Effect of 6-hydroxydopamine on brain and blood catecholamine, ammonia, and amino acid metabolism in rats subjected to high pressure oxygen induced convulsions

Effects of 6-hydroxydopamine (6-OHDA) on rat brain and blood adrenaline (A), noradrenaline (NA), ammonia (NH3), gamma-aminobutyric acid (GABA), and amino acid metabolism prior to and after high pressure oxygen (OHP) induced convulsions have been studied. 6-OHDA reduces GABA and glutamate (Glu) rior to OHP exposure in rat brain so that the concentration is even equal to that seen in nondrugged animals after convulsion. Concomitantly, 6-OHDA reduces the latency of OHP-induced convulsion significantly, and increases brain NH3, glutamine, and asparagine significantly. Although 6-OHDA, in increasing dosage, elevates blood A concentration, convulsion produces a significant further increase in A. Blood NA was not significantly changed in drugged, convulsed animals and was much less than blood NA concentrations in nondrugged convulsed animals. Increasing doses of 6-OHDA also increase NH3 in the blood significantly and convulsion increases its concentration further. Latency of convulsion seems to be related to certain monoamine levels since in some drugged animals where A and total catecholamines are still reduced 96 h after the first of two doses of 6-OHDA, NA concentrations are recovered to relatively normal and the convulsion latency time is also increased although it remains significantly abbreviated from undrugged animals' convulsion time. Low brain GABA levels seem to be a prime effector of convulsive activity.     

EFFECTS OF 6-HYDROXYDOPAMINE ON CATECHOLAMINE CONTAINING NEURONES IN THE RAT BRAIN

After the intraventricular injection of 6-hydroxydopamine (6-OHDA), there was a long lasting reduction in the brain concentrations of noradrenaline (NA) and dopamine (DA). The brain concentration of NA was affected by lower doses of 6-OHDA than were required to deplete DA. A high dose of 6-OHDA which depleted the brain of NA and DA by 81 per cent and 66 per cent respectively, had no significant effect on brain concentrations of 5-hydroxytryptamine (5-HT) or γ-aminobutyric acid (GABA). The fall in catecholamines was accompanied by a long lasting reduction in the activities of tyrosine hydroxylase and DOPA decarboxylase in the hypothalamus and striatum, areas in the brain which are rich in catecholamine containing nerve endings. There was, however, no consistent effect on catechol-O-methyl transferase or monamine oxidase activity in these brain regions. The initial accumulation of [³H]NA into slices of the hypothalamus and striatum was markedly reduced 22–30 days after 6-OHDA treatment. These results are consistent with the evidence in the peripheral sympathetic nervous system that 6-OHDA causes a selective destruction of adrenergic nerve endings and suggest that this compound may have a similar destructive effect on catecholamine neurones in the CNS.     

A possible role for spinal noradrenaline in the mechanisms of 6-hydroxydopamine against pentylenetetrazol induced convulsions in rats

The threshold of the generalized clonic convulsions induced by intravenous infusion of pentylenetetrazol (PTZ) was significantly increased by the intraperitoneal administration of noradrenaline (NA) neurotoxin, 6-hydroxydopamine, which produced no changes in the levels of catecholamines in discrete areas of rat brain, but the effect was accompanied by spinal depletion of NA. Moreover, the anticonvulsant effects of phenobarbitone (PB) and diphenylhydantoin (DPH) against PTZ convulsions were also significantly increased in the animals pretreated with 6-OHDA. These results suggest that the observed elevation of PTZ convulsive threshold and the potentiation of anticonvulsant activity of PB and DPH in 6-OHDA treated rats were possibly mediated through spinal cord depletion of NA.     

