g body wt.) or saline was injected SC daily, and PMS (5 IU) injected every other day. In intact rats, the testicular PRL receptor levels were about 400 fmoles/testis after either 1 or 7 daily injections of saline. Administration of LHRH-A decreased PRL receptors to 12% of that of saline-injected control rats at day 1, and to 20% at day 2, and PRL receptor levels were partially restored to 55% at day 7. In hypophysectomized rats given daily injections of saline for 7 days PRL receptor levels were only 20% of those in saline-injected intact rats. Injections of LHRH-A in hypophysectomized animals did not further decrease PRL receptor numbers at this time. Administration of PMS to hypophysectomized rats for 7 days partially reversed the reduction of PRL receptors that occurred after hypophysectomy, to 46% of those in intact controls. Injections of LHRH-A into hypophysectomized. PMS-treated animals did not significantly alter PRL receptors on day 1 (117% of that of saline-injected, hypophysectomized, PMS-treated rats at day 1) or day 2 (96% of same-day controls), but decreased PRL receptors on day 7 to 102 fmoles/testis (55% of same-day controls). This latter concentration is nearly the same as that in saline-injected, 7-day hypophysectomized rats not treated with PMS. These findings suggest that: (1) the effects of LHRH-A on testicular PRL receptors differ depending on the presence or absence of gonadotropin, (2) gonadotropin, primarily FSH, maintains some population of testicular PRL receptors, and these gonadotropin-dependent PRL receptors are suppressed by direct action of LHRH-A upon the testes, and (3) there is a population of PRL receptors which is not affected by LHRH-A or gonadotropin.     

The effect of subchronic, intermittent L-DOPA treatment on neuronal nitric oxide synthase and soluble guanylyl cyclase expression and activity in the striatum and midbrain of normal and MPTP-treated mice

We have investigated the effects of low (10 mg/kg) and high (100 mg/kg) doses of L-DOPA on the expression and activity of neuronal nitric oxide synthase (nNOS) and guanylyl cyclase (GC) in the striatum and midbrain of mice. L-DOPA was administered subchronically for 11 days (beginning 3 days after last MPTP/NaCl injection) or for 14 days (with dosing started immediately following the last MPTP/NaCl injection). Adult mice received three intraperitoneal (i.p.) injections of physiological saline or MPTP at 2h intervals (total dose of 40 mg/kg). Normal and MPTP-injected mice were treated twice a day for 11 or 14 days with low (10/2.5 mg/kg bw) or high (100/25mg/kg bw) doses of L-DOPA/benserazide. The present study indicates that several days of treatment with L-DOPA does not affect MPTP-activation of the nNOS/sGC/cGMP pathway or the neurodegenerative processes that occur in the striatum and midbrain of mice. In normal mice, L-DOPA upregulates the expression and activity of nNOS and GC to levels found in MPTP-injected mice. Due to upregulation of nNOS and GC, cGMP levels in the mouse striatum and midbrain are also elevated, however, significantly lower in mice administrated with low dose of L-DOPA. In both investigated brain regions of normal mice cGMP-dependent PDEs activities were elevated after low dose administration of L-DOPA, but no change in PDEs activities has been detected in MPTP and high L-DOPA-injected mice as compared to control values. The enhancement of nNOS mRNA and GCbeta1 mRNA levels were generated by both doses of L-DOPA, given in a time-dependent fashion. L-DOPA-injected for 11 or 14 days caused a decrease in TH protein levels in the striatum and midbrain, respectively; this result was noted irrespective of dose. L-DOPA therapy did not prevent the MPTP-induced decrease in TH protein levels in either investigated brain region.     

Changes in the sensitivity of brain dopamine and serotonin receptors during the prolonged administration of carbidine

Male Wistar rats were treated chronically with either carbidine (10 mg/kg/day) or haloperidol (1 mg/kg/day) for 23 consecutive days. On days 4-5 after the treatment discontinuation the animals were challenged with apomorphine HCl (0.5 mg/kg) or 5-OTP (150 mg/kg i. p) in combination with pargiline (40 mg/kg i. p) and stereotype responses were scored. In carbidine-treated rats the intensity of stereotype sniffings was increased after apomorphine treatment. In contrast, animals treated with haloperidol exhibited more intensive gnawing after apomorphine in comparison to vehicle-treated rats. 5-OTP-induced head twitches were increased only in carbidine-treated rats. Prolonged carbidine treatment in contrast to haloperidol induced a decrease in 5H-spiperone and 3H-LSD binding in the frontal cortex, with the density of D-2 receptors in the striatum practically unchanged. It is concluded that neuroleptic carbidine in contrast to classical neuroleptics has a more selective effect in serotonin (S-2) receptors and antidepressive properties of this compound may be due to the down-regulation of S-2 receptors in the brain.     

