Blockage of narcotic-induced dopamine receptor supersensitivity by cyclo(Leu-Gly).

We have previously reported that the administration of cyclo(Leu-Gly) to mice prior to morphinization blocked the development of tolerance to the analgesic effects of morphine as well as the development of some signs of physical dependence. In the present series of experiments, the effect of the same peptide treatment on changes in dopamine receptor sensitivity induced by chronic morphine treatment were determined. Changes in dopamine receptor sensitivity were determined by measuring (i) the effect of the dopamine agonist apomorphine on locomotor activity and (ii) the hypothermic response to another dopamine agonist, piribedil. Mice that had received the chronic morphine treatment were found to require significantly less apomorphine to produce an increase in locomotor activity, and they exhibited a significantly greater hypothermic response to piribedil than did morphine-naive mice. The injection of 0.2 mumol of cyclo(Leu-Gly) per mouse 2 hr prio to morphine treatment prevented this increased response to both dopamine agonists. Administration of the peptide after the tolerance and dependence had developed did not alter morphine tolerant and dependent states states or the enhanced response to apomorphine or piribedil. It is concluded that dopamine receptor supersensitivity may be involved in the development of narcotic tolerance and physical dependence.     

EFFECTS OF HEROIN ADDICTION ON THYROTROPHIN, THYROID HORMONES AND PROLACTIN SECRETION IN MEN

Pituitary-thyroid function in male heroin addicts and addicts after abstinence (ex-addicts) was studied and compared with that of healthy euthyroid men. In heroin addicts the increases in circulating total thyroxine and triiodothyronine levels were accompanied by an increase in the thyroid hormone uptake test. These changes may reflect a quantitative increase in thyroxine binding globulin. Reverse triiodothyronine concentrations in heroin addicts were normal. The thyrotrophin-releasing hormone elicited a diminished thyrotrophin response in heroin addicts which was significantly different from that in control subjects and ex-addicts. An elevation of serum prolactin was noted in heroin addicts, while ex-addicts had normal levels. Gradual recovery of pituitary-thyroid function occurred after heroin withdrawal.     

Dyschromatopsia in heroin addicts

The Farnsworth-Munsell 100-hue test was employed to determine whether there was any defect of colour vision in 29 confirmed male heroin addicts who had been successfully detoxified. Forty age-matched males served as controls. A typical normal error score on the FM test is about 40 and an error score of over 100 indicates poor colour discrimination; 86.2% of the eyes of the control group had an error score below 100 while only 17.2% of the eyes of heroin addicts had an error score below 100. The colour confusion among the heroin addicts was in the blue-purple (475–495 mu) range. These results indicate that colour vision defects are more common in heroin addicts.     

Effects of chronic heroin addiction on pituitary-thyroid function in man

Pituitary-thyroid function has been studied in heroin addicts. Data have been obtained in 10 male addicts, aged 18-24 years, with histories of addiction to heroin alone lasting from 8 months to 4 years, and in 9 controls matched for sex and age. Basal plasma levels of TSH, T4 and T3 were measured. A TRH stimulation test was done, injecting 500 micrograms of TRH iv as a bolus and assaying TSH levels before the injection and at 30 min intervals up to 2 h afterwards. The results revealed no difference between addicts and controls in basal levels of TSH, T4 and T3. The TRH stimulation test induced a blunted TSH rise in 50% of the cases. The possible mechanism of action of heroin on pituitary-thyroid axis is discussed.     

Effect of the hypnotic flurazepam on the sleep of pentazocine and heroin addicts during withdrawal

Fourteen male heroin addicts being detoxified on methadone and 14 male pentazocine addicts being detoxified drug-free were observed over a 24-hour period for 2 weeks in their sleeping patterns to assess the effects of flurazepam upon sleep during withdrawal. Results of objective and subjective measures find that flurazepam use is associated with more objective nighttime arousals and less total sleep for the heroin group compared to the pentazocine group. Heroin patients felt they had a poorer quality of sleep and took flurazepam more frequently than did the pentazocine patients. Heroin patients' assessments of their sleep and number of arousals correlated poorly with observations.     