神经节苷脂对6-OHDA损毁交感神经末梢的对抗作用

单次6-OHDA (15mg/kg.i.p.)注射后24h,可使雌性成年小鼠颌下腺内儿茶酚胺荧光神经末梢几乎完全消失;同时用 HPLC 测得腺体内去甲肾上腺素(NA)和多巴胺(DA)的含量下降至正常值的3—4%以下。随着受损交感神经末梢再生过程,NA 和 DA 水平有缓慢的恢复。在损毁2周时 NA 和 DA 含量分别达到正常水平的50%和28%,且在4周时完全恢复。在注射6-OHDA 的同时,和在损伤后12h 内给动物注射4次神经节苷脂(每次50mg/kg.i.p.)并在其后的一周內每天注射一次,可使颌下腺内 NA 含量维持在正常水平;在损毁后4h 及损毁前4d 开始施用神经节苷脂,也可不同程度地对抗交感神经末梢损伤,但作用强度不如前者。实验结果提示:(1)神经节苷脂通过减弱6-OHDA 及其代谢产物的损伤效应能够保护交感神经末梢膜,它可能还有促损伤末梢再生性长芽的作用;(2)损伤后神经节苷脂处理得越早,其效果越好。     

Differential effects of experimentally induced blood pressure changes on the release of catecholamines in hypothalamic and limbic areas of rats

The effects of longer lasting blood pressure changes on the release of endogenous catecholamines (CA) in limbic and hypothalamic areas were studied in anaesthetized rats. For this purpose the central nucleus of the amygdala (AC), ventral hippocampus (VH) and medial hypothalamus (MH) were simultaneously superfused through push-pull cannulae with artificial cerebrospinal fluid and the release of the endogenous catecholamines dopamine (DA), noradrenaline (NA) and adrenaline (A) was determined before and after blood pressure manipulations. A fall in blood pressure elicited by the ganglionic blocking agent chlorisondamine resulted in different changes of the various CA release patterns in AC. Short lasting increased CA release rates as compared to prehypotension levels could be observed in the hippocampus. The activity of catecholaminergic neurons in MH remained unchanged. A rise in arterial blood pressure induced by intravenous injection of tramazoline did not change the release rates of DA in all 3 brain areas studied. In hippocampus, NA levels in the superfusates decreased initially during hypertension but returned to normal values 40 min after drug injection. In the late phase of hypertension increased rates of release of NA in the amygdala and of A in the hypothalamus could be observed. The different patterns in the release of CA suggest that DA, NA and A are differentially implicated in the regulation of experimentally induced blood pressure changes.     

Central catecholamine depletion inhibits peripheral lymphocyte responsiveness in spleen and blood

Experimental and clinical evidence has demonstrated extensive communication between the CNS and the immune system. To analyse the role of central catecholamines in modulating peripheral immune functions, we injected the neurotoxin 6-hydroxydopamine (6-OHDA) i.c.v. in rats. This treatment significantly reduced brain catecholamine content 2, 4 and 7 days after injection, and in the periphery splenic catecholamine levels were reduced 4 days after treatment. Central catecholamine depletion induced an inhibition of splenic and blood lymphocyte proliferation and splenic cytokine production and expression (interleukin-2 and interferon-gamma) 7 days after injection. In addition, central treatment with 6-OHDA reduced the percentage of spleen and peripheral blood natural killer (CD161 +) cells, and T-cytotoxic (CD8 +) cells in peripheral blood. The reduction in splenocyte proliferation was not associated with a glucocorticoid alteration but was completely abolished by prior peripheral sympathectomy. These data demonstrate a crucial role of central and peripheral catecholamines in modulating immune function.     

Melanophore Responses and Intermediatelobe Activity in the Eel Anguilla anguilla after Injection of 6-OH-dopamine

When 6-OH dopamine (6-OHDA) was injected into the body cavity of eels (Anguilla anguilla L.), which had been kept on a light background with continuous artificial illumination or a natural day-night regime in May and June, evident but heterogeneous chromatic reactions were induced. After peripheral drug effects during the first 6 hours, the eels became darker for 2 or 3 days, whereupon the melanophore index (MI), in most cases, decreased. Darkening was accompanied by significant nuclear hypertrophy and moderate degranulation of the MSH (melanophore-stimulating hormone) cells. Probably only some of the adrenergic nerves in the neural lobe were affected. The blood supply to the brain was decreased for several days after each injection. The results support the assumption that in the eel catecholamines released from nerve endings in the neural lobe inhibit the release of MSH from intermedia cells by their own action as an inhibiting factor, or by affecting an MIF (MSH-release inhibiting factor) and/or an MRF (MSH-releasing factor).     

The time course of brain and blood catecholamines, catechol O-methyltransferase, and amino acids in rats convulsed by oxygen at high pressure.

