Chronic nicotine treatment increases dopamine levels and reduces dopamine utilization in substantia nigra and in surviving forebrain dopamine nerve terminal systems after a partial di-mesencephalic hemitransection

Summary In order to further study the previously demonstrated protective action of chronic nicotine treatment on lesioned meso-striatal dopamine (DA) pathways, the following study was carried out on DA utilization in these lesioned neurons. Male Sprague-Dawley rats were partially hemitransected at the meso-diencephalic junction and treated with nicotine (0.125 mg · kg^–1 · h^–1) by means of Alzet minipumps implanted subcutaneously for 2 weeks. The overall serum nicotine level obtained was 64.6 ± 2.7 ng · ml^–1.The results demonstrated that partial di-mesencephalic hemitransections produced a marked reduction of DA fluorescence (quantitative histofluorimetry) on the lesioned side in the nucleus caudatus putamen, anterior nucleus accumbens and posterior lateral tuberculum olfactorium. No significant effects were observed on the intact side. Furthermore, studies on changes in DA utilization as evaluated 2 h after tyrosine hydroxylase inhibition showed an augmentation in the -methyl-(±)-p-tyrosine methyl ester (-MT)-induced depletion of the DA stores on the hemitransected side in comparison with the operated side of the sham-operated animals. On the hemitransected side chronic nicotine treatment increased DA stores in the DA nerve terminals of the nucleus caudatus putamen and the posterior lateral tuberculum olfactorium. No significant effects were observed on the intact side. Following chronic nicotine treatment a marked and preferential attenuation of the -MT-induced depletion of DA stores was seen in the various DA nerve terminal systems of the forebrain on the hemitransected side. In the substantia nigra reduced DA levels (HPLC) were demonstrated on the hemitransected side, while no effects on the non-operated side were observed. Also an increase of the -MT-induced depletion of the DA stores was seen on the hemitransected side in comparison with the operated side of the sham-operated animals. In contrast, on the non-operated side an attenuation of the a MT-induced depletion of the DA stores was found. Following chronic nicotine treatment the lesion induced reduction of the nigral DA stores on the hemitransected side was counteracted, as was the lesion induced increase in the -MT-induced depletion of DA stores, which was replaced by a reduction of the -MT-induced depletion of the nigral DA stores. However, on the non-operated side an increased DA depletion was observed after -MT treatment in rats treated chronically with nicotine. Chronic nicotine treatment under the present conditions did not significantly alter serum levels of corticosterone and reduced prolactin serum levels in sham-operated rats.The present results indicate that a partial hemitransection produces marked increases in DA utilization of the forebrain and of the substantia nigra on the lesioned side; whereas on the non-operated side a reduction in nigral DA utilization was found. On the hemitransected side chronic nicotine treatment increases DA stores of the nucleus caudatus putamen, tuberculum olfactorium and substantia nigra, suggesting a protective action of nicotine. Chronic nicotine treatment preferentially and substantially reduces striatal, accumbens and nigral DA utilization on the lesioned side. On the non-operated side chronic nicotine treatment abolished the lesion-induced reduction of DA utilization in the substantia nigra. These results are in support of the hypothesis that a protective action of chronic nicotine treatment on ascending DA systems may be produced via a desensitization of excitatory nicotine cholinoceptors regulating the ascending DA pathways, leading to reduced firing rates and thus to reduced energy demands. The endocrine system does not seem to be involved in these effects.Abbreviations ACC dif anterior part of nucleus accumbens - ACC dot posterior part of nucleus accumbens - LAUD cent central part of nucleus caudatus - CAUD marg marginal zone of nucleus caudatus - CAUD med medial part of nucleus caudatus - DA dopamine - HPLC high performance liquid chromatography - -M -methyl-(±)-p-tyrosine methyl ester - TUB dif posterior lateral part of the olfactory tubercle - TUB dot posterior medial part of the olfactory tubercle Send offprint requests to A. M. Janson at the above address     

Rapid and discrete changes in hypothalamic catecholamine nerve terminal systems induced by audiogenic stress, and their modulation by nicotine-relationship to neuroendocrine function

