'Diagnostic orphans' among young adult cannabis users: persons who report dependence symptoms but do not meet diagnostic criteria

OBJECTIVE: To examine the characteristics of 'diagnostic orphans' among cannabis users-those who report one or two symptoms of DSM-IV dependence but do not meet diagnostic criteria for DSM-IV abuse or dependence. METHOD: Data were collected from a representative population cohort of 1601 young adults aged 20-21 years. Those who reported that they had used cannabis at least weekly at some point within the past year were assessed for symptoms of DSM-IV cannabis abuse and dependence using the Composite International Diagnostic Interview. RESULTS: Approximately 2.8% of the cohort could be classified as diagnostic orphans, with another 3.0 and 7.5% meeting criteria for abuse and dependence, respectively. Diagnostic orphans were: similar to those who met criteria for cannabis abuse or dependence in terms of demographic characteristics; similar to those who met criteria for cannabis abuse in terms of cannabis use patterns; and similar to those who met criteria for abuse and dependence in their rates of heavy alcohol use and DSM-IV alcohol dependence. However, they did not appear to have elevated rates of illicit drug use or mental health problems compared to non users. CONCLUSIONS: Diagnostic orphans reported using cannabis in a manner similar to persons meeting criteria for cannabis abuse, and had similar rates of alcohol dependence and other illicit drug use. Strict adherence to DSM-IV diagnoses of abuse and dependence may overlook a substantial proportion of young persons who experience cannabis-related problems. There is a need to consider (a) subthreshold levels of cannabis-related problems among those seeking treatment for other problems; and (b) interventions for this group to prevent escalation of such problems.     

Decreased numbers of progenitor cells but no response to antidepressant drugs in the hippocampus of elderly depressed patients

Imaging studies have consistently documented hippocampal volume reductions in depression. Although depressive disorders are traditionally considered to have a neurochemical basis, recent studies suggest that impairments of structural plasticity contribute to the volume reductions and the related cognitive changes. This might result from repeated periods of stress that are a wellknown risk factor for depression. Adult neurogenesis is a prominent example of neuroplasticity that in rodents, is reduced by stress but stimulated by antidepressant drugs. Although reductions in neurogenesis have been proposed to contribute to the etiology of depression, only two studies have so far examined hippocampal cytogenesis in depression, but this was in a limited number of subjects with considerable interindividual variation, and these studies came to different conclusions. We therefore collected hippocampal tissue of 10 elderly control subject and 10 well-matched depressed patients that were highly comparable in terms of age, sex, pH-CSF and postmortem delay, and tested whether the numbers of MCM2-positive progenitors and PH3-positive proliferating cells were altered by depression or antidepressant treatment. A significant reduction was found in MCM2-, but not PH3-immunopositive cells in depression. Although this result is consistent with the concept that structural plasticity is decreased in depression, we could not confirm that antidepressant drugs had a stimulatory effect on these cells. This discrepancy may relate to anatomical differences, in medication, to neurogenesis-independent mechanisms of antidepressant action, or the age of the patients that was higher than in previous studies. Whether the reduction is a cause or consequence of depression awaits to be determined.     

Short-term serotonergic but not noradrenergic antidepressant administration reduces attentional vigilance to threat in healthy volunteers

Anxiety is associated with threat-related biases in information processing such as heightened attentional vigilance to potential threat. Such biases are an important focus of psychological treatments for anxiety disorders. Selective serotonin reuptake inhibitors (SSRIs) are effective in the treatment of a range of anxiety disorders. The aim of this study was to assess the effect of an SSRI on the processing of threat in healthy volunteers. A selective noradrenergic reuptake inhibitor (SNRI), which is not generally used in the treatment of anxiety, was used as a contrast to assess the specificity of SSRI effects on threat processing. Forty-two healthy volunteers were randomly assigned to 7 d double-blind intervention with the SSRI citalopram (20 mg/d), the SNRI reboxetine (8 mg/d), or placebo. On the final day, attentional and interpretative bias to threat was assessed using the attentional probe and the homograph primed lexical decision tasks. Citalopram reduced attentional vigilance towards fearful faces but did not affect the interpretation of ambiguous homographs as threatening. Reboxetine had no significant effect on either of these measures. Citalopram reduces attentional orienting to threatening stimuli, which is potentially relevant to its clinical use in the treatment of anxiety disorders. This finding supports a growing literature suggesting that an important mechanism through which pharmacological agents may exert their effects on mood is by reversing the cognitive biases that characterize the disorders that they treat. Future studies are needed to clarify the neural mechanisms through which these effects on threat processing are mediated.     