The time course of changes in blood and brain catecholamines, catechol O-methyltransferase (COMT), ammonia, and amino acids leading to convulsion by high pressure oxygen breathing (OHP) in rats has been investigated. Brain catecholamines were suppressed by OHP. They changed in phase with brain COMT concentration and consequently were not due to the action of this degrading enzyme. Convulsive actions seem not to be influenced by brain catecholamine concentration. Blood adrenaline concentrations are, however, significantly elevated both prior to and during convulsions. In both brain and blood, ammonia concentration increases, glutamate decreases, and glutamine-aspargine increases. It is proposed that the efficacy of the glutamate-glutamine ammonia buffering system in blood and brain is important in the prevention of the onset of convulsions but that when brain gamma-aminobutyric acid is depressed to critical levels, convulsions result.     

Behavioral and neurotrophic activity of ACTH-(7-16)NH2

The behavioral and neurotrophic effects of ACTH-(7-16)NH2 were assessed in a number of tests in which other ACTH fragments are active. Subcutaneous injection of ACTH-(7-16)NH2 increased motor activity of group-housed rats tested under low light intensity and induced hypokinesia in rats subjected to the mild stress of a nonfunctional "hot" plate. In rats with 6-OHDA lesions in the nucleus accumbens daily subcutaneous treatment with ACTH-(7-16)NH2 during the first week following the lesions reversed the lesion-induced motor hypoactivity. The ED50's for the effects of ACTH-(7-16)NH2 on the environmentally induced changes in motor activity, the stress-induced hypokinesia and the impaired motor activity of 6-OHDA lesioned rats were approximately 8 micrograms/kg. 6.3 micrograms/kg and 0.45 micrograms/kg respectively. It is concluded that ACTH-(7-16)NH2 may mimic the effect of an ACTH-like peptide in the brain involved in brain processes triggered by changes in the environment and by brain damage.     

The behavioral changes and the EEG of the rat brain induced by hyperactivation of the amygdaloid body under noradrenergic deficiency]

The brain NA deficit was produced by bilateral injection of 6-OHDA into the locus coeruleus. Three weeks later amygdala hyperactivation was initiated by local penicillin injection (1% solution, 0.5 mcl). Saline in the same volume was used in control groups in both cases. It was shown that the decrease in NA level facilitated the development of epileptiform activity in rat brain and appearance of immobility-related high-voltage spindles during waking. The amygdala hyperactivation after NA deprivation resulted in a decrease in exploratory activity and disruption of the reaction to novelty. The delta component of the EEG power spectrum increased. The alterations appeared 1-2 weeks after the experimental procedure and became more pronounced towards the end of the third week.     

Rat metabolic adaptation to ammonia inhalation

Rats exposed to 25 or 300 ppm NH3 vapor for 5-15 days 6 hr daily showed dose-dependent blood ammonia after 5 days. Brain and blood glutamine were also increased at the same time in rats exposed to 300 ppm. The blood ammonia concentration of the exposed rats resumed control levels at 10 and 15 days while hepatic citrulline synthesis increased above that of the controls. The animals exposed to 300 ppm NH3 showed initially a slight acidosis. As circulating ammonia decreased, brain and blood glutamine returned to the control range. Our findings support the idea that ureagenesis is aimed mainly at the removal of NH+4 with only secondary and small effects on the acid-base balance.     

Blood-brain barrier permeability to ammonia in liver failure: a critical reappraisal

In patients with acute liver failure (ALF), hyperammonemia is related to development of cerebral edema and herniation. The present review discusses the mechanisms for the cerebral uptake of ammonia. A mathematical framework is provided to allow a quantitative examination of whether published studies can be explained by the conventional view that cerebral uptake of ammonia is restricted to diffusion of the unprotonated form (NH(3)) (the diffusion hypothesis). An increase in cerebral blood flow (CBF) enhanced ammonia uptake more than expected, possibly due to recruitment or heterogeneity of brain capillaries. Reported effects of pH on ammonia uptake were in the direction predicted by the diffusion hypothesis, but often less pronounced than expected. The published effects of mannitol, cooling, and indomethacin in experimental animals and patients were difficult to explain by the diffusion hypothesis alone, unless dramatic changes of capillary surface area or permeability for ammonia were induced. Therefore we considered the possible role of membrane protein mediated transport of NH(4)(+) across the blood-brain barrier (BBB). Early tracer studies in Rhesus monkeys suggested that NH(4)(+) is responsible for 20% or even more of the transport of ammonia from plasma to brain. In other locations, such as in the thick ascending limb of Hendle's loop and in isolated astrocytes, transport protein mediated translocation of NH(4)(+) is predominant. Many of the ion-transporters involved in renal NH(4)(+) reabsorbtion are also present in brain capillary membranes and could mediate uptake of NH(4)(+). Astrocytic uptake of NH(4)(+) is associated with increased extracellular K(+), which is a potent cerebral vasodilator. Such interference between transport of NH(4)(+) and other cations could be clinically important because increased cerebral blood flow often precedes cerebral herniation in acute liver failure. We suggest that protein mediated transport of NH(4)(+) through the brain capillary wall is a realistic possibility that should be more intensely studied.     

