Intracerebroventricular administration of substance P increases dopamine content in the brain of 6-hydroxydopamine-lesioned rats

The interactions existing between substance P- and dopamine-positive neurons, notably in the basal ganglia, suggest that substance P may have therapeutic use in treatment of Parkinson's disease characterized by impaired dopaminergic transmission. The effects of intracerebroventricularly administered substance P were tested on the levels of dopamine and its metabolites in the striatum, nucleus accumbens and frontal cortex of 6-hydroxydopamine-lesioned rats. Intracerebroventricular injection of 6-hydroxydopamine decreased the levels of dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid in the brain structures under investigation. Administration of substance P in low dose (0.35 nmol/kg) had no effect on the 6-hydroxydopamine-induced reduction of the dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid contents in the brain. However, treatment with substance P in higher dose (3.5 nmol/kg) increased the concentrations of dopamine and its metabolites in the striatum, nucleus accumbens and frontal cortex relative to saline-treated group. Additionally, 6-hydroxydopamine lesions significantly increased 3,4-dihydroxyphenylacetic acid/dopamine and homovanillic acid/dopamine ratios in the striatum and nucleus accumbens. Substance P (3.5 nmol/kg) partially reversed lesion-induced increases in 3,4-dihydroxyphenylacetic acid/dopamine and homovanillic acid/dopamine ratios in the striatum, but did not alter these ratios in nucleus accumbens. To test whether substance P fragmentation is responsible for this phenomenon, substance P_5–11, which is one of the main substance P fragments in rat CNS, was administered in equimolar dose. Substance P_5–11 was found to have no effect on the content of dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid in the striatum and nucleus accumbens. In the frontal cortex, substance P_5–11 produced decreases in dopamine levels and increases in homovanillic acid/dopamine ratio.The results of this study suggest that substance P helps to restore dopamine deficit in the brain in an animal model of Parkinson's disease, with the positive effects being more prominent on the nigrostriatal than on the mesocorticolimbic dopaminergic system, but substance P_5–11 is not responsible for this effect.     

Deep brain stimulation of subthalamic neurons increases striatal dopamine metabolism and induces contralateral circling in freely moving 6-hydroxydopamine-lesioned rats

Recent studies have reported a genetic association between the -1438 G/A polymorphism within the promoter region of the 5-HT(2A) receptor gene and eating disorders (ED), with conflicting results. To clarify the role of the -1438 G/A polymorphism in different ED categories we have analyzed the genotype and allele frequency distribution in 54 Italian patients with Binge ED (BED) compared to 132 obese non-BED subjects. No significant differences were found between obese BED and obese non-BED individuals, suggesting that this polymorphism does not genetically distinguish these two phenotypes. Moreover, the evaluation of 148 patients with anorexia nervosa and 86 patients with bulimia nervosa revealed an association of the A allele with both these disorders.     

Substance P administration to neonatal rats increases adult sensitivity to substance P

Substance P (SP) administered subcutaneously to neonatal rats on days 1-7 after birth produced long-term physiological changes. The changes included altered pain perception and increased sialogogic response to SP, although the hypotensive response to SP was unchanged. Early exposure to the peptide therefore influenced development, particularly with respect to two systems in which SP is physiologically active. Both changes may reflect an increased sensitivity of these systems to the effects of SP.     

Enhanced striatal glutamate release after the administration of rimonabant to 6-hydroxydopamine-lesioned rats

While recent studies have shown that the blockade of cannabinoid CB(1) receptors might be beneficial to alleviate the motor inhibition typical of Parkinson's disease (PD), the neurochemical substrates for this effect remain elusive. Here we have carried out microdialysis experiments to determine whether the effects of rimonabant, a selective antagonist of CB(1) receptors, might be associated with changes in striatal glutamate release in a rat model of PD generated by intracerebroventricular injection of 6-hydroxydopamine. Our data demonstrate that the treatment with rimonabant slightly increased striatal glutamate release in control rats, although this effect was only evident with the highest dose of rimonabant tested (1mg/kg). However, the increase in glutamate release was much more marked in the parkinsonian rats where similar changes were observed at a dose of 1 and 0.1mg/kg, exactly the same dose that relieved motor inhibition in previous behavioral studies. In summary, the potential of rimonabant to act as a possible antihypokinetic agent in parkinsonian rats seems to be related to enhanced glutamate release from excitatory afferents to the striatum. This observation is of potential clinical interest, particularly for those parkinsonian patients that exhibit a poor response to classic levodopa treatment.     

Behavioral evidence of depolarization block of mesencephalic dopamine neurons by acute haloperidol in partially 6-hydroxydopamine-lesioned rats.