The change of prefrontal QEEG theta cordance as a predictor of response to bupropion treatment in patients who had failed to respond to previous antidepressant treatments

The aim of the study was to examine whether the reduction of theta prefrontal quantitative EEG (QEEG) cordance after one week of bupropion administration is a predictor of response to a 4-week treatment in patients that had failed to respond to previous antidepressant treatments. Method: EEG data of 18 inpatients were monitored at baseline and after one week. QEEG cordance was computed at 3 frontal electrodes (Fp1, Fp2, Fz). Response to treatment was defined as a ≥ 50% reduction of MADRS score. Results: Nine of the eleven responders and one of the seven non-responders showed decreased prefrontal cordance value after the first week of treatment (p = 0.01). Positive and negative predictive values of cordance reduction for the prediction of response to the treatment were 0.9 and 0.75, respectively. Conclusion: Similar to other antidepressants, the reduction of prefrontal QEEG cordance might be helpful in the prediction of the acute outcome of bupropion treatment.     

Add-on aliskiren elicits stronger renoprotection than high-dose valsartan in type 2 diabetic KKAy mice that do not respond to low-dose valsartan

We hypothesized that aliskiren provides renoprotection in diabetic animals that did not receive sufficient renoprotection by AT1-receptor antagonist treatment. Type 2 diabetic KKAy mice were treated with group 1: vehicle or group 2: valsartan (15 mg/kg per day) from 12 to 16 weeks of age. The mice were subsequently divided into 4 groups and treated with the following combinations of drugs for another 6 weeks: 1: group 1 kept receiving vehicle, 2: group 2 continuously received 15 mg/kg per day of valsartan (Val-Val15), 3: group 2 received 50 mg/kg per day of valsartan (Val-Val50), 4: group 2 continuously received 15 mg/kg per day of valsartan with 25 mg/kg per day of aliskiren (Val-Val+Ali). Aliskiren exerted significant anti-albuminuric effects, whereas valsartan failed to ameliorate the albuminuria in the first four weeks. Surprisingly, the increasing dosage of valsartan in the Val-Val50 group showed non-significant tendencies to attenuate the albuminuria compared with vehicle infusion. Val-Val+Ali significantly suppressed the development of albuminuria and podocyte injury. Val-Val50 and Val-Val+Ali showed similar suppression of angiotensin II contents in the kidney of KKAy mice. In conclusion, the anti-albuminuric effect that was observed in the type 2 diabetic mice showing no anti-albuminuric effect by valsartan can be attributed to the add-on aliskiren.     

Dilated intercellular spaces and lymphocytes on biopsy relate to symptoms in erosive GERD but not NERD

Aliment Pharmacol Ther 2011; 33: 1202–1208

Summary

Background Mechanisms of symptom perception among patients with gastro‐oesophageal reflux disease (GERD) remain to be fully elucidated. Aim To correlate quantitative reflux symptom scores with microscopic oesophageal histopathology. Methods Prior to endoscopy, patients with reflux symptoms completed a validated reflux disease questionnaire (score 0–36). Erosive oesophagitis (EO) was graded using the LA classification. Oesophageal biopsies were graded 0–2 for basal cell hyperplasia, papillary elongation, dilated intercellular spaces (DIS), necrosis or erosion, eosinophils and neutrophils by a blinded gastrointestinal pathologist as previously described. Additionally, lymphocyte density was also evaluated. Pearson’s correlation coefficients were computed. Results Thirty‐two EO and 21 non‐erosive reflux disease (NERD) patients were prospectively enrolled. For EO vs. NERD, mean reflux symptom scores (10.7 vs. 8.8, P = 0.35) and histology scores were similar (4.29 vs. 4.25; P = 0.9). However, when symptom scores were compared with histology scores, a correlation was found in the EO group, but not in the NERD group (r = 0.34, P = 0.05 vs. r = 0.22, P = 0.36). On further analysis, DIS was associated with symptom scores in the EO group (P ≤ 0.001), but not in the NERD group (P = N.S.). Similarly, lymphocyte density was associated with symptom scores in the EO group (r = 0.56, P = 0.0009), but not in the NERD group (r = 0.002, P = 0.9). Conclusions Although mean symptom and histology scores were similar in the EO and NERD groups, a significant correlation of symptom scores with histology scores, DIS and lymphocytes was found in the former, but not in the latter. EO and NERD patients may have different symptom perception mechanisms and thus, dissimilar symptom resolution rates with acid suppression.     

