Blockade of the discriminative stimulus effects of cocaine in rhesus monkeys with the D1 dopamine antagonist SCH 23390.

To investigate the role of D1 dopamine receptors in the discriminative stimulus effects of cocaine, two rhesus monkeys were trained in a two-lever, food-reinforced, drug discrimination paradigm to discriminate cocaine (0.2 mg/kg, IM) from saline. Administration of various doses of cocaine resulted in a dose-related increase in the percentage of responses that occurred on the drug-appropriate lever. Administration of the D1 antagonist SCH 23390 20 min before cocaine reduced drug-appropriate responding from 100% to 0% in all subjects and increased by 4-8-fold the cocaine dose necessary to induce drug-appropriate responding. A mutual antagonism of the rate-decreasing effects of cocaine and SCH 23390 was also observed. These findings suggest that D1 receptors play a significant role in the discriminative stimulus and rate-decreasing effects of cocaine.

Anxiolytic-like effects of N-methyl-D-aspartate-associated glycine receptor ligands in the rat potentiated startle test.

Competitive and non-competitive NMDA receptor complex antagonists have been shown to be active in various models of anxiolytic activity. This study examined the effects of ligands at the NMDA receptor-associated glycine site and two competitive NMDA receptor antagonists on the fear-potentiated startle response model for anxiolytic activity. The results show that the NMDA receptor antagonists, 2-amino-7-phosphonoheptanoate (30 mg/kg) and 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonate (3 mg/kg), the glycine receptor antagonist 7-chlorokynurenate (100 mg/kg), and the glycine receptor partial agonists 3-amino-1-hydroxy-2-pyrrolidinone ((+)-HA-966) (30 mg/kg), 1-aminocyclopropane carboxylate (200-500 mg/kg) and D-cycloserine (30-300 mg/kg) blocked the potentiated startle effect. These results extend the findings of earlier studies showing anxiolytic-like effects of NMDA antagonists and glycine receptor ligands by demonstrating their effectiveness in the rat potentiated startle paradigm. These results also demonstrate the anxiolytic potential of D-cycloserine.

Phencyclidine established as a discriminative stimulus using ethanol as a reinforcer.

Long-Evans hooded rats were initially trained to lever press, in standard, operant conditioning chambers, according to a fixed-ratio 1 (FR1) reinforcement schedule using 0.06ml deliveries of 8% w/v ethanol as the reinforcer, during daily Monday-Friday, 1h experimental sessions. Next, experimental sessions were reduced to 0.5h, the FR value was increased to 5, and the rats were trained to discriminate 2.0mg/kg s.c. phencyclidine (PCP) from saline vehicle using standard, drug discrimination training procedures, with 8% ethanol as the reinforcer. Following training, dose-response tests with PCP (0.1-4.0mg/kg), ketamine (0.1-18mg/kg), dexoxadrol (1.0-5.6mg/kg) and morphine (1.0-9.0mg/kg) were conducted. More PCP-lever presses were emitted than saline-lever presses at several doses of PCP, ketamine, and dexoxadrol, indicating generalization from the 2.0mg/kg PCP stimulus. When morphine was tested, more saline-lever than PCP-lever presses were made, and percent PCP-lever pressing never exceeded an average of 12% at any dose tested. This study demonstrates that one drug of abuse, PCP, can serve as a discriminative stimulus when another drug of abuse, ethanol, serves as the reinforcing stimulus, and is the first explicit laboratory demonstration of drug discriminative stimulus control during drug self-administration.

A comparison of radiographic signs of pulmonary inflammation during ECMO between silicon and poly-methyl pentene oxygenators.

INTRODUCTION: The inflammatory response caused by extracorporeal membrane oxygenation (ECMO) is clearly visible within the first 24 h of cannulation. The inflammatory process affects all areas of the lung, even areas previously spared by the primary disease. OBJECTIVE: To compare the change in the radiographic signs of inflammatory response to ECMO between poly-methyl pentene and silicon oxygenators. STUDY DESIGN: Retrospective review of neonates and adults pre- and post-replacement of silicon oxygenators with poly-methyl pentene devices. Data were collected from Extracorporeal Life Support Organisation (ELSO) registry forms and patient records. Results were analysed by quantitative and semi-quantitative methods. RESULTS: There was a significant reduction in the radiographic signs of inflammatory response to ECMO, and a reduction in the time taken to revert to pre-ECMO state in the neonatal poly-methyl pentene group compared to silicon. However, there was no significant reduction in the duration of ECMO runs and the percentage survival between these groups in the neonates. In adults, there was no difference in severity of radiographic signs between groups. However, the inflammatory changes were relatively delayed in the adult poly-methyl pentene group. CONCLUSION: Polymethyl pentene (Medos) oxygenators have reduced the host's response phenomenon 'white out' in neonates, and caused a delayed response in adults. This is most likely a consequence of smaller blood contact surface area combined with the effect of heparin coating of the oxygenator membrane. However, recovery was not a function of the type of gas exchange device used.