The effects of acute haloperidol (HAL) and apomorphine (APO) administration were tested on the responsiveness of rats to medial forebrain bundle (MFB) brain stimulation reward (BSR) before and 28 days after partial dopamine (DA) depletion. Before 6-hydroxydopamine (6-OHDA) lesioning, HAL (50-100 micrograms/kg) and APO (25 micrograms/kg) both caused moderate decreases in the animals' responsiveness to BSR. In contrast, the same moderate doses of HAL completely abolished BSR after lesioning. However, postlesion responding for BSR after HAL could be reinstated by APO. The results of this study provide behavioral evidence that is consistent with recent electrophysiological data showing that acute HAL causes DA cells that survive 6-OHDA lesions to be driven into a state of depolarization block.     

Intracerebroventricular injection of capsaicin or substance P provokes the micturition reflex in the rat

Acute intracerebroventricular injection of 25 micrograms capsaicin or 40 micrograms substance P in isotonic saline elicited approximately similar effects on the micturition reflex, but capsaicin had twice as much effect as substance P. This effect is specific, since acute intracerebroventricular injection of isotonic saline did not produce the micturition reflex. It can be hypothesized that capsaicin and substance P may act on the brain micturition centers directly or by mediation of neuropeptides such as tachykinins, but other hypotheses are also made.     

Intracerebroventricular administration of nocistatin reduces inflammatory hyperalgesia in rats.

Nocistatin is a biologically active peptide derived from prepronociceptin, and its intrathecal administration has been reported to reduce nociceptin- or prostaglandin E2-induced hyperalgesia and allodynia in mice. In this study, we investigated the effects of intracerebroventricular (i.c.v.) administration of nocistatin on the inflammatory hyperalgesia induced by hindlimb intraplantar injection of carrageenan/kaolin in the rat paw-pressure test. Intracerebroventricular administration of nocistatin (0.5-50 pmol/rat) dose-dependently reduced carrageenan/kaolin-induced hyperalgesia, which peaked at 15-30 m. However, i.c.v. administration of nocistatin (50 pmol/rat) had no effect on the nociceptive threshold of non-inflamed rats. These results indicate that nocistatin has anti-hyperalgesic effects on the inflammatory hyperalgesia induced by carrageenan/kaolin at the supraspinal level.     

Effect of substance P on the content of catecholamines and on the enzymes of their synthesis in the brain of chronically alcoholized rats

The effect of a single administration of the endogenous peptide substance P on the content of dopamine (DA), and norepinephrine (NE), and on the activity of tyrosine hydroxylase (TH) and dopamine β-hydroxylase (D-β-H) is studied in the hypothalamus and midbrain of rats after a 6-month alcoholization. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 118, N ^o 7, pp. 46–48, July, 1994     

Dopamine D1- and D2-receptor interaction in turning behaviour induced by dopamine agonists in 6-hydroxydopamine-lesioned rats

The selective dopamine D2-antagonist sulpiride potentiated contralateral circling behaviour induced by the D1-agonist CY 208-243 in rats with unilateral lesions of substantia nigra, but reduced the effects of the selective D2-agonist bromocriptine. Similarly, the D1-antagonist SCH 23390 tended to increase the effects of bromocriptine but markedly inhibited CY 208-243 induced turning. The mixed D1/D2-antagonist fluphenazine was effective in reducing circling behaviour induced by either agonist, whereas pimozide (D1/D2) inhibited only the actions of bromocriptine. These results indicate that the actions of CY 208-243 and bromocriptine are mediated via distinct but interacting receptor subtypes.     

Intracerebroventricular administration of endothelin-1 impairs the habituation of rats to a novel environment in conjunction with brain serotonergic activation

The effects of i.c.v. administration of endothelin-1, at a low dose that does not produce abnormal behaviors such as barrel-rolling, on the emotional state of rats exposed to a novel environment were examined. Changes in the emotional state of rats with a novel environment were evaluated in terms of changes in exploratory activity in the hole-board apparatus, i.e., locomotor activity as well as the number and duration of rearing and head-dipping behaviors. Rats treated with i.c.v. saline showed marked exploratory behaviors immediately after exposure to the hole-board apparatus, but these exploratory behaviors decreased rapidly with time. On the other hand, the habituation of rats to a novel environment was prolonged by the i.c.v. administration of endothelin-1 (0.3 and 1 pmol). Furthermore, we also found that i.c.v. administration of endothelin-1 (1 pmol) significantly increased the serotonin (5-hydroxytryptamine) turnover in some brain regions, i.e., the cerebral cortex, hippocampus and midbrain, and the inhibition of brain 5-hydroxytryptamine synthesis by treatment with p-chlorophenylalanine (200 mg/kg/day, s.c.) for 2 days suppressed the behavioral effects of endothelin-1 (1 pmol, i.c.v.). In addition, i.c.v. administration of endothelin-1 (1 pmol) did not affect the spontaneous motor activity of rats. The present study demonstrated that i.c.v. administration of low doses of endothelin-1 impairs the habituation of rats to a novel environment in conjunction with brain 5-hydroxytryptaminergic activation. These results suggest that the central endothelin system may play a significant role in mediating emotionality.     

