Discrimination of a drug mixture in rats: role of training dose, and specificity

Many drugs produce compound discriminative stimuli with at least two elements; in contrast, the present study examines discrimination of a mixture of two drugs and tests the role of training dose in, and the specificity of, such a discrimination. Rats discriminated a mixture of nicotine (0.2mg/kg s.c.) and midazolam (0.1mg/kg s.c.) from saline in a two-bar operant conditioning procedure with accuracy of at least 80%. Stimulus control was analyzed by testing each drug separately. Initially, stimulus control was mainly attributable to the midazolam. The doses of drugs used to maintain the discrimination were then altered. As the training dose of nicotine increased and that of midazolam decreased, the magnitudes of responses to the separate drugs were progressively reversed, until stimulus control was mainly attributable to nicotine. Thus, responses to the components of the compound stimulus were systematically related to the amounts of drugs in the mixtures used to maintain the discrimination, and there was some evidence that a strong stimulus produced by one drug may have overshadowed a weaker stimulus produced by a different agent. To test specificity, generalization to other drugs was examined. There was no generalization to amphetamine, morphine or quipazine, up to doses that reduced overall rates of responding. It follows that cues produced by mixtures of drugs may be as specific as those produced by single agents.     

Temporal factors in drug discrimination: Experiments with nicotine

The role of the presession interval (PI) in drug discrimination research has been studied in rats trained to discriminate nicotine from saline in a two-bar operant conditioning procedure. Different groups of rats were trained at different Pls, varying between 5 and 35 min, and tests were then carried out for qualitative and quantitative differences between the cues. There was complete generalization from nicotine cues trained at one time to tests carried out at other times. The sensitivity of the cues at different Pls to the nicotinic antagonist mecamylamine was very similar. Generalization to amphetamine was nearly complete when the nicotine cue was established with PI of 20-35 min and only partial when the PI for the nicotine was 5 min. Thus, there was no clear evidence for any qualitative difference between nicotine cues established with different PIs. However, the PI influenced quantitative aspects of the nicotine cue in a marked and complex manner. Increasing the PI during training produced a two- to three-fold decrease in the ED(50), whereas increasing the PI during testing produced a two- to three-fold increase in the ED(50). This shows that the effects of changing the PIs during training and testing were similar in magnitude but opposite in direction. These changes in ED(50) values can be explained by pharmacokinetic considerations in conjunction with knowledge of the role of training dose in the discrimination of nicotine. The quantitative sensitivity of the drug discrimination procedure can be substantially influenced by the choice of temporal parameters used in training and testing.     

Interaction of nicotine with dopaminergic mechanisms assessed through drug discrimination and rotational behaviour in rats

Biochemical and electrophysiological studies have suggested that nicotine may interact with dopaminergic systems so as to enhance the release and utilization of dopamine. The functional significance of these effects has been assessed using drug discrimination and rotational behaviour in rats. The dopamine antagonists haloperidol and Sch 23390 attenuated the discriminative stimulus effect of nicotine and reduced overall rates of responding. In contrast, droperidol and pimozide were without significant effect on discrimination of nicotine at doses that reduced response rates. There was partial generalization from nicotine to the dopamine D-1 agonist SKF 38393. In rats with unilateral, 6-hydroxydopamine lesions of the nigrostriatal dopamine pathway, nicotine produced rotation towards the side of the lesion, a characteristic effect of indirectly acting dopamine agonists such as amphetamine. The nico tinic-cholinergic antagonist mecamylamine, and haloperidol, blocked rotation produced by nicotine. A dose of nicotine that was too small to produce amphetamine-like effects itself enhanced both the discriminative stimulus and the rotational behaviour produced by amphetamine. However, mecamylamine did not weaken the discriminative effect of amphetamine. The results suggest that there may be a minor component of the nicotine discriminative stimulus that is mediated, indirectly, through a dopaminergic mechanism. There also appears to be a facilitatory, nicotinic influence on behavioural functions linked to the dopamine system.     

