In vivo release of dopamine in the nucleus accumbens of the rat: modulation by cholecystokinin

We observed that the release of endogenous dopamine (DA), induced by perfusion of a 55 mM K⁺-containing buffer in the nucleus accumbens, was Ca²⁺-dependent and confined to a local region. We also demonstrated that the sulphated form of cholecystokinin octapeptide, but not the unsulphated form, suppressed this stimulated release of dopamine in a concentration-dependent manner. This suggests that cholecystokinin may act as a functional antagonist to dopamine within this structure.     

Effect of nomifensine on the toxicity of 6-hydroxydopamine for mesotelencephalic dopamine neurons

The ability of nomifensine to protect the dopaminergic cells of the substantia nigra and ventral tegmental areas against 6-hydroxydopamine-induced destruction was evaluated. Nomifensine at high doses (20 mg/kg, i.p.) protected the cells from the effects of low amounts of 6-hydroxydopamine (2 micrograms) injected intracerebrally. This protective effect was markedly decreased with an increased amount of 6-hydroxydopamine (8 micrograms), or by lower doses of nomifensine (6.7 mg/kg). These doses of nomifensine are higher than those required to protect dopaminergic nerve terminals.     

Evidence for a dopaminergic innervation of the cat lateral habenula: its role in controlling serotonin transmission in the Basal ganglia

The presence of a dopaminergic innervation of the cat lateral habenula and its possible role in modulating serotonin transmission within the basal ganglia were investigated using both in vitro and in vivo approaches. A high density of [³H]spiroperidol binding sites with similar affinities for domperidone and apomorphine as those present in the cat striatum were found in the habenula. By means of the push-pull cannula technique, a substantial release of [³H]dopamine continuously formed from [³H]tyrosine was detected in the lateral habenula of halothane-anesthetized cats since the amount of [³H]catecholamines was enhanced in the presence of benztropine, an inhibitor of dopamine uptake into dopaminergic nerve terminals. Furthermore, in anesthetized animals with a push-pull cannula implanted in each caudate nucleus and substantia nigra habenular applications of dopamine (10⁻⁷ M) reduced nigral but not striatal release of [³H]serotonin continuously formed from [³H]tryptophan. This change was prevented either by the delivery of domperidone to the lateral habenula or by the blockade of GABAergic transmission (picrotoxin 10⁻⁵ M) in the dorsal raphe. These data support the involvement of habenula-raphe pathways in the regulation of serotonin transmission in the cat basal ganglia and indicate that dopaminergic inputs to the lateral habenula participate in such a control.     

Glass-plastic push-pull cannula system for regional perfusion of sites in the brain

A new non-metallic push-pull cannula device is described for the localized perfusion of brain sites in the rat or other animal. Comprised entirely of glass and plastic materials, the cannula is intended for usage in an experiment in which the presence in tissue of metal tubing for delivery of perfusate is methodologically inappropriate. The main features of the cannula include its light weight, a Delrin pedestal base, a micro-glass guide tube, a polyethylene stylet, plastic spacers for adjustment of depth of perfusion, a protective cap for the chronic maintenance of the preparation, low cost and re-usability. The push-pull cannula is of concentric design and is fashioned from glass capillary and polyethylene tubing which are bonded at their common junctions by an epoxy cement. During a push-pull perfusion a special perfusion cap is used not only to hold the cannula firmly in place but also to protect the glass components from external damage. To further coincide with the metal-free requirements of the preparation, bone screws of nylon are used during the surgical implantation of the pedestal base. A prototype experiment illustrating its use in an unrestrained animal also is presented. The special applications for this cannula system are discussed which include its usage in experiments in either the anesthetized or unanesthetized rat exposed to microwave radiation where the presence of metal in the field would result in unwanted 'hot spots' in the cerebral tissue.     

Effects of fencamfamine on single unit activity of mesencephalic dopaminergic neurons in rats

Summary Systemic fencamfamine (0.5–16 mg/kg, i.v.) significantly but incompletely inhibited spontaneous activity of nigrostriatal and mesolimbic/mesocortical dopamine (DA) neurons. Inhibition was reversed by haloperidol (0.1 mg/kg, i.v.) and prevented by pretreatment with -methyltyrosine (50 mg/ kg, i.v.) plus reserpine (5 mg/kg, i.p.). Pretreatment with -methyltyrosine alone attenuated inhibition at high but not low doses of fencamfamine. Microiontophoresed fencamfamine had little direct effect on DA neurons and did not consistently modulate the effects of co-microiontophoresed DA. In contrast, systemic fencamfamine blocked the inhibitory effects of low doses of apomorphine (10–40 g/kg, i.v.). Fencamfamine appears to be an indirect DA agonist which interacts with both vesicular and newly synthesized DA storage pools. Fencamfamine may also cause a rapid desensitization to the effects of DA autoreceptor stimulation.     