Prior D1 dopamine receptor stimulation is required to prime D2-mediated striatal Fos expression in 6-hydroxydopamine-lesioned rats

Repeated dopamine agonist administration to rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway potentiates behavioral and neuronal activation in response to subsequent dopamine agonist treatment. This response sensitization has been termed "priming" or "reverse-tolerance". Our prior work has shown that three pretreatment injections of the mixed D1/D2 agonist apomorphine (0.5 mg/kg) into 6-hydroxydopamine-lesioned rats permits a previously inactive dose of the D2 agonist quinpirole (0.25 mg/kg) to induce robust contralateral rotation and striatal Fos expression in striatoentopeduncular "direct" pathway neurons. These striatal neurons typically express D1 but not D2 receptors. Because apomorphine acts as an agonist at both D1 and D2 receptors, the present study sought to determine whether D1, D2, or concomitant D1/D2 receptor stimulation was required to prime D2-mediated contralateral rotation and striatal Fos expression. Twenty-one days following unilateral stereotaxic injection of 6-hydroxydopamine into the medial forebrain bundle, rats received three pretreatment injections, at three- to six-day intervals, with either: the mixed D1/D2 agonist apomorphine, the D1 agonist SKF38393, the D2 agonist quinpirole, or a combination of SKF38393 + quinpirole. Ten days following the third pretreatment injection, 6-hydroxydopamine-lesioned rats were challenged with the D2 agonist quinpirole (0.25 mg/kg). Pretreatment with SKF38393 (10 mg/kg), quinpirole (1 mg/kg) or SKF38393 (1 mg/kg) + quinpirole (0.25 mg/kg) permitted an otherwise inactive dose of quinpirole (0.25 mg/kg) to induce robust contralateral rotation which was similar in magnitude to that observed following apomorphine priming. However, only pretreatment with SKF38393 (10 mg/kg) or SKF38393 (1 mg/kg) + quinpirole (0.25 mg/kg) permitted the same dose of quinpirole (0.25 mg/kg) to induce striatal Fos expression. These results demonstrate that while prior stimulation of D1, D2 or D1/D2 receptors can effectively prime D2-mediated contralateral rotation, prior stimulation of D1 receptors is required to prime D2-mediated striatal Fos expression. This study demonstrates that priming of 6-hydroxydopamine-lesioned rats with a D1 agonist permits a subsequent challenge with a D2 agonist to produce robust rotational behavior that is accompanied by induction of immediate-early gene expression in neurons that comprise the "direct" striatal output pathway. These responses are equivalent to the changes observed in apomorphine-primed 6-hydroxydopamine-lesioned rats challenged with D2 agonist. In contrast, D2 agonist priming was not associated with D2-mediated induction of striatal immediate-early gene expression even though priming of D2-mediated rotational behavior was not different from that observed following priming with apomorphine or D1 agonist. Therefore, while priming-induced alterations in D2-mediated immediate early gene expression in the "direct" striatal output pathway may contribute to the enhanced motor behavior observed, such changes in striatal gene expression do not appear to be required for this potentiated motor response in dopamine-depleted rats.     

Repeated subinflammatory ultraviolet B irradiation increases substance P and calcitonin gene-related peptide content and augments mustard oil-induced neurogenic inflammation in the skin of rats

The objective of the present study was to investigate interactions between odor hedonic tone, perceived odor intensity, olfactory judgments and stimulated nostril laterality. Subjects were stimulated in the right and the left nostril separately, with two odors: vanillin (pleasant); and indole (unpleasant). They had two tasks to perform: an intensity judgment; and an affective judgment. Two concentrations (one strong and one weak) of each odor were presented. Odors were presented for a short period corresponding to one inhalation (about 1 s). The inter-stimulus interval was always 30 s. The nostril stimulated and task presentation order were counterbalanced according to a Latin square. Odor presentation order was randomized for each subject. Results indicated that response times for unpleasant odors were significantly shorter than for pleasant odors during affective judgment and right nostril stimulation, indicating greater right hemisphere efficiency for the decoding of unpleasant affects induced by odors.     

