强迫症患者血小板5-羟色胺、血浆催乳素及地塞米松抑制试验的研究

目的　从神经递质与神经内分泌角度探讨强迫症的生化病理机制。方法　采用高效液相色谱法及放射免疫测定法 ,分别测定 2 9例强迫症患者和 2 8名正常对照者血小板 5 羟色胺 (5 HT)含量及血浆催乳素 (PRL)含量 ,并进行地塞米松抑制试验 (DST)。结果　强迫症组血小板 5 HT水平[(0 8± 1 0 )nmol/10 9个血小板 ]低于正常对照组 [(1 4± 1 2 )nmol/10 9个血小板 ],差异有显著性 (P <0 0 5 ) ;而血浆PRL水平 [(337± 192 )nmol/L]与对照组 [(2 87± 116 )nmol/L]相比 ,差异无显著性 (P >0 0 5 ) ;强迫症组于晨 8时的血浆基础皮质醇含量 [(375± 15 2 )nmol/L]高于正常对照组 [(2 6 2± 138)nmol/L],差异有非常显著性 (P <0 0 1) ,其DST阳性率为 2 4 %～ 17% ,与正常对照组 (14 %～ 11% )相比 ,差异无显著性 (P >0 0 5 )。结论　强迫症患者存在 5 HT能低下和神经内分泌功能的紊乱 ,强迫症的 5 HT能假说能解释其某些内分泌功能紊乱。     

Neuroendocrine responses to serotonergic agents in alcoholics.

Previous studies have suggested a possible deficit in serotonergic function in alcoholism. In order to further assess the serotonergic system in alcoholism, the plasma cortisol and prolactin (PRL) responses following 6-chloro-2-[1-piperazinyl]pyrazine (MK-212), a direct-acting serotonin2 (5-HT2)/5-HT1c receptor agonist, L-5-hydroxytryptophan (L-5-HTP), a precursor of 5-HT, and placebo were compared in male alcoholics and normal controls. The increase in plasma cortisol following L-5-HTP was significantly lower in the alcoholic subjects compared with the normal controls. The plasma PRL, but not the plasma cortisol response, following MK-212 was also significantly lower in the alcoholics. L-5-HTP had no significant effect on plasma PRL levels in either group. The basal plasma cortisol and PRL concentrations of the alcoholics and normal controls were not significantly different. These data are consistent with previous reports of a serotonergic abnormality in alcoholism.     

Stimulation of serum cortisol and prolactin secretion in humans by MK-212, a centrally active serotonin agonist

The effects of MK-212 [6-chloro-2-(1-piperazinyl)-pyrazine] (10, 20, and 40 mg, orally), a centrally acting serotonin (5-HT) receptor agonist and placebo, on serum cortisol, prolactin, and growth hormone levels were studied in eight healthy men over 3-hr. MK-212 produced a dose-related increase in serum cortisol levels, with the 20- and 40-mg doses producing significant elevations. Serum prolactin levels were significantly elevated only by the 40-mg dose. Serum GH levels were not significantly modified by any dose of MK-212. The cortisol and prolactin responses to the 40-mg dose of MK-212 were positively correlated (rho = + 0.85, p less than 0.02). MK-212 was generally well tolerated by the subjects. Headache and nausea were observed at the higher doses, but did not appear to be related to the increase in serum cortisol and prolactin levels. MK-212 may stimulate the secretion of cortisol and prolactin in humans via a serotonin (5-HT2) receptor mechanism and may be a valuable tool with which to study 5-HT receptor sensitivity in humans.     

Effect of the serotonin agonist, MK-212, on body temperature in schizophrenia.