The effects of acute audiogenic stress, with or without simultaneous nicotine treatment (0.3 mg/kg i.v.), on catecholamine levels in discrete dopamine and noradrenaline nerve terminal systems of the hypothalamus, and on the secretion of adenohypophyseal hormones and of corticosterone, were studied using quantitative microfluorometric evaluations of catecholamine stores and radioimmunoassays for the determination of serum hormone levels. Audiogenic stress and nicotine induced very rapid and discrete decreases in noradrenaline levels in the subependymal layer (SEL), in the parvocellular part of nuc. paraventricularis hypothalamic (PA FP) and in the posterior periventricular hypothalamic systems, (PV II); the decreases were apparent 2 min following the onset of treatment. Increases of arterial blood pressure were observed after nicotine treatment but could not have been a major factor in producing the changes in catecholamine levels. These changes in NA levels may be related to the nicotine- and stress-induced increases of ACTH (SEL and PA FP) and prolactin secretion (PV II) found in the present experiments. Stress enhanced the rapid but variable increase in vasopressin secretion induced by nicotine, suggesting one possible mechanism by which stress combined with smoking can contribute to the development of increased arterial blood pressure and finally to sustained hypertension.     

抗精神病药物对男性精神分裂症患者性激素水平的影响

目的探讨男性精神分裂症患者血清雌二醇、催乳素、睾酮和孕酮的水平及抗精神病药物对其影响。方法60例男性精神分裂症患者随机分为氯氮平组(30例)和利培酮组(30例),分别给予氯氮平和利培酮治疗4周,应用电化学发光免疫分析(ECLIA)技术分别于治疗前后测定血清雌二醇、催乳素、睾酮和孕酮水平,并与60名健康对照进行比较。结果治疗前患者组血清催乳素、孕酮高于对照组(P<0.05);治疗后患者组血清雌二醇、催乳素和孕酮高于对照组(P<0.05);与治疗前相比,治疗后氯氮平组血清催乳素显著升高(P<0.01),利培酮组血清雌二醇、催乳素、睾酮显著升高(P<0.01)。治疗后氯氮平组血清催乳素低于利培酮组(P<0.01),雌二醇、睾酮及孕酮的差异无统计学意义(P>0.05)。结论男性精神分裂症患者治疗前后均存在高催乳素状态,可能是精神分裂症的一种属性标志。氯氮平和利培酮均对男性精神分裂症患者性激素水平产生不同程度的影响。     

Effect of buspirone on rat plasma prolactin levels and striatal dopamine turnover

Buspirone, an effective antianxiety compound, produced a dose-dependent, relatively prolonged increase in rat plasma prolactin (PRL) levels. The stimulation of PRL secretion by buspirone was additive with the effect of -methyl-p-tyrosine (AMPT) or -butyrolactone. In vitro, buspirone itself had no effect on the release of PRL from rat pituitary glands but it blocked the inhibitory action of dopamine (DA). Buspirone also increased DA turnover in the striatum as measured by the AMPT-induced depletion of striatal DA levels. These results demonstrate the ability of buspirone to block pituitary and striatal DA receptors.     

Activity of tuberoinfundibular dopaminergic neurons and concentrations of serum prolactin in the rat following lithium administration

Maintenance of rats on a lithium-containing diet for 3–21 days resulted in a suppression of prolactin (PRL) secretion in vivo and in vitro. Lithium treatment also resulted in an increase in the activity of tuberoinfundibular dopaminergic neurons, as evidenced by an increased accumulation of dihydroxyphenylalanine (DOPA) in the median eminence after inhibition of DOPA decarboxylase and an increased concentration of dopamine in the anterior pituitary gland. The accumulation of DOPA in the neurointer-mediate lobe of the pituitary gland, the prefrontal cortex, the striatum and the nucleus accumbens was also enhanced by lithium treatment. It is concluded that lithium treatment enhances the synthesis of dopamine in many brain regions and that an increased activity of tuberoinfundibular dopaminergic neurons results in an enhanced inhibitory control of PRL secretion.     