Increased cardiovascular risk without generalized arterial dilating diathesis in persons who do not have abdominal aortic aneurysm but who are first‐degree relatives of abdominal aortic aneurysm patients

There is a strong genetic predisposition towards abdominal aortic aneurysm (AAA), but it is unknown whether persons without AAA but with first‐degree relatives who are AAA patients have a generalized dilating diathesis, defect arterial wall mechanics, or increased cardiovascular risk. The aim of the study was to investigate arterial diameters and wall mechanics at multiple arterial sites in these subjects and compare them with controls without a family history of AAA. This study included 118 first‐degree relatives of patients with AAA and 66 controls (age: 40–80 years). The abdominal aorta, common carotid artery, common femoral artery, and popliteal artery were investigated by echo‐tracking ultrasound. The relatives had no arterial dilatation, but they did tend to have smaller diameters than controls. Relatives had a higher heart rate, diastolic blood pressure, and mean arterial pressure than controls. The distensibility coefficient and the compliance coefficient were decreased in all arteries in male relatives, adjusted for age and smoking; these coefficients were normalized after adjustment for mean arterial pressure and heart rate. Female relatives had a lower compliance coefficient in the abdominal aorta, adjusted for age and smoking. After adjustment for mean arterial pressure and heart rate, the difference disappeared. No general arterial dilatation in relatives without AAA was found, supporting the hypothesis that the dilating diathesis is linked to the aneurysmal manifestation in the abdominal aorta. Although the threat of aneurysmal dilatation and rupture seems to be lacking in these subjects, heart rate, blood pressure, and arterial wall stiffness were all increased, which may indicate a higher risk of developing cardiovascular morbidity and mortality.     

Blockade of the GABAB receptor increases neurogenesis in the ventral but not dorsal adult hippocampus: Relevance to antidepressant action

GABA_B receptor antagonists have been shown to have antidepressant-like properties in animal models and thus, could represent a novel approach for the treatment of depression. The neurobiological mechanisms underlying these effects are currently unknown. Adult hippocampal neurogenesis (the birth of new neurons) is thought to play a role in antidepressant drug action. However, the ability of GABA_B receptors to modulate the proliferation and survival of newly-born cells in the adult hippocampus remains unexplored. Therefore, we investigated whether the GABA_B receptor antagonist, CGP 52432, can induce antidepressant-like behaviour and increase hippocampal neurogenesis in the stress-sensitive mouse strain, BALB/c. Male mice were treated with CGP 52432 either acutely (one injection, 3; 10; 30 mg/kg, i.p.), subchronically (7 days, 3; 10 mg/kg, i.p.) or chronically (21 days, 3; 10 mg/kg, i.p.) and antidepressant-like behaviour was assessed using the forced swim test (FST). The effects of CGP 52432 on the proliferation and survival of newly-born cells in the hippocampus were assessed using BrdU immunohistochemistry. Acute, subchronic and chronic treatment with CGP 52432 induced antidepressant-like behavioural effects in the FST. Moreover, chronic but not acute or subchronic treatment with CGP 52432 increased hippocampal cell proliferation but had no effect on the survival of newly-born cells. This temporal effect is consistent with the time course for the therapeutic action of antidepressants. Interestingly, CGP 52432-induced increases in cell proliferation occurred in the ventral but not in the dorsal hippocampus. This topographical segregation concurs with the hypothesis that the ventral hippocampus is primarily involved in the regulation of stress and emotionality. Taken together, our data suggest that increased hippocampal cell proliferation is a plausible mechanism for the antidepressant-like effects of GABA_B receptor antagonists following chronic but not acute treatments. Moreover, altered behavioural effects in the FST does not correlate with changes in neurogenesis.     

