Comparison of agar plate and real-time PCR on enumeration of Lactobacillus, Clostridium perfringens and total anaerobic bacteria in dog faeces.

AIMS: To compare agar plate and real-time PCR methods on enumeration of total anaerobic bacteria, Lactobacillus and Clostridium perfringens in dog faeces. METHODS AND RESULTS: Thirty-two faecal specimens from Labrador retriever dogs were used to compare agar plate and real-time PCR enumeration methods for Lactobacillus, C. perfringens and total anaerobic bacteria. Total anaerobic bacteria, C. perfringens and Lactobacillus of faeces were counted (as CFU g(-1) faeces) for 48-h incubation at 37 degrees C in an anaerobic gas chamber on genus-selective media. Total genomic DNA from samples was extracted by the QIAamp DNA stool mini kit. The quantification of DNA (as DNA copy per gram faeces) by real-time PCR was performed with a LightCycler system with the QuantiTect SYBR green PCR kit for PCR amplification. The results indicated that there was a significant correlation between CFU and DNA copy of Lactobacillus (R2 = 0.78, P < 0.01) and total anaerobic bacteria (R2 = 0.21, P < 0.05); but no correlation was found between CFU and DNA copy of C. perfringens. The regression equations for Lactobacillus and total anaerobic bacteria were log(DNA copy) = 0.83 x log(CFU) + 1.43 and log(DNA copy) = 1.62 x log(CFU) - 6.32 respectively. CONCLUSIONS: The real-time PCR method could be used to enumerate Lactobacillus within 2 days when compared with plating method which requires 5-6 days. SIGNIFICANCE AND IMPACT OF THE STUDY: The real-time PCR method and the primer set for Lactobacillus spp. harboured in the dog intestine can be used for rapid enumeration of lactobacilli and monitoring of the faecal Lactobacillus community.

Generalization to atypical antipsychotic drugs depends on training dose in rats trained to discriminate 1.25 mg/kg clozapine versus 5.0 mg/kg clozapine versus vehicle in a three-choice drug discrimination task.

The prototypical atypical antipsychotic drug (APD) clozapine (CLZ) elicits a discriminative cue that appears to be similar to the stimulus properties elicited by atypical, but not typical, antipsychotic drugs in two-choice drug discrimination procedures. However, the ability of CLZ to generalize to atypical APDs depends on the training dose, since several atypical APDs (e.g. sertindole, risperidone) do not substitute for a 5.0 mg/kg CLZ training dose in rats, but do so for a 1.25 mg/kg CLZ training dose. Yet, a 1.25 mg/kg CLZ discriminative stimulus has not generalized to all atypical APDs either (e.g. quetiapine); thus, both 1.25 mg/kg and 5.0 mg/kg CLZ discriminative stimuli may be necessary to provide a better screen for atypical APDs. The present study sought to determine whether a three-choice 1.25 mg/kg CLZ versus 5.0 mg/kg CLZ versus vehicle drug discrimination task in rats might better distinguish atypical from typical APDs. Adult male Sprague-Dawley rats were trained in this three-choice drug discrimination task with a fixed ratio 30 reinforcement schedule for food. Clozapine produced full substitution (>or=80% condition-appropriate responding) for both the 1.25 mg/kg CLZ dose (ED50=0.09 mg/kg) and the 5.0 mg/kg CLZ dose (ED50=2.71 mg/kg). The atypical APD olanzapine produced full substitution for the 5.0 mg/kg CLZ dose, but not for the 1.25 mg/kg CLZ dose (ED50=1.55 mg/kg). In contrast, the atypical APD quetiapine produced full substitution for the 1.25 mg/kg CLZ dose (ED50=0.13 mg/kg), but not for the 5.0 mg/kg CLZ dose. Similarly, the atypical APD sertindole produced full substitution for only the 1.25 mg/kg CLZ dose (ED50=0.94 mg/kg). Risperidone, another atypical APD, produced partial substitution (>or=60% and

Fructooligosaccharide supplementation in the yearling horse: effects on fecal pH, microbial content, and volatile fatty acid concentrations.

Short-chain fructooligosaccharides (FOS) were supplemented to the diets of nine quarter horses ranging in age from 489 to 539 d with initial BW averaging 400.6 +/- 21.2 kg. The objectives of this study were to determine the effects of dietary FOS on the fecal responses in terms of pH, the microbial population, and VFA concentrations. The horses were used in a 3 x 3 replicated Latin square design, fed according to NRC requirements, and their individual diets were supplemented with no FOS (CON), 8 g of FOS/d (LOW), or 24 g of FOS/d (HIGH) over three 10-d feeding periods. On the last 3 d of each 10-d feeding period, a single fecal sample was collected between 0730 and 0930. Fecal pH decreased linearly (P = 0.01) from 6.48 with the CON diet to 6.38 with the HIGH diet, but there was no change (P = 0.19 for linear effect) in fecal consistency among treatments. A quadratic effect (P < 0.01) was observed for fecal Escherichia coli population, but no difference (P = 0.88 for linear effect) was found in fecal Lactobacilli enumeration among treatments. The presence of fecal Bifidobacteria was unable to be confirmed and was therefore not reported. Fecal acetate concentrations increased linearly (P = 0.03), with means of 2.13, 2.18, and 2.52 mg/g of wet feces for CON, LOW, and HIGH treatments, respectively. Similarly, fecal propionate concentrations increased linearly (P = 0.01), with means of 0.58, 0.64, and 0.73 mg/g for CON, LOW, and HIGH treatments, respectively. Fecal butyrate concentrations also increased linearly (P = 0.02), with means of 0.40, 0.46, and 0.54 mg/g for CON, LOW, and HIGH treatments, respectively. Total VFA (P = 0.01) and lactate (P = 0.02) concentrations increased linearly, with total VFA means of 3.47, 3.69, and 4.25 mg/g for CON, LOW, and HIGH treatments, respectively, and lactate means of 0.36, 0.41, and 0.47 mg/g for CON, LOW, and HIGH treatments, respectively. Supplementing FOS in diets fed to yearling horses altered fecal microbial populations, fecal VFA concentrations, and pH.