Effect of the local administration of 5,7-DHT and 6-OHDA into the neocortex on the learning and exploratory behavior of rats in an open field

On Wistar rats characteristics were studied of investigating behaviour in the open field, of learning of conditioned food-reinforced reaction and also of BA and their metabolites content in various brain structures under local intracerebral injections of specific neurotoxins; 6-hydroxydopamine (6-OHDA) and 5,7-dihydroxytryptamine (5,7-DHT), abolishing correspondingly catecholaminergic and serotoninergic terminals. Bilateral injection of 6-OHDA in the neocortex led to a weakening of rats investigating activity in the open field and to an increase of the time of fulfillment of the forming of conditioned food-reinforced reaction. Administration of 5,7-DHT was accompanied by an increase of the investigating behaviour in the open field and a reduction of the duration of the forming of conditioned reaction. Administration of 6-OHDA to the neocortex caused a lowering of catecholamines level in the frontal area of the neocortex and the hippocampus. Analogous administration of 5,7-DHT elicited simultaneously with a deep level lowering of 5-HT and its metabolite in these structures, a change of catecholamines content which testifies to a lesser specificity of the neurotoxin 5,7-DHT in comparison with 6-OHDA. Structures lesion of serotoninergic and catecholaminergic systems of the frontal cortex and the hippocampus brought about by a local administration of 6-OHDA and 5,7-DHT in the neocortex was accompanied by differently directed changes in animals behaviour.     

Induction of proliferating cell nuclear antigen (PCNA)-immunoreactive cells in goldfish retina following intravitreal injection with 6-hydroxydopamine

1. The dopaminergic neurotoxin, 6-hydroxydopamine (6-OHDA), was injected intravitreally into the eyes of juvenile (5- to 6-cm) goldfish. 2. Proliferation of rod neuroblasts caused by 6-OHDA (2 micrograms in 2 microliters saline) was detected in retinal wholemounts by immunofluorescence for proliferating cell nuclear antigen (PCNA) 3, 7, 14, 20, or 30 days after injection. 3. The injected dose of 6-OHDA was sufficient to cause permanent loss of dopaminergic interplexiform and serotonergic amacrine cells in the injected eye but not in the contralateral control eye. 4. 6-OHDA increased the density (mm-2) of PCNA-ir cells in the outer nuclear layer (ONL) of the injected eye to 2.65 times the initial density 20-30 days after injection, and it increased the density of PCNA-ir cells in the ONL of the contralateral, untreated eye, equally but after a delay of less than or equal to 7 days with respect to the injected eye. 5. 6-OHDA also increased the density of PCNA-ir cells in the inner nuclear layer (INL) to greater than 20 times the initial density 7 days after injection, followed by a rapid decline almost to control levels by 14 days after injection. 6. The sequence of responses to 6-OHDA, with PCNA-ir cells first scattered in the ONL and then clustered in the INL, suggests that neuroblasts from the ONL migrate to the INL to compensate for toxin-induced cell loss. 7. Double staining for 5-bromodeoxyuridine (BrUdR; a thymidine analogue) and PCNA, carried out on 7 days after intravitreal injection with 6-OHDA, showed that 77% of all PCNA-ir cells in the outer nuclear layer had been in S phase during the previous 24 hr. 8. Immunoreactivity for PCNA was found to be a valid marker for rod neuroblasts which have entered S phase within 1-2 days before sampling and was shown to be especially convenient for investigating the distribution of proliferating cells in whole mounts. 9. In controls injected unilaterally with saline or saline plus 1% dimethyl sulfoxide (DMSO), the differences in densities of PCNA-ir rod precursor nuclei 2-30 days after injection vs. day 0 (uninjected) were statistically insignificant in both injected and uninjected eyes (Negishi et al., 1991). Therefore the local effect of injecting 6-OHDA was due to 6-OHDA itself, not to mechanical damage or nonspecific actions of foreign substances.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effect of intraventricular administration of noradrenaline and dopamine on the levels of corticosterone in rats and denervation hypersensitivity resulting from intraventricular administration of 6-hydroxydopamine.