The effects of 6-chloro-2-(1-piperaziny)pyrazine (MK-212), a centrally acting 5-HT1C/5-HT2 agonist, on body temperature and behavior were assessed using a single-blind cross-over design in 23 schizophrenic patients and 22 normal controls. Body temperature was assessed before drug administration and at 30-min intervals for 3 hr. Each subject was administered placebo or MK-212. MK-212 significantly elevated temperature in normal controls. There was no overall MK-212-induced increase in temperature compared to placebo in the schizophrenic patients; however, 13 of 23 (56.5%) patients had a larger increase in temperature after MK-212 than placebo, 3 of 23 (13.1%) had no change, whereas the temperature change after placebo was greater than after MK-212 in 7 of 23 (30.4%) patients. MK-212 produced significant increases in nausea, feeling strange, and arousal but these effects did not differ between groups. These results are consistent with decreased 5-HT2 receptor responsivity in some patients with schizophrenia.     

Neuroendocrine and behavioral responses to challenge with the indirect serotonin agonist dl-fenfluramine in adults with obsessive-compulsive disorder.

Neuroendocrine and behavioral responses to a single 60-mg oral dose of the indirect serotonin agonist dl-fenfluramine were assessed in unmedicated adults with obsessive-compulsive disorder (OCD) and neuroendocrine results contrasted with those in normal control subjects. Net fenfluramine-induced prolactin release did not differ significantly between OCD patients and normal controls. Prolactin responses in the OCD group were not significantly correlated with baseline Yale-Brown Obsessive Compulsive Scale scores for either obsessions or compulsions, but were positively correlated with the baseline Hamilton Depression Scale score and Hamilton Anxiety Scale score. No clear difference in the severity of patients' obsessions or compulsions was found following challenge with fenfluramine versus placebo. Although the present study does not demonstrate a serotonergic abnormality in OCD, this may be more a reflection of limitations of the test procedures than evidence that central nervous system (CNS) serotonergic function is normal in the disorder.     

Acute intravenous administration of ondansetron and m-CPP,alone and in combination,in patients with obsessive–compulsive disorder (OCD): behavioral and biological results

Obsessive–compulsive disorder (OCD) has been linked to abnormal function of brain serotonin (5-HT) pathways. Since ondansetron is a highly selective 5-HT₃ receptor antagonist, the present study was undertaken to investigate 5-HT₃ function in OCD. We administered m-CPP (0.08 mg/kg i.v.) and the potent 5-HT₃ antagonist, ondansetron (0.15 mg/kg i.v.), to 11 OCD patients. All of the subjects received four separate challenges (m-CPP+placebo, m-CPP+ondansetron, ondansetron+placebo and placebo+placebo). In comparison to placebo, administration of m-CPP was associated with significant behavioral effects, particularly self-rated measures of anxiety, altered self-reality, functional deficit and OCD symptoms. Pretreatment with ondansetron did not affect any of the self-rated behavioral symptoms. After administration of m-CPP relative to placebo, significant increases in plasma cortisol and prolactin were found. These changes were not affected by ondansetron. In conclusion, our results do not support the hypotheses that 5-HT₃ receptor-mediated mechanisms modulate m-CPP's behavioral and neuroendocrine effects in patients with OCD.     

Clomipramine in obsessive-compulsive disorder. Further evidence for a serotonergic mechanism of action

Data from several previous studies link clomipramine's potent serotonergic effects to its clinical efficacy in reducing the symptoms of obsessive-compulsive disorder (OCD). To investigate this relationship further, we administered the serotonin (5-HT) receptor antagonist, metergoline, and placebo to ten patients with OCD in a crossover study carried out under double-blind, random-assignment conditions. In a previous study of untreated patients with OCD, we found no differences in the behavioral response to single-dose administration of metergoline or placebo. In the present study, patients with OCD receiving clomipramine hydrochloride on a long-term basis (with an average 40% lessening in OC symptoms) responded to a four-day period of administration of metergoline with significantly greater self- and observer-rated anxiety compared with the four-day placebo period. Obsessive-compulsive symptoms also tended to be greater during the metergoline phase, with significant drug-time interactions for both OC symptoms and anxiety peaking on day 4 of the metergoline phase. As anticipated, metergoline lowered plasma prolactin concentrations (providing evidence of physiologically significant 5-HT antagonism) but did not alter plasma clomipramine concentrations. These data further support the hypothesis that clomipramine's therapeutic behavioral effects in OCD are mediated via serotonergic mechanisms.     