Dopamine independent rotational response to unilateral intranigral injection of serotonin

Unilateral injections of 5-hydroxytryptamine (5-HT) into the pars reticulata of the substantia nigra of rats pretreated with a monoamine oxidase inhibitor induced a strong and long-lasting contralateral circling behaviour which was selectively increased as a function of time after degeneration of central 5-HT neurons with 5,7 dihydroxytryptamine. Rotations were not abolished after 6-hydroxydopamine lesion of nigrostriatal dopamine (DA) neurons, or after striatal kainic acid lesions, but were on the contrary increased. It is concluded that the contralateral circling response to intranigral 5-HT injection is caused by a specific stimulation of certain post-synaptic nigral 5-HT receptors susceptible to the development of denervation supersensitivity but does not require the participation of nigrostriatal DA neurons.     

Dopamine receptor sensitivity after repeated morphine administrations to rats.

It was studied in rats, if chronic morphine treatment induces a supersensitivity of dopamine receptors in brain. The rats were treated twice daily for 8–11 days with single doses of morphine, increasing from 10 to 20 mg/kg i.p. The experiments were carried out 16–20 hours after the last injection of morphine. After chronic morphine treatment, the potency of apomorphine in lowering the striatal dopamine turnover was increased. On the other hand, apomorphine was not more potent in inducing stereotypies (sniffing, licking, gnawing) after chronic morphine administration than in saline controls. Finally, dopamine activated the adenylate cyclase in striatal homogenates of rats after chronic morphine treatment to a similar extent as in homogenates of control rats. The results suggest that a supersensitivity of dopamine receptors in brain is not necessarily involved in symptoms of an increased dopaminergic activity after chronic morphine application.     

Alteration of neurotensin receptors in MPTP-treated mice.

We examined the sequential changes in neurotensin receptors in the striatum and substantia nigra of mouse brains lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by receptor autoradiography, in comparison with the alterations in dopamine uptake sites. The mice received four intraperitoneal injections of MPTP (10 mg/kg) at 1-h intervals and then the brains were analyzed at 6 h and 1, 3, 7, and 21 days after the treatments. [3H]Neurotensin and [3H]mazindol were used to label neurotensin receptors and dopamine uptake sites, respectively. [3H]Neurotensin binding was significantly decreased in the striatum from 6 h to 21 days after MPTP treatment. In the substantia nigra, pars reticulata also showed a significant decrease in [3H]neurotensin binding from 3 to 21 days post-MPTP treatment. However, no significant change in [3H]neurotensin binding was observed in the pars compacta even after 21 days. On the other hand, [3H]mazindol binding was markedly decreased in the striatum and substantia nigra from 6 h to 21 days after MPTP treatment. These results indicate that neurotoxin MPTP can produce a severe decrease in neurotensin receptors and dopamine uptake sites in the striatum and substantia nigra of mice. Thus, our findings provide evidence that the dysfunction in neurotensin receptors may be involved in the degenerative processes causing Parkinson's disease.     

Rotation produced by administration of dopamine and related substances directly into the supersensitive caudate nucleus

Dopamine and related compounds were administered directly into the caudate nucleus ipsilateral to a unilateral 6-OHDA induced lesion of the substantia nigra in rats. Dopamine, norepinephrine, epinine, epinephrine, apomorphine and ADTN produced vigorous long-lasting, dose-related contraversive circling. Dopamine was the most potent substance tested, its threshold for significant activity was 0.06 μg and the dose producing the maximal rate of rotation was 0.40 μg. Serotonin produced modest rotation which was not dose-related. Piribedil, although more effective than its metabolite S584, produced only a short period of activity at very high doses. Isoproterenol and clonidine were inactive.The effects of dopamine were compared in lesioned and non-lesioned rats. The supersensitivity of the lesioned rats was manifested as an increase in the potency of dopamine and as an increase in the maximal response, defined as rate of rotation. Rotation was produced in non-lesioned rats only after pretreatment with tranylcypromine, which had no significant effect in lesioned rats.     

Effects of Systemic Administration of 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine to Mice on Tyrosine Hydroxylase, l-3,4-Dihydroxyphenylalanine Decarboxylase, Dopamine β-Hydroxylase, and Monoamine Oxidase Activities in the Striatum and Hypothalamus

The effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (30 mg/kg subcutaneously per day for 8 days) to C57BL/6N mice were studied on tyrosine hydroxylase (TH), L-3,4-dihydroxyphenylalanine decarboxylase (DDC), and monoamine oxidase (MAO) activities in the striatum, and TH, DDC, dopamine-beta-hydroxylase (DBH), and MAO activities in the hypothalamus. Treatment with MPTP led to a large decrease in TH activity and a parallel decrease in DDC activity in the striatum, as compared with the saline controls. In contrast, MPTP administration did not cause a decrease of the activities of TH, DDC, and DBH in the hypothalamus. There was also no reduction in MAO activities of striatum and hypothalamus. These data indicate that MPTP administration to mice results in specific degeneration of the dopaminergic nigrostriatal pathway and that DDC in the mouse striatum may mainly be localized in the dopaminergic neurons with TH.