Hyperresponsiveness to the inhibitory action of dopamine agonists on luteinizing hormone secretion in the monosodium-L-glutamate-treated, orchidectomized rat

The tuberoinfundibular (A12) dopaminergic pathway, which originates in the arcuate and periventricular nuclei, is thought to play an inhibitory role in the regulation of episodic luteinizing hormone (LH) secretion. Neonatal treatment of rats with the neurotoxin monosodium-L-glutamate (MSG) causes extensive damage to the arcuate nuclei and up to 60% depletion of dopamine (DA) in the mediobasal hypothalamus. We hypothesized that such DA depletion should result in a hyperresponsiveness to subsequent administration of a DA agonist. To test this hypothesis, male rats were treated neonatally with MSG. Control rats received injections of equiosmotic saline. As adults the rats were orchidectomized and fitted with indwelling venous catheters. Blood samples were taken from these unanesthetized, unrestrained rats at 5-min intervals for a 1-hour period, at which time the animals received an intraperitoneal injection of one of the following drugs: apomorphine (0.8 mg/kg, a DA receptor agonist), bromocriptine (8.0 mg/kg, a DA receptor agonist), 0.9% saline (vehicle for apomorphine) or 95% ethanol (vehicle for bromocriptine). Blood sampling was continued for a further 2-2.5 h. Plasma LH was measured by RIA. Both apomorphine and bromocriptine produced striking inhibition of circulating LH levels in MSG-treated rats. Neither of the control treatments altered pulsatile LH secretion patterns. Administration of exogenous gonadotropin-releasing hormone produced LH peaks in all animals so treated, including those whose endogenous LH secretion had been inhibited by the DA agonists. These findings suggest that the depletion of DA induced by neonatal MSG treatment results in a supersensitivity to DA agonists.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lack of effect of hyperglycaemia on apomorphine induced growth hormone release in normal man.

Six healthy adult males were studied to evaluate the effect of apomorphine on growth hormone (GH) secretion under normoglycaemic and hyperglycaemic conditions. Both under normoglycaemia and hyperglycaemia all subjects responded to the subcutaneous injection of 0.75 mg apomorphine hydrochloride with a marked increase in plasma GH concentration reaching a maximum after 30-60 min. In control studies no significant changes in plasma GH were observed following the injection of physiological saline. As apomorphine is considered a selective dopamine receptor stimulating agent, the results support the view that GH release in man can be modulated through a dopaminergic mechanism. The finding that the plasma GH rise after the administration of apomorphine is not suppressible by glucose indicates that apomorphine activates dopaminergic receptors localized distally in the hypothalamus or in the anterior pituitary. Amorphine in low dosage may be used clinically to test the capacity of the pituitary to release GH in man, at least in special cases.     

Growth hormone response to low-dose apomorphine in restless legs syndrome.

INTRODUCTION: Low-dose apomorphine challenge has been shown to cause a rise in growth hormone (GH) in patients with Parkinson's disease (PD). This was interpreted as an increased postsynaptic sensitivity of hypothalamic dopamine receptors in the course of a generalized degeneration of dopaminergic neurons. The dopaminergic system in the restless legs syndrome (RLS) has been assumed to play a role in its pathophysiology. It is therefore the aim of this study to determine whether the GH response to subcutaneously applied low-dose apomorphine is generally altered in patients with RLS as compared to healthy controls. PATIENTS AND METHODS: We examined 40 patients with idiopathic RLS as well as 20 age- and sex-matched healthy control subjects by means of the low-dose apomorphine test. GH was analyzed at baseline, as well as 45 and 60 min after subcutaneous low-dose apomorphine injection in the morning. RESULTS: Forty RLS patients (58.3+/-11.9 years, 32 females) with a mean RLS severity scale score of 23.9+/-6.6 (range 10-37) were examined. GH was not significantly increased 45 and 60 min after injection (p=0.397) (2.44+/-2.35 ng/ml at baseline versus 2.71+/-2.29 ng/ml after 45 min and 2.18+/-1.83 ng/ml after 60 min). The results were independent of pre-treatment with levodopa. Age, sex, duration, and severity of the disease did not show a covariate effect with GH levels. There was no difference compared with healthy controls. CONCLUSIONS: RLS patients did not show an increase in GH after stimulation with low-dose apomorphine. Lack of sensitivity alteration of extrastriatal hypothalamic dopamine receptors suggests that RLS is not a general dopaminergic degenerative disease or might only show circadian alterations.     

Decreased nociceptive sensitivity: a biological risk marker for opiate dependence?