阿立哌唑、氯氮平、利培酮对精神分裂症患者泌乳素及雌二醇的影响

目的：比较阿立哌唑、氯氮平、利培酮三种抗精神病药物对精神分裂症患者泌乳素及雌二醇的影响。方法：收集本院精神分裂症患者120例,随机分为阿立哌唑组、氯氮平组、利培酮组,每组40例,治疗前及治疗后8周分别检测泌乳素及雌二醇水平。结果：3种药物治疗前泌乳素及雌二醇水平均无明显差异（P>0.05）。治疗8周后,利培酮组泌乳素水平明显升高（P<0.01）,而雌二醇水平却显著降低（P<0.05）;氯氮平组泌乳素和雌二醇水平无明显变化(P>0.05);阿立哌唑组泌乳素水平无明显变化(P>0.05),雌二醇水平则显著上升（P<0.05）。结论：利培酮治疗的患者容易出现泌乳素升高、雌二醇降低的现象;阿立哌唑会使雌二醇升高,但对泌乳素无明显影响;氯氮平对两者均无明显影响。     

Clozapine: Plasma levels and prolactin response

Serial plasma clozapine levels and serum prolactin levels were determined in two schizophrenic patients receiving clozapine, a novel antipsychotic drug. Despite marked therapeutic response and substantial clozapine blood levels, prolactin levels obtained 11–12 h after the last oral dose were unaffected or only minimally elevated. This confirms previous evidence of clozapine's unusal characteristics.     

Antipsychotic drugs stimulate prolactin release

Antipsychotic drugs have been found to markedly stimulate prolactin secretion in male and female rats. The amount of prolactin released was greater in females than in males. Most non-antipsychotic phenothiazines failed to alter prolactin. These results imply that the dopamine receptor that inhibits prolactin release may be similar to the dopamine receptor involved in the action of antipsychotic drugs.     

Effect of flupenthixol and butaclamol isomers on prolactin secretion in rats

Cis ()-flupenthixol and (+)-butaclamol are effective anti-psychotic agents but trans ()-flupenthixol and (-)-butaclamol are not. -Flupenthixol was found to be 245 times more active in elevating rat plasma prolactin than the -isomer. The discrepancy between (+)-butaclamol and (-)-butaclamol was even greater. These results support the hypothesis that the dopamine receptors that mediate the effects of dopamine on prolactin secretion are similar to those that mediate the anti-psychotic effect of neuroleptic drugs.     

治疗剂量多巴胺对心衰病人呼吸及免疫水平的影响

目的探讨多巴胺与泌乳素分泌及内皮功能、组织氧合关系.方法比较30例低剂量多巴胺治疗的心衰患者及32例常规抗心衰治疗的患者,治疗前后血清一氧化氮（NO）、内皮素（ET）、血清泌乳素（PRL）及动脉血氧分压（PaO2）、二氧化碳分压（PaCO2）、血氧饱和度（SaO2%）变化.结果多巴胺组治疗前后NO、ET、PRL均有显著性差异.对照组治疗前后NO、PRL、PaO2、PaCO2、SaO2%有显著性差异.两组治疗前PaCO2有显著性差异.两组治疗后PRL有显著性差异.两组治疗后NO、SaO2%有显著性差异.结论多巴胺抑制泌乳素分泌,导致机体免疫功能下降;心衰时较长时间应用多巴胺可影响组织氧合,心衰病人应用多巴胺时需充分考虑其对呼吸和免疫的影响.     

Effect of metabolites of chlorpromazine on plasma prolactin levels in male rats

Since prolactin secretion is under vigorous dopaminergic inhibition, neuroleptic drugs can, because of their capacity to block dopamine receptors, produce large increases in plasma prolactin levels in man and laboratory animals. The capacity of intramuscular (i.m.) chlorpromazine and 6 of its metabolites to increase plasma prolactin levels in male rats was compared. 7-Hydroxychlorpromazine produced increases in plasma prolactin equivalent to those produced by chlorpormazine. The following metabolites had no effect on plasma prolactin levels after i.m. injections of 5 mg/kg: 8-hydroxychlorpromazine; 7, 8-dihydroxychlopromazine; 8-hydroxy-7-methoxychlorpromazine; 7-methoxychlorpromazine; and chlorpromazine sulfoxide. 8-Hydroxychlorpromazine, 7-methoxychlorpromazine, 7, 8-dihydroxychlorpromazine and chlorpromazine sulfoxide had no effect even after 25 mg/kg i.m. The capacity to increase rat plasma proclactin correlates highly with other methods of determining potential antipsychotic activity of chlorpromazine and its derivatives.     