Periadolescent male but not female rats have higher motor activity in response to morphine than do adult rats

Little has been done to investigate the effects of opioid exposure during adolescence. First we determined behavioral differences in response to acutely administered morphine between periadolescent and adult male and female rats. Second, we determined the impact of age of morphine exposure on sensitivity to morphine-induced locomotion later in life. For the acute morphine studies, antinociceptive responses were assessed using cumulative morphine dosing (0.5-12 mg/kg) followed by a time course after the last morphine injection (相似文献   

Cluster analysis of symptoms during antidepressant treatment with Hypericum extract in mildly to moderately depressed out-patients. A meta-analysis of data from three randomized,placebo-controlled trials

Abstract Rationale. Although extracts from Hypericum have long played a major role in the treatment of mild to moderate depression, information pertaining to the drug's therapeutic profile is sparse. Objectives. To investigate whether the administration of the Hypericum extract has a selective effect on particular signs and symptoms of depression as opposed to a more general acceleration of recovery. Methods. A meta-analysis was performed on the original data of three double-blind, randomized multicenter trials, during which 544 out-patients suffering from mild to moderate depression according to DSM-IV criteria received 3×300 mg/day Hypericum extract (WS? 5570 or WS? 5572) or placebo over a double-blind treatment period of 6 weeks. The primary outcome measure for treatment efficacy in the original trials was the change in the total score of the Hamilton Rating Scale for Depression (HAMD, 17-item version) between baseline and treatment end. The relationship between the symptoms of depression represented by the items of the HAMD was assessed by means of cluster analysis and individual item analysis. Results. Two clusters of items were identified which were stable in several independent subsets of the full data set. While cluster 1 (HAMD items 1, 2, 3, 7, 8, 12, 13, 14, 16) was interpreted to represent the core symptoms of depression (including somatic aspects), cluster 2 (items 4, 5, 6, 9, 10, 11, 15, 17) was primarily composed of items assessing depression-related anxiety and insomnia. In both clusters, Hypericum extract reduced the symptoms of depression more effectively than placebo. However, the herbal drug was particularly effective in the core symptoms of the disorder. Conclusions. The results indicate that Hypericum extract accelerated the recovery from depression in a rather general manner, by influencing all investigated signs and symptoms of the disease. The drug's therapeutic profile was thus found to be similar to the profile of selective serotonin reuptake inhibitors. Electronic Publication     

Regulation of G proteins by chronic antidepressant drug treatment in rat brain: tricyclics but not clorgyline increase Go alpha subunits.

The effect of long-term (3-week) administration of various antidepressant drugs on the steady-state concentrations of G protein alpha subunits, Gs alpha, Gi alpha, and Go alpha, has been investigated in rat brain using an enzyme-linked immunosorbent assay. Tricyclic antidepressants and clorgyline decreased Gs alpha and, to a lesser extent, Gi alpha in several brain regions, while Go alpha was increased by tricyclics but not clorgyline. We conclude that long-term treatment with antidepressant drugs exerts differential effects on G protein alpha subunits, and that antidepressant efficacy may potentially be based on functional modifications of signal transduction.     

'Compulsive' lever-pressing in rats is attenuated by the serotonin re-uptake inhibitors paroxetine and fluvoxamine but not by the tricyclic antidepressant desipramine or the anxiolytic diazepam

Rats undergoing extinction of lever-pressing for food after the attenuation of an external feedback for this behavior, exhibit excessive lever-pressing unaccompanied by an attempt to collect a reward, which may be analogous to the excessive and unreasonable behavior seen in obsessive-compulsive disorder (OCD). Given that one of the most salient features of OCD is its selective response to treatment with serotonin re-uptake inhibitors (SRIs), the present study compared the effects of the SRIs paroxetine and fluvoxamine on compulsive lever-pressing, with those of the tricyclic antidepressant, desipramine, and the benzodiazepine, diazepam, which are not effective in the treatment of OCD. Paroxetine (1-15 mg/kg) and fluvoxamine (10-20 mg/kg) dose-dependently reduced the number of compulsive lever-presses and the number of lever-presses followed by an attempt to collect a reward; desipramine (5-15 mg/kg) dose-dependently reduced only the number of lever-presses followed by an attempt to collect a reward; diazepam (2-10 mg/kg) did not affect either type of lever-pressing, except for the highest dose (10 mg/kg), which almost completely abolished lever-press responding. When administered in an extinction session not preceded by signal attenuation, paroxetine, fluvoxamine and desipramine affected only the number of lever-presses followed by an attempt to collect a reward, whereas diazepam (4-8 mg/kg) decreased both types of lever-presses. The present findings strengthen the suggestion that compulsive lever-pressing may serve to model compulsive behavior in OCD, and lends the model predictive validity.     