Effects of chronic fluoxetine treatment on behavioral and neuroendocrine responses to meta-chlorophenylpiperazine in obsessive-compulsive disorder

To investigate the effect of fluoxetine on serotonergic sensitivity in obsessive-compulsive disorder (OCD), the partial serotonin agonist metachlorophenylpiperazine (mCPP) was compared to placebo under double-blind conditions in six patients with OCD before and during treatment with fluoxetine. Readministration of oral mCPP (0.5 mg/kg) after at least 12 weeks of fluoxetine treatment did not increase obsessive-compulsive (OC) symptoms, in contrast to exacerbation of OC symptoms produced by mCPP before treatment. Chronic fluoxetine treatment resulted in a significant increase in prolactin and cortisol response to mCPP. This may be accounted for, however, by substantially increased plasma mCPP levels during fluoxetine treatment. Chronic fluoxetine treatment diminished the behavioral sensitivity to mCPP and did not diminish, but may have partially normalized, the neuroendocrine response to mCPP in patients with OCD. These adaptive homeostatic effects may reflect fluoxetine's antiobsessional mechanism.     

Serotonin function in obsessive-compulsive disorder. A comparison of the effects of tryptophan and m-chlorophenylpiperazine in patients and healthy subjects

To evaluate the role of serotonin (5-HT) function in obsessive-compulsive disorder (OCD), behavioral and biochemical responses to the 5-HT receptor agonist m-chlorophenylpiperazine (MCPP) and the 5-HT precursor tryptophan were examined in healthy subjects and patients with OCD. Baseline prolactin levels and the prolactin rise following MCPP were significantly reduced in female patients compared with female healthy subjects. In contrast, the increase in prolactin level following tryptophan administration was not significantly different between male or female patients with OCD and the respective sex-matched healthy subjects. The prolactin responses to MCPP and tryptophan were both significantly higher in female patients and healthy subjects than in their male counterparts. The cortisol and growth hormone responses to MCPP and tryptophan were similar in the patients and healthy subjects and were not related to gender. The behavioral responses to MCPP or tryptophan were not consistently different between patients and healthy subjects, and neither MCPP nor tryptophan had effects on obsessive or compulsive symptoms. These results lend only partial support to the hypothesis that 5-HT dysfunction may be linked to the pathophysiology of OCD and point to the need for the evaluation of other neurotransmitter systems in future investigations of OCD.     

Neuroendocrine and behavioral responses to mCPP in Obsessive-Compulsive Disorder

Patients with Obsessive-Compulsive Disorder (OCD) have been shown to demonstrate blunted cortisol and prolactin responses along with an exacerbation of obsessive-compulsive symptoms in response to oral administration of the pharmacological probe, meta-chlorophenylpiperazine (mCPP). In an attempt to replicate these findings, mCPP was administered orally in the dose of 0.5 mg/kg body weight in a randomized double-blind design to 34 OCD patients who were either drug-naive or drug-free for a minimum period of four weeks. The cortisol and prolactin responses were contrasted with those of 18 drug-free healthy subjects. The OCD patients showed significantly blunted cortisol and prolactin responses to mCPP challenge as compared to normal subjects. However, mCPP did not produce any significant exacerbation of obsessive-compulsive symptoms in the patient group. The results are suggestive of a serotonin (5-HT) receptor hyporesponsivity in the HPA axis. Even though previous studies indicate a hyperresponsivity of the 5-HT receptor system in the orbitofrontal-striatal-pallido-thalamo-cortical pathway as shown by significant symptom worsening following serotonergic challenge, the present study failed to replicate those results. 5-HT receptor hyporesponsivity in the HPA axis may be considered as a biological "trait marker" of OCD, and may not be directly involved in the mediation of symptomatology of the disorder.     