Relapse following clozapine withdrawal: effect of neuroleptic drugs and cyproheptadine

The objective of this study was to report the effect of the slow withdrawal of clozapine from 19 patients withneuroleptic-responsive schizophrenia at the end of a 2-year clinical trial of clozapine and to compare this with the results of naturalistic discontinuation of clozapine treatment in 64neuroleptic-resistant schizophrenic patients. Nineteen neuroleptic-responsive schizophrenic patients who received clozapine were withdrawn from clozapine by tapering it over 3-week period with and without the addition of a typical neuroleptic. Fifteen of the 19 neuroleptic-responsive patients experienced the return of psychotic symptoms during or after the clozapine taper, which were most severe in the ten patients in whom the withdrawal of clozapine was carried out without prior addition of neuroleptic treatment. Addition of a neuroleptic prior to clozapine withdrawal prevented the emergence of positive symptoms during clozapine withdrawal in each of eight patients. Nevertheless, psychotic symptoms emerged, usually within a week after discontinuing clozapine, in six of the eight patients. Neuroleptic treatment, with or without an anticholingergic drug, was much less effective in treating positive symptoms in these patients immediately after the clozapine withdrawal than it had been 2 years previously. Cyproheptadine, a non-selective serotonin receptor antagonist, augmented the antipsychotic effect of neuroleptics in each of four patients who relapsed following withdrawal from clozapine and relieved extrapyramidal symptoms in a fifth patient. The frequency of relapse following withdrawal of clozapine in 64 neuroleptic-resistant patients was significantly lower (25/64, 39.1%) than in the neuroleptic-responsive patients.     

Co-release of noradrenaline and dopamine from noradrenergic neurons in the cerebral cortex induced by clozapine,the prototype atypical antipsychotic

Rationale. Clozapine has been shown to increase extracellular dopamine (DA) and noradrenaline (NA) in the medial prefrontal cortex (mPFC). A recent study of ours suggested that extracellular DA in the PFC originates not only from dopaminergic but also from noradrenergic terminals, its release being controlled by α₂-adrenoceptors. Objectives. Since clozapine binds to α₂-adrenoceptors, the possibility that it might co-release DA and NA was studied. Methods. By means of microdialysis coupled to HPLC with electrochemical detection, the effect of clozapine on extracellular DA and NA in the mPFC, densely innervated by DA and NA, was compared to that in the occipital cortex, equally innervated by NA but receiving few DA projections. Results. Extracellular NA was found to be the same in the two cortices, consistent with homogeneous NA innervation. On the other hand, extracellular DA in the occipital cortex was only 29% lower than in the mPFC, in spite of the scarce dopaminergic innervation in the occipital cortex. Clozapine (10 mg/kg IP) increased extracellular DA and NA not only in the mPFC (by about 320% and 290%, respectively) but also in the occipital cortex (by 560% and 230%, respectively). Administration of the α₂-agonist clonidine (0.15 mg/kg) reversed the effect of clozapine in both cortices, while the D₂-agonist quinpirole (0.1 mg/kg IP) was ineffective. Conclusions. The results suggest that clozapine, by inhibiting α₂-adrenoceptors, co-releases DA and NA from noradrenergic terminals in the occipital cortex and that the same mechanism might be responsible for the concomitant increase of the two monoamines in the mPFC. Electronic Publication     