Beta-lactam antibiotic decreases acquisition of and motivation to respond for cocaine, but not sweet food, in C57Bl/6 mice

No medication is approved to treat cocaine addiction, but mounting evidence suggests that glutamate-directed approaches may reduce cocaine dependence and relapse. We tested the hypotheses that the glutamate transporter subtype 1 activator, ceftriaxone, disrupts acquisition of cocaine self-administration, motivation to self-administer cocaine, and conditioned place preference in mice. Repeated ceftriaxone (200 mg/kg) reduced the ability of mice to acquire cocaine and the motivation to self-administer cocaine after successful acquisition without affecting acquisition of or motivation for sweet food. Repeated ceftriaxone had no effect on cocaine-conditioned place preference. These results suggest that a β-lactam antibiotic reduces the direct reinforcing strength of cocaine without producing nonspecific deficits in conditioned learning processes.     

Involvement of tissue kallikrein but not plasma kallikrein in the development of symptoms mediated by endogenous kinins in acute pancreatitis in rats

In order to investigate the mechanism of kinin release leading to vascular symptoms in acute interstitial-oedematous pancreatitis, the novel, selective inhibitors of tissue kallikrein, (2S,2'R)-2-(2'-amino-3'-(4'-chlorophenyl)propanoylamino)-N-(3-guanidinopropyl)-3-(1-naphthyl)propanoamide (FE999024, CH-2856), and of plasma kallikrein, (2'S,2"R)-4-(2'-(2"(carboxymethylamino)-3"-cyclohexyl-propanoylamino)-3'-phenyl-propanoylamino)piperidine-1-carboxamidin (FE999026, CH-4215), were used in experimental caerulein-induced pancreatitis in rats. Oedema formation and plasma protein extravasation during the 2 h infusion of caerulein were inhibited in a dose-dependent manner by i.p. pretreatment with FE999024 (7-60 micromol kg(-1)) while FE999026 had no effect at the same doses. Haemoconcentration and hypovolaemia associated with the pancreatic oedema formation during pancreatitis were significantly attenuated by FE999024 at a dose of 20 micro mol kg(-1). The reduction in circulating plasma volume was not affected by FE999026. Accumulation of amylase and lipase in the pancreas was dose-dependently reduced by FE999024 while enzyme activities in the blood serum were increased by FE999024 at 60 micromol kg(-1) indicating improved enzyme removal from the tissue. Enzyme activities in the tissue and in the blood remained unaffected by FE999026. FE999024 (20 micromol kg(-1)) largely inhibited increased tissue kallikrein-like activity in the pancreas during acute pancreatitis and also strongly attenuated influx of plasma kallikrein into the tissue. FE999026 (20 micromol kg(-1)) significantly inhibited plasma kallikrein-like activity in the pancreas but had no effect on tissue kallikrein-like activity. In conclusion, vascular kinin-mediated symptoms observed during oedematous pancreatitis in the rat are caused by the action of tissue kallikrein in the pancreas whereas an involvement of plasma kallikrein seems to be unlikely.     

Haemorrhages due to defective blood coagulation do not occur in mice and guinea-pigs fed butylated hydroxytoluene, but nephrotoxicity is found in mice.