Hyperresponsivity to the serotonin agonist m-chlorophenylpiperazine in Alzheimer's disease. A controlled study

The serotonin agonist m-chlorophenylpiperazine (mCPP) was administered intravenously to 12 patients with Alzheimer's disease and ten age-matched controls. It produced distinct behavioral effects in both treatment groups; however, significantly greater responsivity to mCPP was found in patients with Alzheimer's disease than in controls in measures of psychomotor activation, restlessness, and perceptual abnormalities. Significant and similar increases in plasma prolactin and cortisol levels were found in both patients with Alzheimer's disease and controls following the administration of mCPP vs placebo. Furthermore, blood pressure and pulse changes following mCPP were not significantly different between the groups. Elderly controls, however, did show a significantly greater temperature response following mCPP than did patients with Alzheimer's disease. The overall cognitive effects of mCPP were minimal; however, mCPP produced significantly greater worsening in recent memory and knowledge memory in patients with Alzheimer's disease than in controls. These findings could not be explained by pharmacokinetic differences across populations, because plasma concentrations of mCPP were similar in patients with Alzheimer's disease and controls. The increased behavioral responsivity but unchanged neuroendocrine or other physiologic responsivity to mCPP may be related to damaged brain serotonin neurons or other neuronal systems that interact with serotonin neurons that have been found in postmortem and biopsy studies of patients with Alzheimer's disease.     

焦虑症的生化病理机制探讨

目的：从神经递质与神经内分泌角度探讨焦虑症的生化病理机制。方法：采用高效液相色谱法及放射免疫测定法，分别测定25例焦虑症患者和28例正常对照者血小板5—羟色胺(5—HT)含量及血浆催乳素(PRL)含量、地塞米松抑制实验(DST)皮质醇含量。结果：广泛性焦虑(GAD)组血小板5—HT水平高于正常对照组，惊恐障碍(PD)组与正常对照组无显著差异；GAD组与对照组血浆PRL均极显著低于PD组；GAD组与PD组血浆基础皮质醇含量均显著高于正常对照组，两组DST阳性率均为20％，正常对照组为14．3％，3组阳性率无显著性差异；汉密尔顿焦虑量表(HAMA)评分与血浆皮质醇浓度呈显著正相关。结论：焦虑症患者存在神经递质和神经内分泌功能的紊乱，但不同亚型间可能存在不同的病理机制，皮质醇浓度可能是焦虑水平的标志因子。     

Hypersensitivity of 5-HT2 receptors in OCD patients. An increased prolactin response after a challenge with meta-chlorophenylpiperazine and pre-treatment with ritanserin and placebo

INTRODUCTION: Several studies in obsessive compulsive disorder (OCD) have provided circumstantial evidence that the 5-HT-system is involved in the pathophysiology of OCD. To further examine the role of 5-HT receptors we studied the behavioural and neuroendocrine effects of different doses of meta-chlorophenylpiperazine (mCPP) in OCD patients and healthy controls, after pre-treatment with ritanserin, a 5-HT2 receptor antagonist, and placebo. DESIGN: Twenty patients and 20 healthy controls received 0.1, 0.3 or 0.5 mg/kg mCPP or placebo orally. Each subject was tested two times, receiving both times the same dosage of mCPP or placebo with ritanserin or placebo pre-treatment. All was done under double-blind conditions. OC-symptoms and hormone levels were measured. RESULTS: The increase in prolactin level after mCPP administration was more robust in patients than in controls. The prolactin response following 0.5 mg/kg of mCPP was partially blocked by ritanserin in patients, but totally blocked in healthy controls. The cortisol responses in both groups did not differ statistically significant from each other and were entirely blocked by ritanserin. None of the subjects experienced an exacerbation of obsessive compulsive symptoms. CONCLUSION: The neuroendocrine results show an enhanced susceptibility of OCD patients for the mCPP-induced prolactin response, which effect seems to be due to an increased sensitivity of 5-HT2 receptors.     