In recent studies using a cold pressor test we could show that former opiate addicts are persistently less pain-sensitive than healthy controls, indicating a neurophysiologic dysfunction in these patients. In the present study we addressed the issue of whether this dysfunction was caused by the drug abuse or already existed prior to the heroin addiction, and whether it is restricted to pain sensitivity or affects somatosensory or nociceptive sensitivity in general. After validating the method we obtained retrospective ratings for the pain, cold and warmth sensitivity for the time before addiction, during addiction and during detoxification. Ex-addicts perceive themselves less pain- and cold-sensitive than healthy controls, and no difference was detectable between the pre-addiction and the rehabilitation ratings, although nociceptive sensitivity is highly increased during detoxification. Warmth sensitivity was not different to healthy controls and was not affected by drug withdrawal. Our findings suggest that a decreased nociceptive sensitivity may already precede opiate addiction pointing to physiological dysfunctions in heroin pre-addicts.     

Impaired circadian rhythmicity of beta-lipotrophin, beta-endorphin and ACTH in heroin addicts

The circadian rhythm of plasma proopiocortin-related peptides was studied in 15 heroin addicts and in 6 sex- and age-matched controls. ACTH, beta-lipotrophin, (beta-LPH), beta-endorphin (beta-EP) and cortisol were measured by RIA either directly (cortisol), or after plasma extraction (ACTH) and Sephadex G-75 gel chromatography (beta-LPH and beta-EP) every 4 h from 8 a.m. to 8 p.m. and again at 8 a.m. the next morning. The means of the two 8 a.m. measurements of beta-LPH (2.67 +/- 0.34 fmol/ml, mean +/- SE), ACTH (2.74 +/- 0.71) and cortisol (218 +/- 31 pmol/ml) levels in heroin addicts were significantly lower than those in controls (6.28 +/- 0.61, 10.1 +/- 0.74 and 364 +/- 27, respectively, P less than 0.01) while beta-EP concentrations in heroin addicts (5.1 +/- 0.6) were similar to those of healthy volunteers (6.44 +/- 0.56). In controls, all three peptides and cortisol show a circadian rhythm of secretion, the lowest values being in the evening and the highest ones in the morning. Heroin addicts partially lack this phenomenon showing constant levels of the three proopiocortin-related peptides throughout the day, with a slight but significant decrease of plasma cortisol. In the 7 subjects who took heroin throughout the study, no systematic changes were observed in the three proopiocortin-related peptides, while it seems that this group of addicts shows a cortisol decrease in the evening to a lesser extent than subjects receiving methadone maintenance only.(ABSTRACT TRUNCATED AT 250 WORDS)     

Methadone-induced behavioral changes: circular movements, aggression, and electrophysiological aspects.

Behavioral changes are induced in animals by methadone administration. The dose-dependent CM effect is present 2 to 3 minutes after methadone administration. This effect can be partially blocked by nalline. A Complete blockade occurs when the naline-reserpine combination is given prior to the administration of methadone. Atropine sulfate dose not block the CM effect. Methadone withdrawal produces mild symptoms of aggression, and they can be intensified by amphetamine and apomorphine. During the process of development of tolerance and addiction, electrophysiological changes are produced. These changes can be intensified by apomorphine treatment in the methadone-withdrawal animals. On the basis of pharmacological manipulation in our experimental conditions, the involvement of cerebral biogenic amines, especially dopamine, is proposed.     

Reduced dopamine D4 receptor mRNA expression in lymphocytes of long-term abstinent alcohol and heroin addicts

Aim It has been repeatedly suggested that dopamine receptor expression in peripheral blood lymphocytes reflects, to some extent, brain status. The aim of the present study was to investigate dopamine receptor expression in peripheral blood lymphocytes of long‐term abstinent alcohol and heroin addicts against the background of the hypothesis, that a persisting dysfunction of the dopaminergic system contributes a biological cause to the chronic character of addiction. Design Dopamine D3 and D4 receptor mRNA expression in peripheral blood lymphocytes was measured by real‐time polymerase chain reaction (PCR) in 19 alcohol addicts, abstinent for 6.2 ± 4.7 months (mean ± SD), and 20 heroin addicts, abstinent for 6.7 ± 3.7 months (mean ± SD), and compared to a control group of 29 age‐ and sex‐matched individuals with no life‐time history of substance abuse. Findings One‐way anova showed significant differences in D4 mRNA expression between the groups (P = 0.005): both groups of addicts showed an approximately 50% reduction in D4 receptor mRNA expression in peripheral blood lymphocytes (PBL) compared to controls. No differences were found for D3 mRNA expression between the groups. Conclusion The results of the present study indicate a withdrawal‐persisting dopaminergic imbalance in abstinent addicts as measured by a suggested peripheral marker.     