Prolactin stimulating effects of amoxapine and loxapine in psychiatric patients

The effects of acute and chronic administration of a new antidepressant, amoxapine, on serum prolactin levels were compared to the effects of loxapine, its parent compound, which is a widely used neuroleptic. Serum prolactin levels were significantly elevated after amoxapine. These elevations were not significantly different from those of patients given loxapine. This suggests that amoxapine, in contrast to most other antidepressants, can block dopamine receptors at the anterior pituitary, which usually is associated with blockade of dopamine receptors in the striatum and limbic system, leading to extrapyramidal side effects and antipsychotic properties, respectively. The implications of these findings for the clinical use of amoxapine are discussed,Supported in part by USPHS MH 29206 and MH 30938, and by the Department of Mental Health, State of Illinois. HYM is recipient of USPHS MH 47808.     

The central effects of a novel dopamine agonist

A new peripheral dopamine agonist which causes dopaminergic renal vasolidation, was tested for central dopaminergic activity. SK & F 38393 stimulated the dopamine-sensitive adenylate cyclase in homogenates of rat caudate, as a partial agonist, and caused contralateral rotation in rats with unilateral 6-OHDA lesions of substantia nigra. Rotation was shown to be due to a direct effect on supersensitive dopamine receptors. Stimulation of cAMP formation and rotation were blocked by dopamine antagonists. In contrast to other dopamine agonists, SK & F 38393 did not cause stereotypy, emesis or inhibition of prolactin release, nor did SK & F 38393 affect dopamine turnover. The results suggest that SK & F 38393 may selectively stimulate supersensitive central dopamine receptors in vivo or may activate only a certain subclass of dopamine receptors including the receptor in the renal vasculature and the adenylate cyclase coupled postsynaptic receptor in the caudate.     

The putatively selective dopamine autoreceptor antagonists (+)-AJ 76 and (+)-UH 232 stimulate prolactin release in rats

The 2-aminotetralin derivatives cis-(+)-(1S,2R)-5-methoxy-1-methyl-2-(n-propylamino)tetralin, (+)-AJ 76, and cis-(+)-(1S,2R)-5-methoxy-1-methyl-2-(di-n-propylamino)tetralin, (+)-UH 232, are novel centrally acting stimulants with a putative action as selective dopamine (DA) autoreceptor antagonists. In the present study these compounds were evaluated with respect to their effects on prolactin release in male rats. Both (+)enantiomers caused a pronounced increase in plasma prolactin levels in previously untreated animals. The effects of (+)-AJ 76 and (+)-UH 232 were virtually similar, except for a higher initial increase after the latter compound. In agreement with earlier reports, the reserpine-induced elevation of plasma levels of prolactin was strongly suppressed by the DA autoreceptor agonist B-HT 920. This effect of B-HT 920 was completely blocked by (+)-AJ 76 and by (+)-UH 232, indicating that both (+)enantiomers antagonize lactotroph DA receptors. The present findings support the notion that lactotroph DA receptors resemble DA autoreceptors rather than postsynaptic DA receptors. A possible difference between the auto-/lactotroph vs. postsynaptic DA receptors with respect to both the responsiveness to agonists and to the affinity of pure antagonists is discussed.     

Predictable individual differences in the initiation of cocaine self-administration by rats under extended-access conditions are dose-dependent

RATIONALE: The characterization of self-administration (SA) under extended access conditions is necessary for the development of addiction models. OBJECTIVE: The purposes of this experiment were to investigate: (1) dose effects on the initiation of cocaine SA under extended access conditions; (2) predictable individual differences in SA under these conditions and their relationships to neuroendocrine function and cocaine dose. METHODS: After they were tested for their locomotor responses to novelty and to cocaine and trained to lever-press under a food-reinforced schedule, male Sprague-Dawley rats were allowed to SA cocaine (0.25, 0.5, 1.0, or 2.0 mg/kg per infusion, IV) by lever-pressing under a FR1 schedule during five consecutive daily 10-h sessions. Plasma corticosterone (CORT) and prolactin (PRL) were measured throughout the experiment. RESULTS: Rats tested at higher cocaine doses more readily acquired and showed increased drug intake and more regular patterns of SA. High responders (HR) to novelty self-administered greater amounts of cocaine, acquired more rapidly and displayed more regular SA compared to LR rats, but only at the lowest cocaine dose tested (i.e., 0.25 mg/kg per infusion). HR rats also exhibited a greater high-dose escalation of SA compared to LR rats. Novelty-induced (but not cocaine-induced) locomotor activity, pre-SA plasma CORT, and pre-SA food-reinforced lever-pressing predicted SA, but only at the lowest cocaine dose tested. No differences in plasma CORT or PRL were observed between LR and HR rats. CONCLUSIONS: The present findings indicate that predictable individual differences in cocaine SA under extended access conditions are relevant only at low doses and are surmountable by increasing the available dose of cocaine.     