Groups of ten male Slc:ddY mice were fed a purified diet containing butylated hydroxytoluene (BHT) at levels of 0, 1.35, 1.75, 2.28, 2.96, 3.85 or 5.00%. They were kept in cages with soft-wood chips as bedding for 30 days. Groups of five Slc:ddY male mice were kept in cages with stainless-steel wire-mesh bottoms (without wood-chip bedding) and fed BHT at 0, 0.5, 1.0 or 2.0% in the diet for 21 days. Male Crj:Hartley guinea-pigs were given a purified ration containing BHT at levels of 0, 0.125 or 0.25% (five animals per group) for 14 days, or at 0, 0.5, 1.0 or 2.0% for 17 days (six animals per group). When BHT was given to mice housed in the mesh-bottomed cages there were one, one and two deaths during the experiment in the 0.5, 1.0 and 2.0% dose groups, respectively. Lung haemorrhages were observed in these dead mice, but in all other mice and guinea-pigs no haemorrhages were found. Indices of prothrombin time and kaolin-activated partial thromboplastin time were significantly decreased by up to 30 and 40%, respectively, in the mice kept on wood-chip bedding, and by up to 40 and 60% in the mice kept in cages with wire bottoms. In guinea-pigs, the prothrombin index was significantly reduced only in the 1.0% BHT group. We conclude that the BHT-induced lung haemorrhages in mice are not caused by a severe reduction in the coagulation process, as they are in rats, and that BHT does not cause bleeding like that observed in rats. However, dose-related toxic nephrosis was found in mice given 1.35-5.0% BHT in the diet. The nephrotoxic ED50(1 month) was 2.3 g/kg body weight/day. The results suggest that an extremely large dose of BHT can cause renal toxicity in mice.     

Sensorimotor gating is disrupted by acute but not chronic systemic exposure to caffeine in mice

Rationale

Caffeine is a psychostimulant drug that blocks adenosine A₁ and A_2A receptors (A₁Rs and A_2ARs). However, its ability to disrupt early sensory gating as indexed by prepulse inhibition (PPI), which is consistently disrupted by other psychostimulant agents, has never been convincingly demonstrated.

Objectives

To compare the impact of caffeine on PPI expression in C57BL/6 mice by two dose-response experiments differing in terms of chronicity, regimen, and route of administration. To study separately the acute effect of selective antagonists against A₁R or A_2AR.

Methods

Caffeine (10, 30, 100 mg/kg, intraperitoneal (i.p.)) was either administered shortly before testing or via caffeinated drinking water (0.3, 1.0, 2 g/l) in home cages over 3 weeks. Two separate dose-response studies tested the acute effect of the selective A₁R antagonist, 1,3 dipropyl-8 cyclopentyl xanthine (DPCPX), and the selective A_2AR antagonist, 5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c] (SCH 58261) (0.2, 1.0, 5.0 mg/kg, i.p.). The two drugs were combined in a final experiment to identify their potential synergistic interaction.

Results

While the two lower acute doses of caffeine attenuated PPI, the highest dose potentiated PPI. By contrast, chronic caffeine exposure did not affect PPI. Neither DPCPX nor SCH 58261 altered PPI, and no synergism was observed when the two drugs were combined.

Conclusions

This is the first demonstration that acute caffeine disrupts PPI, but the relative contribution of A₁R and A_2AR blockade remains unclear, and possible non-adenosinergic mechanisms cannot be ruled out. The null effect under chronic caffeine exposure might involve the development of tolerance, but the precise receptor subtypes involved also warrant further investigation.     

Inhibition of head twitch response to quipazine in rats by chronic amitriptyline but not fluvoxamine or citalopram

Chronic (twice daily/14 days), but not acute, treatment with 10 mg/kg PO amitriptyline reduced the number of quipazine (5 mg/kg)-induced head twitches in rats, measured 2 h (but not 72 h) after the last administration of the drug. Similar treatment with fluvoxamine or citalopram, which are more potent and much more specific serotonin uptake inhibitors than amitriptyline, did not affect the quipazine-induced response. In acute experiments, fluvoxamine (10 mg/kg PO) and citalopram (10 mg/kg PO) potentiated the head twitch reaction induced by l-5-hydroxytryptophan (50 mg/kg IP) given together with Ro 4-4602 (25 mg/kg IP), a peripheral decarboxylase inhibitor. Amitriptyline (10 mg/kg PO) slightly decreased the number of l-5-hydroxytryptophan (5-HTP)-induced head twitches. Higher doses of amitriptyline (20–40 mg/kg PO) also inhibited the quipazine-induced head twitch reaction. The brain level of amitriptyline measured 0.5–24 h after the last oral administration of the chronic dose of 10 mg/kg was always much higher than that observed at the same time intervals after an acute oral dose of 20 or 40 mg/kg. The results obtained indicate that a postsynaptic rather then presynaptic mechanism is responsible for the development of subsensitivity of the central serotonin receptors in the course of chronic treatment with amitriptyline.The results were presented at the 8th Congress of the Polish Pharmacological Society, Warszawa, 26–28 September 1983 Offprint requests to: L Pawowski