Mechanism of tolerance development to 2,5-dimethoxy-4-iodoamphetamine in rats: down-regulation of the 5-HT2A, but not 5-HT2C, receptor

  Rationale: Defining the mechanism of tolerance development to hallucinogenic drugs will help to explain their mechanism of action. Objectives: The present study was conducted to determine first, if tolerance develops to the discriminative stimulus (DS) properties of the hallucinogen, 2,5 dimethoxy-4-iodo-amphetamine (DOI) and second, the mechanism mediating tolerance. Methods: Rats were trained to discriminate 0.75 mg/kg DOI from saline on a concurrent VI-30-min schedule of reinforcement with a 15-min time-out for incorrect responses. To evaluate tolerance development, rats were assigned to one of four groups and treated with either chronic saline or chronic DOI. Prior to chronic treatment, two groups were tested for choice behavior following vehicle administration while the remaining two groups were tested following the administration of 0.375 mg/kg DOI. One group from each pre-test condition was injected with either saline or DOI (1 mg/kg) for 8 days. Twenty-four hours after the last chronic injection the pre-test treatments were replicated. Using receptor autoradiography, the density of 5-HT_2A and 5-HT_2C receptors was measured in independent groups of rats that had received identical treatment conditions. Results: Animals receiving chronic DOI showed a 60% decrease in DOI lever responding (from 100% to 40%) when tested on 0.375 mg/kg DOI, while animals receiving chronic saline showed no change in percent choice (100%) on the DOI lever. Significant changes in binding were observed in 5-HT_2A receptors but not 5-HT_2C receptors. The results of tests with antagonists were consistent with the changes in binding. Conclusions: These results suggest that behavioral tolerance to DOI reflects neuroadaptive changes in 5-HT_2A receptors. Received: 17 July 1998 / Final version: 19 January 1999     

Characterizing withdrawal in rats following repeated drug administration using an amphetamine-vehicle-haloperidol drug discrimination

Rationale: Previous research using an amphetamine (AM)-haloperidol (HA) drug- drug discrimination task has shown that predominant responding on the HA-appropriate lever occurs 24 h after a single or multiple administrations of 10 mg/kg AM. Conversely, rebound responding on the AM-appropriate lever occurs following single or multiple administrations of 1 mg/kg HA. HA-appropriate responding was also observed 24 h following a single injection of AM using a three-lever, AM-vehicle-HA discrimination task. However, a single administration of HA did not produce robust rebound responding on the AM-appropriate lever. The present studies seek to clarify the discrepancy between responding following HA in the two- and three-choice tasks. Objective: Experiment 1 examined the extent of rebound responding that could be achieved following ten daily administrations of either 10 mg/kg AM or 1 mg/kg HA. Experiment 2 explored potential differences between the two- and three-choice tasks in characterizing the post-HA cue. Methods: Animals were trained to discriminate 0.35 mg/kg AM, vehicle, and 0.033 mg/kg HA. In experiment 1, animals received ten daily injections of 10 mg/kg AM, vehicle, or 1 mg/kg HA, and were tested 24 h after the final injection, and again 8, 15, and 22 days post-treatment. In experiment 2, animals were retrained and then treated daily with either vehicle or 1.0 mg/kg HA for 10 days, and then tested 24 h after the final injection, and again 5 and 11 days post-treatment, with either all three levers or with only the AM- and HA-appropriate levers available. Results: In experiment 1, multiple injections of AM produced robust HA lever responding, which is consistent with results from previous studies that used the two-choice, AM-HA discrimination task. However, multiple injections of HA did not produce predominant responding on the AM-appropriate lever. In experiment 2, animals treated with either vehicle or HA responded predominantly on the vehicle-appropriate lever when tested with all three levers present. When tested with the vehicle lever removed, however, animals treated with vehicle responded predominantly on the HA-appropriate lever, whereas those treated with HA responded predominantly on the AM-appropriate lever. Conclusions: These results suggest that the two-choice and three-choice task used here differ in how the post-HA withdrawal cue is characterized. This finding emphasizes the importance of knowing the relative locations of the agonist-, vehicle-, and antagonist-produced cues on the interoceptive stimulus continuum established by discrimination training. Received: 3 December 1997/Final version: 16 November 1998     