Neuroendocrine Evidence for Reduced Dopamine Receptor Sensitivity in Alcoholism

Postsynaptic dopamine (DA) receptor sensitivity was assessed during abstinence in 15 male patients with alcohol dependence. The DA receptor sensitivity was evaluated using growth hormone (GH) responses to the DA receptor agonist apomorphine (0.18-0.24 mg intravenously). The patients were cared for in an alcoholism treatment unit for the 2 months prior to the investigation. They were carefully controlled for sobriety during this period. Thirteen healthy men were used as controls. The maximum GH responses to apomorphine were significantly reduced in patients compared with those in the control group. The patients had a significantly higher proportion of blunted GH responses. The findings suggest reduced postsynaptic DA, possibly D2, receptor sensitivity in abstinent alcoholics. The question whether this abnormal DA receptor status is genetically determined or acquired after long-term alcohol consumption remains to be addressed.     

Effects of central cholinergic blockade on striatal dopamine release measured with positron emission tomography in normal human subjects.

Previously we demonstrated that positron emission tomography (PET) can be used to measure changes in the concentrations of synaptic dopamine and acetylcholine. Whether induced directly or indirectly through interactions with other neurotransmitters, these studies support the use of PET for investigating the functional responsiveness of a specific neurotransmitter to a pharmacologic challenge. In an extension of these findings to the human brain, PET studies designed to measure the responsiveness of striatal dopamine release to central cholinergic blockade were conducted in normal male volunteers using high-resolution PET and [11C]raclopride, a D2-dopamine receptor antagonist. [11C]Raclopride scans were performed prior to and 30 min after systemic administration of the potent muscarinic cholinergic antagonist, scopolamine (0.007 mg/kg). After scopolamine administration, [11C]raclopride binding decreased in the striatum (specific binding) but not in the cerebellum (nonspecific binding) resulting in a significant decrease, exceeding the test/retest variability of this ligand (5%), in the ratio of the distribution volumes of the striatum to the cerebellum (17%). Furthermore, scopolamine administration did not alter the systemic rate of [11C]raclopride metabolism or the metabolite-corrected plasma input function. These results are consistent not only with the known inhibitory influence that acetylcholine exerts on striatal dopamine release but also with our initial 18F-labeled N-methylspiroperidol and benztropine studies. Thus these data support the use of PET for measuring the functional responsiveness of an endogenous neurotransmitter to an indirect pharmacologic challenge in the living human brain.     

Shortened time horizons and insensitivity to future consequences in heroin addicts

Aims. To investigate whether heroin addicts demonstrate shortened time horizons and decreased sensitivity to future consequences of their behavior compared to non-drug users . Design Setting and Participants. Thirty-four heroin addicts enrolled in a buprenorphine treatment clinic and 59 non-drug-using controls completed a personality questionnaire and two laboratory tasks . Measurements. The Stanford Time Perception Inventory (STPI) personality questionnaire assessed orientation to the future, and the Future Time Perspective (FTP) task elicited predictions of the timing and ordering of future events. The Bechara card task measured preferences for decks of cards that range in magnitude and probability of delayed and immediate rewards and punishers . Findings. Heroin addicts scored significantly lower than controls on the STPI scale indicative of future orientation. In the FTP, heroin addicts were less likely to predict events far into the future and less likely to systematically organize events in the future. In the card task, heroin addicts were less likely to win money than controls. They were more likely to play from a deck that contained greater immediate gains but that resulted in large, delayed punishers and overall net losses. They also made fewer selections from a deck that provided an overall net gain via relatively low immediate rewards and frequent small punishments . Conclusions. Shortened time horizons and decreased sensitivity to delayed consequences may explain drug abusers' persistent use of drugs, despite the long-term negative consequences associated with drug use.     

Metyrapone-induced withdrawal symptoms

The metyrapone test is widely used in endocrinological testing to assess the integrity of hypothalamic-pituitary-adrenal axis function; we have used it to study the metabolic basis of addictive disease and opioid dependence. In recent studies, we have observed that metyrapone administration in long-term methadone-maintained patients and in patients undergoing slow dose reduction to drug-free status following chronic treatment may induce a narcotic withdrawal-like syndrome. Although metyrapone is known to produce mild adverse reactions in non-opiate dependent subjects, narcotic withdrawal-like symptoms have not been previously observed or reported. The metyrapone test was administered to 15 former heroin addicts: 10 (8 male, 2 female) in steady-state methadone maintenance therapy (30 to 90 mg/d) and 5 (3 male, 2 female) in the final phase of a slow methadone dose reduction procedure (0 to 10 mg/d). Eight out of 15 methadone maintenance subjects exhibited a narcotic withdrawal-like syndrome ranging from ‘moderate’ to “severe’ and four additional subjects had‘mild’ symptoms, occurring within 1 h after metyrapone administration, and resolving within 2 h of onset. No significant symptoms were seen in 3 methadone maintained subjects nor in any of 9 normal volunteers (7 male, 2 female). The mechanism by which metyrapone induces symptoms resembling narcotic withdrawal in opiate-dependent individuals is unknown but physicians performing this test should be aware of this possible response.     