Metergoline blocks the behavioral and neuroendocrine effects of orally administered m-chlorophenylpiperazine in patients with obsessive-compulsive disorder

The pharmacological probe, meta-chlorophenylpiperazine (m-CPP), administered orally to patients with obsessive-compulsive disorder (OCD) has been shown to induce an acute exacerbation in OCD symptoms as well as an exaggerated anxiogenic response in comparison with controls. The mechanism of m-CPP's behavioral effects in humans remains controversial. To further study m-CPP's actions in OCD patients, we completed a series of double-blind pharmacological challenges in 12 OCD patients. Six OCD patients received four separate challenges: placebo, metergoline, m-CPP, and metergoline plus m-CPP; the second group (n = 6) received metergoline and metergoline plus m-CPP in separate challenges. OCD patients receiving placebo or metergoline alone failed to show evidence of significant changes on any of the behavioral rating scales, in contrast to the patients who received m-CPP alone who exhibited significant increases in anxiety and OCD symptoms. However, the 12 OCD patients who received pretreatment with metergoline before m-CPP experienced no significant changes from baseline OCD symptoms or other behavioral changes. m-CPP's ability to elicit elevations in plasma prolactin was blocked by metergoline pretreatment. Metergoline's ability to block m-CPP's effects on behavior and plasma prolactin lends further support to a serotonergic mediation of m-CPP's effects, including its elicitation of OCD symptoms.     

Effects of serotonin antagonists on m-chlorophenylpiperazine-mediated responses in normal subjects

The serotonin (5HT) agonist, m-chlorophenylpiperazine (MCPP), has been used as a challenge agent to assess central 5HT receptor sensitivity in normal subjects and patients with panic disorder, obsessive-compulsive disorder, and major depression. Adrenocorticotropin, cortisol, and prolactin responses to MCPP were among the variables measured. MCPP's usefulness as a probe of 5HT receptors, however, hinges on its 5HT selectivity. To address MCPP's selectivity for 5HT, this study tested whether two different 5HT antagonists, methysergide (4 mg p.o.) and metergoline (4 mg p.o.), could block the hormonal and behavioral effects of MCPP (0.5 mg/kg p.o.) in 10 normal male subjects in comparison to placebo. Both 5HT antagonists abolished the prolactin release to MCPP. Metergoline, the antagonist with the more potent 5HT binding affinity, significantly blocked MCPP's effect on cortisol release as compared to placebo, and methysergide showed a nonsignificant trend to that effect. MCPP alone did not have a significant effect on behavioral variables, perhaps explaining why neither 5HT antagonist affected these measures. The findings from this study suggest that both MCPP-induced prolactin release and cortisol release are indeed 5HT-mediated effects.     

Serotonergic responsivity in obsessive-compulsive disorder. Comparison of patients and healthy controls

To examine the "serotonin hypothesis" of obsessive-compulsive disorder (OCD), we studied the behavioral and neuroendocrine effects of metachlorophenylpiperazine (mCPP), a serotonergic agonist, in patients with OCD and healthy controls. Twelve patients and 20 controls were given a single dose of 0.5 mg/kg of mCPP, administered orally under double-blind, placebo-controlled, random-assignment conditions. Following mCPP, but not following placebo, patients with OCD experienced a transient but marked exacerbation of obsessive-compulsive symptoms. Moreover, compared with healthy controls, patients exhibited greater other behavioral (but not endocrinologic or thermal) changes after mCPP. These findings are consistent with a special role for the neurotransmitter serotonin in OCD psychopathology.     

Serotonergic dissection of obsessive compulsive symptoms: a challenge study with m-chlorophenylpiperazine and sumatriptan

We have conducted a pharmacological challenge experiment in 10 medication-free obsessive compulsive (OC) disorder (OCD) patients. We used a placebo-controlled paradigm for m-chlorophenylpiperazine (mCPP) and sumatriptan challenges. Endocrine, physiological and behavioral variables were assessed at baseline and over a 3-hour period after the challenge. Both cortisol and prolactin were significantly elevated in OCD patients following mCPP administration. Both mCPP and sumatriptan caused significant OC symptom exacerbation with the response to sumatriptan being more robust. We conclude that the 5-HT(1Dbeta) receptor may play a role in the pathophysiology of OCD.     