Biochemical indices of reactivity and habituation in rats with hippocampal lesions

The response of rats with hippocampal lesions to acute and repeated footshock stress was assessed by measurement of pituitary cyclic AMP, plasma corticosterone and plasma prolactin. Levels of pituitary cyclic AMP and plasma prolactin and corticosterone were similar in never-shocked sham controls, and never-shocked hippocampal and neocortical lesion groups. Acute first time shock markedly elevated all measured stress indices with no statistically significant differences observed among surgical groups. In rats subjected to repeated stress (one 15 min footshock session per day for 10 days) and sacrificed 24 hours after the last shock session, levels of pituitary cyclic AMP and plasma hormones were similar to levels in never-shocked shams with the exception of the hippocampal animals. The rats with hippocampal lesions had higher levels of pituitary cyclic AMP, plasma corticosterone and plasma prolactin compared to never-shocked animals. We suggest that these data reflect a hyperreactive response of the hippocampal animals to a situation previously associated with shock. Finally, rats in all surgical groups subjected to repeated stress and sacrificed immediately after the last shock session showed a diminished cyclic AMP response to the stressor as compared to first footshock session response, demonstrating a habituation to the stressor as measured by this index. No differences in habituation were observed among hippocampal, neocortical and sham groups. Plasma hormone responses did not habituate in any group. These data support the behavioral observations of hyperreactivity in hippocampal animals and indicate that hippocampal animals are able to habituate to repeated stressful stimuli.     

Habituation to repeated stress is stressor specific

Rats were exposed to 15 min of restraint or footshock or forced running in an activity wheel once a day for 10 days. Control groups were handled only. On the 11th day, rats from each stressor group and controls were exposed to 15 min of one stressor in a crossed design such that all combinations of one chronic stressor and one acute stressor were performed. Rats were sacrificed immediately following removal from their home cage or after 15 min stressor exposure on the 11th day and plasma corticosterone and prolactin and pituitary cyclic AMP levels were determined. There were no measured differences in these stress indices among groups of rats sacrificed immediately upon removal from their home cage on day 11 regardless of previous history on days 1 through 10. Plasma corticosterone and plasma prolactin and pituitary cyclic AMP levels were elevated in all rats exposed to any of the three stressors immediately prior to sacrifice as compared to all rats not exposed to stress immediately before sacrifice. However, plasma prolactin and pituitary cyclic AMP responses to each of the 3 stressors were attenuated in rats which had previous exposure to that specific stressor as compared to rats which had previous experience with a different or no stressor. We conclude that habituation results from behavioral experience with a particular stressor rather than biochemical adaptation resulting from repeated challenge to hormonal and neurochemical systems responsive to stress.     

Inhibition by naloxone of the rise in hypothalamic dopamine and serum prolactin induced by ethanol

We investigated the effect of naloxone on the concentration of dopamine in the hypothalamus and on the concentration of prolactin in serum and anterior pituitary of male rats acutely treated with ethanol. Acute ethanol administration increased serum prolactin levels and hypothalamic dopamine concentration. Pituitary prolactin was not modified by this treatment. Naloxone administered 15 min before the animals were sacrificed decreased serum prolactin levels and hypothalamic dopamine concentration in ethanol-treated rats. These results suggest that ethanol increases prolactin secretion because it decreases the release of dopamine by the hypothalamus. Naloxone decreases prolactin release probably because it antagonizes the inhibitory action of opioids on dopaminergic neurons.