DA1 receptor activity opposes anorectic responses to amino acid-imbalanced diets

The serotonin3 (5-HT3) receptor plays an important role in the aminoprivic feeding model. Other neurochemical systems, including cholecystokinin (CCK) and dopamine (DA), are known to affect food intake. We pretreated rats systemically with tropisetron, a 5-HT3 receptor antagonist, alone and combined with antagonists of DA1 and DA2 receptors, and measured intake of an amino acid-imbalanced diet (IMB). As expected, tropisetron significantly increased intake of IMB. SCH-23390, a DA1 antagonist, increased IMB anorexia. When combined with tropisetron, DA2 antagonism with eticlopride reduced short-term intake of both the basal diet (BAS) and IMB. In the IMB model, specificity of 5-HT3-DA2 interactions, and of 5-HT3-CCK(A) interactions from previous studies, prompted investigation of CCK(A)-DA2 interactions; there appeared to be none. SKF-38393, a DA1 agonist, combined with the CCK(A) receptor antagonist, devazepide, increased BAS and tended to increase IMB intake. Thus, CCK(A)-DA1 interactions were not specific for IMB. These data suggest that DA1 receptor activity opposes IMB anorexia, possibly via an interaction with the 5-HT3 receptor.     

Pharmacokinetics and Safety of a Selegiline Transdermal System Relative to Single-Dose Oral Administration in the Elderly

This open-label, two-phase cross-over study compared the safety and pharmacokinetics of transdermally administered selegiline and orally administered selegiline hydrochloride in elderly men and women (n = 6/gender). Single oral doses of 10 mg selegiline hydrochloride and single 1/2 and 1 selegiline transdermal system (STS) (delivering similar3.4 and 6.3 mg over 24 h) administered topically were safe and well tolerated in all subjects. Plasma concentrations of selegiline (SEL) and its N-desmethylselegiline (DMS), L-amphetamine (AMP), and L-methamphetamine (MET) metabolites were measured using an HPLC/MS/MS method with lower quantitation limits of 10, 50, 200, and 200 pg/mL, respectively. No significant gender-related differences were observed following single 10-mg oral doses of selegiline hydrochloride or single 24-h applications of 1/2 and 1 STS to elderly males and females. The low level of dermal irritation as assessed by erythema and edema rating scales suggests that the STS was similar to Band-Aid (Johnson & Johnson, Skillman, NJ) controls. The transdermal administration of SEL bypasses the first-pass metabolism, that is significant after oral administration (first-pass extraction >90%). Peak plasma levels of 1.19, 23.22, 4.78, and 14.08 ng/mL were observed for SEL, DMS, AMP, and MET after a single 10-mg oral dose to the elderly. By contrast, peak plasma levels of 2.10, 0.85, 1.06, and 2.71 ng/mL were observed for SEL, DMS, AMP, and MET after a single 24-h application of 1 STS. Comparison of dose-corrected areas under the curve (AUCs) (made under the assumption of linear pharmacokinetics) indicate the SEL exposure after transdermal application was more than 50-fold greater than that obtained orally. This increase in systemic SEL exposure at the expense of metabolite formation that is reduced to <70% of that obtained orally for N-DMS, L-AMP, and L-MET is hypothesized to be of therapeutic value in patients with a variety of neurodegenerative and psychiatric disorders.     

Chemotherapy,early surgical reassessment,and hyperfractionated abdominal radiotherapy in stage III ovarian cancer: results of a gynecologic oncology group study