Intranigral ventral mesencephalic grafts and nigrostriatal injections of glial cell line-derived neurotrophic factor restore dopamine release in the striatum of 6-hydroxydopamine-lesioned rats

We have previously reported that grafting of fetal ventral mesencephalic (VM) tissue to the nigral region of unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats, in conjunction with glial cell line-derived neurotrophic factor (GDNF) injection between nigra and striatum, restores nigrostriatal tyrosine hydroxylase (TH) immunoreactivity. In this study, we investigated the electrochemical indices of dopamine (DA) release in these grafted animals in the striatum and nigra. Adult Sprague-Dawley rats were anesthetized and unilaterally injected with 6-OHDA into the medial forebrain bundle. The completeness of lesions was tested by measuring methamphetamine-induced rotations. One to two months after 6-OHDA administration, fetal VM tissues were grafted in the lesioned nigral area followed by injection of GDNF, brain-derived neurotrophic factor (BDNF), or phosphate-buffered saline (PBS), along a tract from nigra to striatum. Animals receiving transplantation and GDNF, but not BDNF or PBS, injection showed a significant decrease in rotation 1–3 months after grafting. High-speed chronoamperometric recording techniques, using Nafion-coated carbon fiber electrodes, were used to evaluate DA overflow in the striatum. We found that 6-OHDA lesions resulted in a loss of KCl-induced DA overflow in the urethane-anesthetized rats. Three months after GDNF-bridged grafting, application of KCl elicited DA release both in nigra and striatum. The KCl-evoked DA release area was limited to the GDNF-bridging tract in the striatum. On the other hand, KCl did not induce DA release in the BDNF- or PBS-bridged grafts. Immunocytochemical studies indicated that TH-positive neurons and fibers were found in the nigra and striatum after GDNF-bridged grafting. Taken together, our data suggest that fetal nigral transplantation and GDNF injection may restore the nigrostriatal DA pathway and DA release in these hemiparkinsonian animals and support the hypothesis of trophic activity of GDNF on fiber outgrowth from midbrain DA neurons. Received: 8 August 1997 / Accepted: 9 August 1997     

侧脑室注射肾上腺髓质素激活去缓冲神经大鼠最后区神经元

目的观察侧脑室注射肾上腺髓质素(AM)对去缓冲神经大鼠最后区神经元自发放电和Fos蛋白表达的影响。方法应用细胞外记录的电生理学方法,观察雄性SD大鼠神经元自发放电活动;用免疫组化方法检测Fos蛋白的表达。结果侧脑室注射AM(1,3nmol/kg)诱发最后区出现大量Fos样免疫阳性神经元(Fos-LI),最后区神经元自发放电频率明显增加;降钙素基因相关肽受体拮抗剂CGRP8-37(30nmol/kg)可明显减弱AM的效应。结论AM对最后区神经元有直接兴奋作用,降钙素基因相关肽受体介导这一效应。     

Intranasal administration of human IL-6 increases the severity of chemically induced seizures in rats

Here we study the role of a pleiotropic pro-inflammatory cytokine, interleukin-6 (IL-6), in epilepsy. To examine this problem, we used human recombinant IL-6 applied intranasally (400 ng/40 microl) to rats 1h before seizures induced by systemic injection of pentylenenetrazole (PTZ, 75 mg/kg). Overall, compared to the saline-treated control animals (n = 11 in each group), IL-6-treated rats demonstrated elevated levels of IL-6 in the frontal lobe (measured by ELISA) and increased severity of PTZ-induced seizures (shorter latency, longer duration and higher mortality). Our findings show that IL-6 plays a pro-convulsant role in the brain and suggest that the IL-6 system may be a novel target for the development of anticonvulsant drugs.     

Combined intrastriatal dopamine D1 and serotonin 5-HT2 receptor stimulation reveals a mechanism for hyperlocomotion in 6-hydroxydopamine-lesioned rats