The effects of intraventricular administration of noradrenaline (NA) on the resting levels, stress-induced rises and dexamethasone-induced decreases of plasma corticosterone (B) were studied in rats. The effect of pretreatment with intraventricular administration of 6-hydroxydopamine (6-OHDA) on the effects of NA or dopamine (DA), which was injected intraventricularly, was also examined. The results obtained were as follows: 1) Intraventricular administration of 1.0 μg of NA did not cause a decrease in concentrations of plasma B. 2) Ten μg of NA injected intraventricularly resulted in a rise of the levels of plasma B. 3) The stimulating action of centrally administered NA was more marked when the pre-injection concentrations of B were lower. 4) Pretreatment with intraventricular administration of 6-OHDA facilitated the action of intraventricularly administered NA in the regulation of pituitary-adrenocortical functions. The result suggests a development of denervation hypersensitivity caused by the pretreatment. 5) Intraventricular administration of NA did not block stress-induced rises of plasma B. 6) Intraventricular administration of NA counteracted dexamethasone-induced decrements of plasma B. 7) This counteraction was enhanced by pretreatment with intraventricular administration of 6-OHDA. This also suggests a development of denervation hypersensitivity resulting from intraventricular administration of 6-OHDA. 8) Intraventricular administration of 1.0 μg of DA caused no change in the concentrations of plasma B in either control or 6-OHDA treated animals.     

Pressor effects of systemic administration of methionine and leucine enkephalin in the conscious rat

Experiments were designed using conscious Sprague-Dawley rats to determine the blood pressure (BP) and heart rate (HR) responses to intravenous doses of (1) the adrenal catecholamines noradrenaline (NA) and adrenaline (A), (2) adrenal pentapeptides methionine enkephalin (ME) and leucine enkephalin (LE), (3) combination (i.v.) injections of both ME or LE with NA or A that modulate the hemodynamic responses when the adrenal catecholamines were given alone, and (4) the possible receptor mechanisms mediating the resultant BP and HR response to i.v. pentapeptide administration. NA (0.48 and 2.4 nmol) and A (0.3 and 1.5 nmol) given i.v. evoked potent, dose-related pressor responses associated with reflex bradycardia. ME and LE (1.6 - 48 nmol) elicited transient (10-20 s) increases in mean arterial pressure (MAP), which was associated either with no change in mean heart rate (MHR), such as ME, or with slight bradycardia (i.e., LE). Combining ME or LE (16 nmol) with NA (2.4 nmol) or A (0.3 or 1.5 nmol) did not change MAP and MHR from when these respective doses of NA or A were given alone. However, 16 nmol of ME or LE with a low dose of NA (0.48 nmol) increased the pressor response compared with NA (0.48 nmol) given alone. Other experiments whereby specific receptor blockers (naloxone, diprenorphine, atropine, propranolol, phentolamine or guanethidine) were given i.v. 5 min before subsequent i.v. administration of LE or ME (16 nmol) indicated that only phentolamine or guanethidine could completely suppress the pressor responses of LE and ME. Naloxone and diprenorphine pretreatment attenuated the pressor response of LE but did not affect the BP response to ME.(ABSTRACT TRUNCATED AT 250 WORDS)     

交感传出在大鼠糖尿病性痛过敏中的作用

交感传出和前列腺素（ＰＧｓ）在周围神经不全损伤和炎症所引起的痛过敏中起重要作用,它们对糖尿病性痛过敏影响尚不清楚。本工作先给大鼠腹腔注射６－羟多巴胺（６－ＯＨＤＡ）损毁交感节后神经元（ＳＰＧＮｓ）末梢后,再给予链脲佐菌素（ＳＴＺ）以建立６－ＯＨＤＡ糖尿病大鼠模型,在连续４周的观察中这组大鼠伤害性爪回缩阈值（ＮＰＷＴ）和甩尾反向潜伏期（ＴＥＬ）没有明显变化,而糖尿 病组大鼠的痛阈显著降低,并伴有痛过     