PURPOSE: To determine outcomes and treatment toxicities in patients with optimal (< or = 1 cm residual) Stage III ovarian carcinoma treated with three courses of cisplatin-cyclophosphamide, surgical reassessment (SRA), and hyperfractionated whole abdominal irradiation (WAI). METHODS AND MATERIALS: Forty-two eligible patients entered this prospective Phase II study conducted by the Gynecologic Oncology Group (GOG). Disease characteristics were as follows: age range, 32-76 years (median 58); Stage IIIA (n = 1, 2%), IIIB (n = 2, 5%), IIIC (n = 39, 93%); histology-serous papillary (n = 21, 50%); other (n = 21, 50%); Grade 1 (n = 1, 2%); 2 (n = 14, 33%); 3 (n = 27, 54%); residual disease after initial surgery (present: n = 23, 55%; absent: n = 19, 45%). Five patients progressed while on chemotherapy, could not be effectively cytoreduced, and were not eligible for WAI. Of the remaining 37 patients, 35 received WAI. Surgical reassessment was not performed in five patients. RESULTS: Of 37 patients with known SRA status after chemotherapy, 21 (57%) were grossly positive, 4 (11%) were microscopically positive, and 12 (32%) were negative. Based on measurements recorded following initial laparotomy and surgical reassessment, progression during chemotherapy was noted in 40%, stage disease in 37%, and objective response in 23%. Toxicity during hyperfractionated WAI was limited and reversible. No patient beginning WAI failed to complete or required a significant treatment break. Following WAI, six patients underwent laparotomies for abdominal symptoms; five had recurrent disease. Five additional patients were managed conservatively for small bowel obstruction (SBO) or malabsorption, of whom three subsequently developed recurrence. Twenty-two patients having pelvic boosts were significantly more likely to require management for gastrointestinal morbidity (p = 0.0021). Considering all eligible patients, median disease-free and overall survivals were 18.5 and 39 months, respectively. Considering patients completing chemotherapy and WAI, median disease-free and overall survivals were 24 and 46 months, respectively. CONCLUSIONS: (a) Disease progression occurred within three cycles of cisplatin and cyclophosphamide chemotherapy in 40% of patients with optimal (< or = 1 cm residual) Stage III ovarian carcinoma. (b) Following limited chemotherapy, hyper-fractionated WAI was acutely well tolerated. (c) Late radiation-related toxicity was observed in only three patients (8.6%) in the absence of recurrent disease. Late gastrointestinal morbidity was significantly associated with the administration of a pelvic radiotherapy (RT) boost. (d) Short duration chemotherapy followed by SRA and hyperfractionated WAI without a pelvic boost is a promising management option for patients with optimal Stage III ovarian cancer. A Phase III trial will be necessary to determine how this treatment strategy compares with chemotherapy or RT alone in this patient population.     

Development and evaluation of a diagnostic algorithm for depression in childhood

This paper describes the development and validation of a brief questionnaire intended for the rapid assessment of depression in childhood. It is primarily a clinical interview but there is an associated algorithm for the diagnosis of a syndrome of depression. It can equally be used for the clinical diagnosis of a depressive disorder. The current battery includes features representative both of depressive cognitions and endogenous depression. However, it is less effective in the identification of a syndrome of endogenous depression than depressive cognitions.

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Zusammenfassung Wir stellen die Entwicklung und Validierung eines kurzen Fragebogens vor, der zur raschen Feststellung einer Depression im Kindesalter dienen soll. Es handelt sich primär um ein klinisches Interview, aber es gibt zusätzlich einen Algorithmus für die Diagnosestellung eines depressiven Syndroms. Er kann ebenso für die klinische Diagnose einer depressiven Störung benutzt werden. Die vorliegende Batterie umfaßt Merkmale, die sowohl für depressive Kognitionen als auch für die endogene Depression repräsentativ sind. Jedoch können erstere hiermit besser identifiziert werden als das Syndrom einer endogenen Depression.

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Résumé Ce travail décrit le développement et la calidation d'un bref questionnaire ayant pour but l'évaluation repide de la dépression dans l'enfance. Il est en premier un interview clinique, mais il y a un algorythme associé pour le diagnostic d'un syndrome de dépression. Il peut également être utilisé pour le diagnostic clinique d'un trouble dépressif. La batterie courante comprend des traits représentatifs à la fois des cognitions dépressives et de la dépression endogène. Cependant, il est moins efficace dans l'identification d'un syndrome de dépression endogène que dans le cas des cognitions dépressives.

     

Discriminative stimulus properties of l-5-hydroxytryptophan: Behavioral evidence for multiple serotonin receptors

Rats were trained to discriminate the stimulus properties of l-5-hydroxytryptophan (l-5-HTP) (30 mg/kg SC), the immediate precursor of serotonin (5-HT). The peripheral decarboxylase inhibitor R04-4602, administered prior to l-5-HTP, greatly attenuated the disruptive effects observed on responding when l-5-HTP alone was injected. Following acquisition, the discrimination was dosedependent and generalized to fenfluramine, a 5-HT-releasing drug, but not to amphetamine, a catecholamine-releasing agent. Further evidence for the involvement of 5-HT receptor stimulation in mediating the discrimination was that pretreatment with fluoxetine, a highly specific 5-HT uptake inhibitor, markedly potentiated the cue. Nevertheless, the classical 5-HT antagonists methysergide, cyproheptadine, metergoline, and methiothepin did not block the l-5-HTP-related discriminative stimulus. This finding suggested that the cue properties of l-5-HTP might be mediated by a population of 5-HT receptors previously identified electrophysiologically in limbic structures. As in the present experiment, the putative 5-HT antagonists did not block the synaptic effects of 5-HT in these structures.