Loss of dopaminergic innervation to the striatum increases the sensitivity of dopamine (DA) D1 and serotonin (5-HT) 5-HT2 receptor signaling. Previous work from our laboratory has shown that systemic co-administration of D1 and 5-HT2 receptor agonists leads to the synergistic overexpression of striatal preprotachykinin mRNA levels in the DA-depleted, but not intact animals. In the present study, we examined this mechanism as related to locomotor behavior. Adult male Sprague-Dawley rats were subject to bilateral i.c.v. 6-hydroxydopamine (6-OHDA; 200 microg in 10 microl/side) or vehicle (0.9% saline and 0.1% ascorbic acid). After 3 weeks, rats were tested for locomotor responses to bilateral intrastriatal infusions of vehicle (0.9% NaCl), the D1 agonist SKF82958 [(+/-)6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetra-hydro-(1H)-3-benzazepine hydrobromide; 0.1, 1.0 or 10.0 microg/side], the 5-HT2 agonist DOI [(+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane; 0.1, 1.0 or 10.0 microg/side] or subthreshold doses of DOI and SKF82958 (0.1 microg+0.1 microg in 0.8 microl/side). Rats with DA loss demonstrated supersensitive locomotor responses to SKF82958, but not DOI. Combined administration of subthreshold SKF82958 and DOI doses (0.1 microg+0.1 microg) synergistically increased locomotor behavior only in 6-OHDA-lesioned rats. These effects were blocked by either the D1 antagonist SCH23390 3-methyl-1-phenyl-2,3,4,5-tetrahydro-7-chloro-8-hydroxy-(1H)-3-benzazepine or the 5-HT2 antagonist ritanserin (each 1.0 microg in 0.8 microl/side).The results of this study suggest that the behavioral synergy induced by local co-stimulation of D1 and 5-HT2 receptors within the 6-OHDA-lesioned striatum may lead to hyperkinesias that can occur with continued pharmacological treatment of Parkinson's disease.     

Intracerebroventricular administration of an endothelin ETB receptor agonist increases expression of tissue inhibitor of matrix metalloproteinase-1 and -3 in rat brain

Production of tissue inhibitors of matrix metalloproteinases (TIMPs), a family of secreted proteins with inhibitory actions on matrix metalloproteinases (MMPs), is up-regulated following nerve injuries and is suggested to have protective effects against MMP-mediated tissue damages. To clarify the extracellular signals involved in TIMP production in the brain, the effects of endothelins (ETs), a family of vasoconstricting peptides, were examined. I.c.v. administration of 500 pmol/day Ala(1,3,11,15)-ET-1, an ET(B) receptor agonist, increased the level of TIMP-1 mRNA in rat hippocampus, caudate-putamen and cerebrum. Ala(1,3,11,15)-ET-1 increased the level of TIMP-3 mRNA in the cerebrum, but not in the hippocampus or caudate-putamen. TIMP-2 mRNA was not affected in these brain regions. Ala(1,3,11,15)-ET-1 also stimulated the production of TIMP-1 and TIMP-3 proteins in the cerebrum. Immunohistochemical observations in the hippocampi of Ala(1,3,11,15)-ET-1-infused rats showed that NeuN-positive neurons and glial fibrillary acidic protein-positive astrocytes were immunoreactive for TIMP-1. In the cerebrum, astrocytes had TIMP-1 and TIMP3 reactivity, but neurons did not. In rat cultured astrocytes, both 100 nM Ala(1,3,11,15)-ET-1 and ET-1 increased the mRNA levels and protein release of TIMP-1 and TIMP-3 mRNAs. The effects of ET-1 on astrocytic TIMP-1 and TIMP-3 mRNAs were inhibited by BQ788, an ET(B) antagonist. These findings indicate that activation of brain ET(B) receptors causes production of TIMP-1 and TIMP-3, and suggest the involvement of astrocytes in ET-induced TIMP production.     

Intracerebroventricular injection of brain natriuretic peptide inhibits vasopressin secretion in conscious rats

The effect of intracerebroventricular (i.c.v.) injection of brain natriuretic peptide (BNP), a novel peptide purified from the porcine brain, on arginine vasopressin (AVP) secretion was studied in conscious, unrestrained rats and was compared with that of atrial natriuretic polypeptide (ANP). I.c.v. administration of BNP (0.01, 0.1 or 1 nmol) significantly inhibited basal AVP secretion and the effect of BNP was comparable to that of ANP. The AVP secretion induced by i.c.v. injection of angiotensin II (0.1 nmol) was significantly suppressed by the pretreatment with BNP (0.1 or 1 nmol). These results suggest that BNP is involved in the central control of AVP secretion either alone or in combination with brain ANP.     

Scheduled eating increases dopamine release in the nucleus accumbens of food-deprived rats as assessed with on-line brain dialysis

This study examined the effect of scheduled eating on the in vivo release of dopamine (DA) in the nucleus accumbens of rats that were maintained on a food deprivation schedule. DA release was measured by means of a fully automated on-line brain dialysis system. The initiation of eating increased the release of DA, which remained elevated during the entire eating period. Termination of eating caused a gradual decrease of the release of DA to basal values. Increased motor activities did not change the release of DA. These results indicate a link between eating and DA release and demonstrate the suitability of on-line brain dialysis for behavioural experiments.