Role of noradrenaline of the dorsal hippocampus in the mechanism of self-stimulation reaction in rats

In has been established that intrahippocampal bilateral injection of NA did not influence common frequency of lateral hypothalamic self stimulation. After the destruction of hippocampal NA - terminals of 6-OHDA increased the frequency of self stimulation and rearing. It is suggested that NA hippocampus inhibit the recall trace of the memory of sensory reinforcement stimuli in the course of stimulation "reward".     

Effects of peritoneal injection of NH4HCO3 on nitrogen excretion and metabolism in the swamp eel Monopterus albus-- increased ammonia excretion with an induction of glutamine synthetase activity

Monopterus albus has to deal with high environmental ammonia concentrations during dry seasons and agricultural fertilization in rice fields. In this study, NH4HCO3 (10 micromol per g fish) was injected into the peritoneal cavity of M. albus, raising the level of ammonia in the body, in order to elucidate the strategies involved in defense against the toxicity of exogenous ammonia. During the subsequent 24 h after NH4HCO3 injection, there was a significant increase in the ammonia excretion rate, which indicates that the main strategy adopted by M. albus was to remove the majority of the exogenous ammonia through enhanced ammonia excretion. Exogenous ammonia was not detoxified into urea for excretion or accumulation. Six hours post-injection of NH4HCO3, ammonia content in the tissues built up significantly, especially in the brain, which suggests that M. albus had high tolerance of ammonia toxicity at the cellular and sub-cellular levels. By hour 12 post-injection, there were significant increases in the activities of glutamine synthetase in the muscle, liver, and gut, accompanied by significant increases in glutamine contents in the muscle and the liver. There was also a significant increase in the glutamine content in the brain at hour 6 post-injection of NH4HCO3. These results confirm the capability of M. albus to detoxify ammonia through glutamine synthesis. Overall, injection of NH4HCO3 had only minor effects on the contents of FAAs, other than glutamine, in tissues of M. albus because the majority (70%) of the injected ammonia was excreted within the 24-h period.     

Desmethylimipramine pretreatment prevents 6-hydroxydopamine induced somatostatin receptor reduction in the rat hippocampus.

Several studies have shown anatomical and functional interconnections between catecholaminergic and somatostatinergic systems. To assess whether somatostatin (SS) may act presynaptically on catecholamine neurons, SS receptors were measured using radioligand test-tube binding assays on synaptosomes from hippocampus and frontoparietal cortex--areas that are innervated by catecholaminergic neurons with different densities and that have a high number of SS receptors--from control and 6-hydroxydopamine (6-OHDA)-treated rats. Intracerebroventricular (i.c.v.) injection of the catecholamine neurotoxin 6-OHDA (0.78 mg free base/kg of body weight in saline with 0.1% ascorbic acid) lowered hippocampal and frontoparietal cortical noradrenaline (NA) and dopamine (DA) levels at 1 week following the injection. Pretreatment of rats with desmethylimipramine (DMI) (40 mg/kg, intraperitoneal) prevented the drop in NA levels, but was not effective in attenuating DA depletion in the two brain areas studied. Treatment with 6-OHDA lowered the number of 125I-Tyr11-SS receptors in the hippocampus (130 +/- 19 vs. 266 +/- 16 fmol/mg protein, P < 0.001), whereas in the frontoparietal cortex a non significant 20% reduction in receptor number was found. The dissociation constants of 125I-Tyr11-SS binding to synaptosomes from frontoparietal cortex (0.65 +/- 0.06 vs. 0.60 +/- 0.04, P not significant) and hippocampus (0.44 +/- 0.04 vs. 0.63 +/- 0.14, P not significant) were similar in control and treated groups. Pretreatment with DMI reversed up to 80% of the effect of 6-OHDA on hippocampus SS receptors. DMI alone had no observable effect on the number and affinity of SS receptors. The 6-OHDA and the DMI treatment did not affect SLI levels in the brain areas studied. These results suggest that a portion of the hippocampal SS receptors may be localized presynaptically on the noradrenergic and dopaminergic nerve terminals.