Topographical analysis of nucleus accumbens sites at which cholecystokinin potentiates dopamine-induced hyperlocomotion in the rat

Sulfated cholecystokinin octapeptide (CCK) potentiates dopamine-induced hyperlocomotion in the nucleus accumbens of the rat. Immunocytochemical evidence has shown a topographical distribution of terminals containing both CCK and dopamine (DA), within the medial posterior nucleus accumbens. Seven sites within the nucleus accumbens were cannulated and tested for the ability of CCK to enhance the behavioral effects of DA. Close agreement was found between the anatomical sites of CCK-DA coexistence, and the anatomical sites at which CCK potentiated DA-induced hyperlocomotion. Behaviorally inactive sites were found primarily in the anterior nucleus accumbens, where DA-containing terminals do not contain CCK.     

A method for combining field potential recording with local perfusion in the hippocampus of the anaesthetized rat

A method is described for combining local perfusion of discrete brain areas and simultaneous recording of field potentials using a push-pull cannula with attached electrodes.     

Glutamate Peripherally Administered Exerts Somatostatin-Releasing Action in the Conscious Rat

This study was designed to determine whether glutamate is able to stimulate somatostatin release from in vivo conscious animals when somatostatin release is monitored in unanaesthetized rats stereotaxically implanted with a push-pull cannula in the median eminence. One week after implantation, the median eminence was perfused with artificial cerebrospinal fluid alone or with the addition of either CGS 19755, an N-methyl-D-aspartate (NMDA) receptor antagonist (1(10^?6 M), or glutamate (10^?5 M). The latter (which is able to cross the brain-blood barrier at large doses) was also peripherally administered (1 g/kg ip). Median eminence perfusate samples were collected every 15 min and somatostatin was measured by a sensitive radioimmunoassay. In rats receiving ip glutamate injection, somatostatin release from the median eminence was significantly increased (73.3±10.4 versus 24.8 ± 6.2; P < 0.01; n = 5) when compared to baseline levels measured in the same animals, but no effect was observed when local perfusion of the median eminence with glutamate (10^?4 to 10^?5 M; n = 6) was performed. Glutamate-induced somatostatin release was completely blunted (n = 5) by prior local administration of CGS 19755 (10^?5 M), a potent NMDA-type receptor antagonist able to cross the blood-brain barrier. In contrast, administration of glutamic acid diethylester, a competitive antagonist of non-NMDA receptors, at doses of 10^?4 M (n = 4), was not able to alter this response. Our results are the first in vivo evidence in favour of a neuroendocrine role for glutamate on somatostatin release whose site of action seems to exclude the median eminence.     

干细胞移植治疗帕金森病研究进展

帕金森病 (Parkinson’sdisease,PD)是一种人类常见的中枢神经系统退行性疾病 ,主要病理变化是黑质多巴胺神经元损伤 ,是干细胞治疗的最佳适应证之一。动物模型的研究证实 ,干细胞移植可以替代丧失的神经元 ,恢复脑功能和促进脑的自我修复。临床试验显示干细胞移植在PD病人脑部也可达到类似的结果。这些研究展示了干细胞移植临床应用治疗PD的良好前景。然而 ,这样的治疗是否可以永久和完全恢复PD的脑功能仍是一个疑问。     

Presynaptic regulation of the release of catecholamines in the cat hypothalamus

The posterior hypothalamus of cats was superfused through a push-pull cannula and the release of endogenous catecholamines was determined in the superfusate. Superfusion with yohimbine, isoprenaline, salbutamol or tazolol increased, while superfusion with propanolol decreased, the release of all three catecholamines. Transection of the brain caudal to the hypothalamus inhibited ‘resting’ and drug-induced release. It is concluded that α- and β-adrenoceptors of the hypothalamus are involved in the regulation of the release of catecholamines.     