A bibliography of drug discrimination research, 1992-1994

The major content of this publication is a comprehensive bibliography of research into the discriminative stimulus effects of drugs in animal and human subjects for the period 1991-1994. The bibliography is accompanied by a detailed cross-index that facilitates access to this literature through keywords based on the drugs studied, how the drugs were used, and numerous other methodological variables such as species of subject and schedule of reinforcement. The article also explains how users may obtain access to the present and earlier versions of the database, which are available as computer disks and over the Internet. The easy access to this literature made possible by the database should increase the working efficiency of the many groups that employ drug discrimination methods and should also support dissemination of the knowledge acquired to a wider scientific community.     

Tryptophan 650 of human granulocyte colony-stimulating factor (G-CSF) receptor, implicated in the activation of JAK2, is also required for G- CSF-mediated activation of signaling complexes of the p21ras route

Granulocyte colony-stimulating factor (G-CSF) induces rapid phosphorylation of JAK kinases as well as activation of the p21ras route through interaction with its specific receptor (G-CSF-R). The cytoplasmic membrane-proximal region of G-CSF-R (amino acids 631 to 684) is necessary for proliferation induction and activation of JAK2. In contrast, activation of Shc and Syp, signaling molecules implicated in the p21ras signaling route, depends on the phosphorylation of tyrosine residues located in the membrane-distal region (amino acids 685 to 813) of G-CSF-R. We investigated whether G-CSF-induced activation of signaling complexes of the p21ras route depends on the function of the membrane-proximal cytoplasmic region of G-CSF-R. A G- CSF-R mutant was constructed in which tryptophan 650 was replaced by arginine and expressed in BAF3 cells (BAF/W650R). In contrast to BAF3 cell transfectants expressing wild-type G-CSF-R, BAF/W650-R cells did not proliferate and did not show activation of JAK2, STAT1, or STAT3 in response to G-CSF. Immunoprecipitations with anti-Shc and anti-Grb2 antisera showed that mutant W650R also failed to activate Syp and Shc. These data indicate that the membrane-proximal cytoplasmic domain of G- CSF-R is not only crucial for proliferative signaling and activation of JAK2 and STATs, but is also required for activation of the p21ras route, which occurs via the membrane-distal region of G-CSF-R.     

Intraperitoneal chemotherapy for patients with advanced ovarian cancer: a review of the evidence and standards for the delivery of care

OBJECTIVES: To evaluate the role of intraperitoneal (IP) chemotherapy as part of primary treatment in patients with advanced ovarian cancer and to develop standards of care within the context of current clinical practice. METHODS: A multidisciplinary expert panel, convened to develop standards on the use of IP chemotherapy, searched the MEDLINE, EMBASE, and Cochrane Library databases up to December 2006 for randomized trials or published standards on the efficacy and/or delivery of IP chemotherapy. RESULTS: Eight randomized trials comparing IP chemotherapy versus intravenous (IV) chemotherapy were identified. Three trials reported statistically significant improvements in median survival of 8.0, 11.0, and 15.9 months with cisplatin-based IP chemotherapy. In one trial, the 15.9-month improvement in median overall survival (RR=0.75, 95% CI=0.58-0.97) represented a 25% reduction in the risk of death with IP chemotherapy. Severe adverse events and catheter-related complications were often dose limiting with IP chemotherapy. Using a consensus-based approach with a nationally representative panel, multidisciplinary care standards were developed to review medical and surgical criteria, the practice setting, volume requirements, and the institutional criteria required to safely deliver IP chemotherapy. CONCLUSION: The survival benefits with cisplatin-based IP chemotherapy may represent a significant improvement in the outlook for select patients with advanced ovarian cancer. The delivery of IP chemotherapy is more challenging than the IV route; however, severe adverse events and catheter-related complications may be offset through research defining the optimum treatment regimen, and the standardization of care. System-wide standards for the delivery of IP chemotherapy in Canada for patients with optimally debulked stage III ovarian cancer are offered.