Anxiogenic effects of m-CPP in patients with panic disorder: comparison to caffeine's anxiogenic effects.

The behavioral and neuroendocrine effects of meta-chlorophenylpiperazine (m-CPP), a serotonergic agonist, were compared with the effects of caffeine, an adenosine antagonist, in panic disorder patients. Patients with panic disorder were given single oral doses of 0.5 mg/kg m-CPP, 480 mg caffeine, and placebo on separate days under double-blind conditions. Both m-CPP and caffeine had significantly greater anxiogenic and panic-inducing effects than placebo, although caffeine produced nonsignificantly greater increases on all anxiety rating scales than m-CPP. Both m-CPP and caffeine produced significant equivalent increases in plasma cortisol concentrations, but only m-CPP produced plasma prolactin increases. These findings provide further evidence implicating both the serotonergic and adenosinergic receptor systems in the neurobiology of panic disorder.     

The anterior pituitary responds normally to protirelin in obsessive-compulsive disorder: evidence to support a neuroendocrine serotonergic deficit

The prolactin and thyroid-stimulating hormone (TSH) responses to protirelin and the prolactin and cortisol responses to d-fenfluramine were measured in 8 outpatients with DSM-III-R obsessive-compulsive disorder (OCD). The results were compared to those in 8 age- and sex-matched healthy controls. The responses to d-fenfluramine were significantly attenuated in the OCD patients, but there was no significant difference between the responses to protirelin in OCD patients and healthy controls. The data suggest that, in OCD, blunting of prolactin responses to the serotonin-releasing agent d-fenfluramine is due to a central abnormality and not due to a pituitary deficit.     

Neuroendocrine responses to m-chlorophenylpiperazine and L-tryptophan in bulimia.

Preclinical and clinical evidence supports a theory of serotonin (5-hydroxytryptamine [5-HT]) dysregulation in bulimia. We therefore studied the prolactin (PRL) and cortisol responses following challenges with the postsynaptic 5-HT receptor agonist m-chlorophenylpiperazine (m-CPP), 0.5 mg/kg orally, the 5-HT precursor L-tryptophan, 100 mg/kg intravenously, and placebo in a group of 28 normal weight bulimic patients and 16 healthy controls. Patients with bulimia, regardless of the presence of major depression, had significantly blunted PRL responses following m-CPP administration compared with those in controls. In contrast, only bulimic patients with concurrent major depression had significantly blunted PRL responses following L-tryptophan administration compared with those in nondepressed bulimic patients and controls. Cortisol responses following m-CPP were not significantly different for bulimic patients vs controls, although there was a trend toward blunted cortisol responses following L-tryptophan administration in the depressed bulimic patients. These differences in neuroendocrine responses were not related to differences in age, percent of average body weight, medications, time of day, peak plasma drug levels, or baseline estradiol levels. Seasonal variations in PRL responses to both agents were identified, although covariation for season did not alter the group differences. The PRL responses following m-CPP administration were inversely correlated to baseline cortisol levels in the bulimic patients, but not in the controls, suggesting a dampening effect by hypothalamic-pituitary-adrenal axis dysfunction on postsynaptic 5-HT receptor sensitivity. The reasons for the differing hormonal responses to these two serotonergic agents may relate to differential involvement of presynaptic and postsynaptic mechanisms, 5-HT receptor subtypes, and anatomical loci of action. The blunted PRL responses to m-CPP administration suggest that postsynaptic 5-HT receptor sensitivity is altered in bulimia nervosa, and that similar alterations in 5-HT receptors at or above the level of the hypothalamus may contribute to binge eating and other behavioral symptoms.