Release of Vasopressin from the Septum and Hippocampus of Freely Behaving Male Rats: Effect of Bacitracin and Synthetic Vasopressin

This paper describes the release characteristics of arginine vasopressin (AVP) from the dorsal septum and dorsal hippocampus of freely behaving male rats using miniaturized push-pull cannulae and a slow rate of perfusion to minimize tissue damage. The major findings were that) The spontaneous release of immunoreactive AVP (l-AVP) from the dorsal hippocampus was episodic in nature and did not require the presence of bacitracin in the perfusion medium to reliably demonstrate its pattern of release; 2) despite the fact that the septum has close to seven times more I-AVP per/mg of tissue, the dorsal septum perfusates had undetectable levels of the neuropeptide; 3) under these conditions hypertonic saline intraperitoneally did not alter the spontaneous release of this peptide; and 4) only when the perfusion medium contained effective concentrations of bacitracin (10^?4 M) were reliable and detectable levels of I-AVP measured in perfusates from the dorsal septum and exogenous synthetic AVP had a robust positive feedback action on its own release. The physiological relevance and importance of this robust and novel effect of AVP remains to be elucidated.     

Amphetamine-induced motility and nigrostriatal impulse flow

A comprehensive mapping of ascorbate distribution in human brain was carried out by liquid chromatography analysis. The data agree with earlier literature values where comparable and provide new information on several brain regions, including a detailed distribution in the thalamus. While ascorbate concentrations tend to be high in regions rich in catecholamines, there is no real correlation between the two.     

SCH 23390 enhances exogenous L-DOPA decarboxylation in nigrostriatal neurons

Summary. Exogenous L-DOPA enhances dopamine metabolism in the intact and denervated striatum, and is the treatment of choice for Parkinsonism. Aromatic L-amino acid decarboxylase (AAAD) converts L-DOPA to dopamine. Blockade of dopamine D₁-like receptors increases the activity of AAAD in both intact and denervated striatum. A single dose of SCH 23390, a dopamine D₁-like receptor antagonist, increases the activity of AAAD in the striatum and midbrain and induces small changes in dopamine metabolism. When L-DOPA is administered after SCH 23390, there is a significant increase in the formation of 3,4-dihydroxyphenylacetic acid and dopamine turnover in striatum and midbrain compared to L-DOPA alone, suggesting further enhancement of dopamine metabolism. When the studies are repeated in the MPTP mouse model of Parkinson's disease, there is significantly more dopamine metabolism in the striatum of lesioned mice pretreated with SCH 23390 than in a comparison group treated with L-DOPA alone. These studies suggest that it may be possible to enhance the conversion of L-DOPA to dopamine in Parkinson's disease patients by administering substances that augment brain AAAD. Received May 10, 1999; accepted September 14, 1999     

Cholecystokinin peptides, dopamine and schizophrenia — A review

1. CCK-IR is co-localized with DA in some DA neurons projecting to limbic structures. The extent of the co-localization is species dependent. The co-localization of CCK and DA is of interest in view of the DA hypothesis of schizophrenia and the putative role of limbic dysfunction in the pathophysiology of this disorder.

2. In animals biochemical, electrophysiological and behavioural studies point to an interaction between CCK and DA. Whereas some investigations point to an inhibitory effect on DA function, which would be compatible with a potential antischizophrenic action, others point to an enhancement or no effect. CCK peptides show a neuroleptlc-like profile in several screening tests for neuroleptics but not in all studies.

3. In man there is endocrinological evidence for an inhibitory effect of CCK-33 and CCK-8 on DA function. However, alternate explanations are possible. CSF CCK-IR is unchanged or decreased in schizophrenia. Autopsy investigations have shown significant decreases, increases or no change in brain CCK-IR concentrations and a decrease in CCK-33 binding in schizophrenia. Eight of 11 clinical trials with CER, CCK-8 or CCK-33 have shown a therapeutic effect in schizophrenia; only two of these eight trials have been double-blind studies. The three controlled investigations which have shown no effect have used only small patient populations. None of the trials have used an active placebo.

4. It is difficult to reconcile the apparent long duration of antipsychotic activity with the short half-life of the peptides and problems of the peptides in crossing the blood brain barrier. Despite these apparent anomalies information to date is sufficiently impressive to warrant further detailed investigation of CCK-DA-interactions and the evaluation of the clinical effects of a variety of CCK peptides and related compounds, natural and synthetic, which may more easily cross the blood brain barrier and which may show regional selectivity in site of action in brain.