美沙酮维持治疗门诊海洛因依赖者社会支持研究

目的了解南昌市美沙酮维持治疗门诊内海洛因依赖者的社会支持,为开展社会支持干预提供科学依据。方法问卷收集海洛因依赖者的人口学数据;用社会支持评定量表（SSRS）评定海洛因依赖者的社会支持利用度;海洛因依赖者的社会支持总分与正常人群比较采用t检验,多组间均数比较采用单因素方差分析。结果269例海洛因依赖者中以男性为主,占76.2%。海洛因依赖者的社会支持总分显著低于正常人群;不同婚姻状况、文化程度、职业的海洛因依赖者,获得的社会支持不同。结论南昌市美沙酮门诊内海洛因依赖者的社会支持评分低于正常人群,文化程度低、离异、失业是其社会支持评分低的主要原因。     

海洛因成瘾者唾液表皮生长因子含量及相关舌苔的观察

目的测定海洛因成瘾者脱瘾后唾液表皮生长因子(EGF)含量,观察相应的舌苔变化,探讨成瘾者EGF与舌苔的关系及脾虚的本质.方法92例海洛因成瘾者脱毒后15～30d,对照组85例,测定唾液EGF并同时观察舌苔.结果成瘾者唾液EGF含量比对照组显著低下(P＜0.01).成瘾者舌苔厚腻者明显多于对照组.结论海洛因成瘾者脱瘾后EGF低下是其舌苔厚腻和脾虚的原因之一.     

Sensitivity of caudal arteries and the mesenteric vascular bed to norepinephrine in DOCA-salt hypertension

This study was undertaken to determine what factors might contribute to arterial supersensitivity to norepinephrine associated with deoxycorticosterone acetate (DOCA)-salt hypertension in the rat. Experimental groups of male rats were uninephrectomized and 1 week later began receiving twice weekly injections of DOCA (20 mg/kg s.c. in sesame oil) plus 1% NaCl and 0.2% KCl in their drinking water. For each experimental group, a group of age-matched male rats underwent a sham operation and received injections of sesame oil and the NaCl-KCl drinking water. Perfused caudal arteries from 3-week-hypertensive rats were supersensitive to intraluminal and extraluminal norepinephrine administration. However, this difference in sensitivity between hypertensive and control caudal arteries was demonstrable at low rates of perfusion, 0.5 to 1.0 ml/min, but not at rates of 2.0 to 2.6 ml/min. The supersensitivity was not due to differences in neuronal uptake or to inhibition of extraneuronal uptake by DOCA. The perfused mesenteric vascular bed from 3- or 6-week-hypertensive rats was also supersensitive to intraluminal norepinephrine. However, the demonstration of supersensitivity in the mesenteric vasculature was independent of perfusion rate (2.3-6.8 ml/min) and perfusion pressure in the range of 30 to 60 mm Hg. There was little or no supersensitivity to transmural nerve stimulation in either the caudal artery or the mesenteric vasculature, a finding consistent with the observed decrease in endogenous norepinephrine content. Microelectrodes were used to determine resting membrane potential in the smooth muscle cells. No differences in resting membrane potential were detected between caudal or mesenteric arteries from hypertensive compared with control rats 2, 3, or 6 weeks after initiation of the DOCA-salt regimen. It is concluded that 1) the perfusion rate is a critical factor in designing experiments to test the sensitivity of caudal arteries to drugs, 2) the perfused mesenteric vascular bed is a useful preparation for studying sensitivity of blood vessels in hypertension, 3) the supersensitivity of blood vessels in the DOCA-salt model may be of greater importance relative to circulating catecholamines than to sympathetic innervation, and 4) the supersensitivity of blood vessels to norepinephrine in the DOCA-salt model is not due to changes in neuronal uptake, extraneuronal uptake, or membrane potential of the vascular smooth muscle cells.