Partial liquid ventilation.

We describe the technique of partial liquid ventilation and outline its indications. We present our imaging experience with this infrequently used therapy using a wide variety of radiographs from neonatal and adult patients. The radiographic appearance of white lungs, due to the perfluorocarbons used in partial liquid ventilation, may initially be rather perplexing, but can be an advantage in diagnosing certain complications of mechanical ventilation, outlining pathology and demonstrating normal anatomy in an unusual manner.

Antagonists at the serotonin-3 receptor can reduce the fear-potentiated startle response in the rat: evidence for different types of anxiolytic activity?

The current study evaluated three serotonin-3 (5-HT3) antagonists for potential anxiolytic effects in rats by using the fear-potentiated startle paradigm. Because initial studies did not show an effect of the 5-HT3 antagonists, the authors explored the question of whether altering the training conditions under which the conditioned fear is formed would alter the sensitivity of the paradigm to the effects of the 5-HT3 antagonists. Two fear-conditioning protocols were used: 1) 10 conditioning trials on each of 2 days using 0.5 mA of foot shock and 2) 15 conditioning trials in 1 day using 0.25 mA of foot shock. Ondansetron (0.001-1.0 mg/kg), (R)-zacopride (0.0001-1.0 mg/kg), granisetron (0.001-1.0 mg/kg), diazepam (0.32-3.2 mg/kg) and buspirone (0.56-5.6 mg/kg) were evaluated for their ability to reduce the potentiated startle produced by both conditioning protocols. Although diazepam and buspirone effectively reduced the potentiated startle produced by both protocols, the 5-HT3 antagonists were potently effective only in the second protocol. Subsequent experiments demonstrated that the 5-HT3 antagonists block startle potentiation only when the lower (i.e., 0.25 mA) shock intensity is used during training. These results suggest the possibility that different conditioning protocols may produce qualitatively different anxiety states, which can be differentiated by the 5-HT3 antagonists, but not by diazepam or buspirone.

Pharmacological characterization of the discriminative stimulus effects of cocaine in rhesus monkeys.

Rhesus monkeys (n = 6), trained in a two-lever, food-reinforced paradigm to discriminate cocaine (0.2 or 0.4 mg/kg, i.m.) from saline, received injections of cocaine (0.025-0.40 mg/kg, i.v. or i.m.) or various direct and indirect acting agonists (i.v.). Administration of cocaine resulted in a dose-related increase in the percentage of responses that occurred on the drug-appropriate lever. The indirect dopamine agonists GBR 12909 (0.2-1.6 mg/kg), mazindol (0.025-0.4 mg/kg), nomifensine (0.025-0.2 mg/kg) and bupropion (0.1-1.6 mg/kg) each produced dose-related increases in cocaine-appropriate responding, with complete substitution for cocaine achieved at the highest doses of each drug. In contrast, the norepinephrine re-uptake blockers tomoxetine (0.8-6.4 mg/kg) and nisoxetine (0.4-1.6 mg/kg), the serotonin re-uptake blocker fluoxetine (1.6-12.8 mg/kg), the D1 agonist SKF 38393 (3.2-12.8 mg/kg) and the D2 agonist quinpirole (0.05-0.2 mg/kg) failed to engender cocaine-appropriate responding. Administration of the D1 antagonist SCH 23390 (0.05-0.2 mg/kg, i.m.) 20 min before cocaine resulted in a 4- to 8-fold parallel shift to the right in the cocaine dose-response function. Similarly, the D2 antagonist haloperidol (0.003-0.012 mg/kg, i.m.) produced at least a 2-fold shift to the right in the cocaine dose-response function. The results indicate that blockade of dopamine re-uptake is sufficient to mimic the cocaine discriminative stimulus and suggest that stimulation of either D1 or D2 receptors is necessary but not sufficient for the expression of the discriminative stimulus effects of cocaine.