Pre-harvest factors influencing the acid resistance of Escherichia coli and E. coli O157:H7.

The effects of pH, acetate, propionate, or butyrate concentration, and diet on acid resistance of fecal Escherichia coli and E. coli O157:H7 were determined by in vitro and in vivo experiments. The pH tested was from 4.0 to 8.0, and the VFA concentrations tested were 0 to 100 mM. The E. coli O157:H7 used was strain 505B. In an in vivo study, cattle were fed a grain-based diet, then either not switched or switched to a grain-based diet with 3% added calcium carbonate or two fiber-based diets (soybean hulls or hay). Acid resistance was expressed as viability after acid-shock at pH 2.0 for 1 h and 4 h for fecal E. coli and E. coli O157:H7, respectively. Enumeration methods used were multitube fermentation, agar plate, and petri-film methods. The E. coli O157:H7 was not found in continuous culture inocula or in vivo samples. The viability of fecal E. coli decreased linearly (P < 0.01) as the culture pH increased, and viability of E. coli O157:H7 was highest (P < 0.01) when cultivated at pH 6.0. The viability of fecal E. coli and E. coli O157:H7 showed quadratic responses (P < 0.05) as acetate and butyrate concentrations increased at pH 7.2, with maximal acid resistance at 20 and 12 mM, respectively. As propionate concentration increased, the acid resistance was not different (P > 0.05) for fecal E. coli. Acid resistance of E. coli was induced by acetate and butyrate, even though the environmental pH was near neutral. Similar results were measured in the in vivo study, where viability after acid shock was more dependent on VFA concentration than on pH. Increasing the dietary calcium carbonate concentration also increased (P < 0.05) acid resistance of fecal E. coli. Results from these studies demonstrated that culture pH and VFA affect acid resistance of E. coli.

Effects of antipsychotic drugs on operant responding after acute and repeated administration.

RATIONALE: The current generation of atypical antipsychotic drugs represents an improvement over traditional ("typical") antipsychotics in many respects. However, a theoretical framework and adequate preclinical models have not yet been developed to predict or explain differences among the atypical antipsychotics, a necessary component of future development. OBJECTIVES: The purpose of the present set of experiments was to identify differences between the acute and subchronic effects of several atypical antipsychotic drugs and the typical antipsychotic haloperidol on operant responding in rats. METHODS: The effects of haloperidol and the atypical antipsychotics clozapine, olanzapine, risperidone, sertindole, quetiapine, remoxipride, and thioridazine were determined in rats trained to respond for food reward under a multiple fixed ratio 30/fixed interval 60 s schedule. A profile of the acute effects of each drug on response rates, response durations, and within-session effects were determined. Next, the dose of each drug that produced 75% suppression of response rates was administered for 16 consecutive days to determine whether or not tolerance would develop to the rate-suppressing effects of that dose. RESULTS: All drugs produced dose-related decreases in response rates. Only haloperidol and risperidone produced significant increases in response duration, while only haloperidol and remoxipride displayed within-session response decrements. Tolerance was evident for clozapine and to a lesser extent thioridazine. CONCLUSIONS: These results illustrate that the current generation of atypical antipsychotics are a heterogeneous group and that operant procedures may be useful for identifying differences preclinically. Specifically, clozapine appears to possess properties that distinguish it from other atypical antipsychotics, particularly after repeated dosing.

Use of hormonal emergency contraception at a university health centre over a 6 year period.

This was a retrospective review of the use of emergency hormonal contraception at a university-based health centre over a 6 year period. Usage was greater than noted in previous studies. Condom problems, or not using any form of contraception, were the main reasons for requests. Users were significantly more likely to be smokers than the base population.

Clozapine discrimination with a low training dose distinguishes atypical from typical antipsychotic drugs in rats.

RATIONALE: Previous drug discrimination studies with clozapine have not reliably distinguished between atypical and typical antipsychotics. OBJECTIVES: The present study was conducted to determine whether low-dose clozapine drug discrimination could distinguish atypical from typical antipsychotics. METHODS: Rats were trained to discriminate 1.25 mg/kg clozapine from vehicle in a two-lever drug discrimination procedure. RESULTS: Generalization testing revealed full substitution with the atypical antipsychotics olanzapine (90.3% maximum generalization), sertindole (99.8%), and risperidone (87.1%) and partial substitution for quetiapine (seroquel, 66.4%) and the typical antipsychotics haloperidol (56.8%) and thioridazine (74.3%). Remoxipride (23.1%) and the typical antipsychotics chlorpromazine (27.9%) and fluphenazine (29.5%) did not reliably substitute for clozapine. CONCLUSIONS: In contrast to previous clozapine drug discrimination studies with higher training doses, the atypical antipsychotics olanzapine, sertindole, and risperidone reliably substituted for clozapine while typical antipsychotics did not. These results suggest that low-dose clozapine drug discrimination may be a more sensitive assay for distinguishing atypical from typical antipsychotic drugs.

The discriminative stimulus properties of the atypical antipsychotic olanzapine in rats.

RATIONALE: Analysis of the preclinical behavioral effects of atypical antipsychotic agents will provide a better understanding of how they differ from typical antipsychotics and aid in the development of future atypical antipsychotic drugs. OBJECTIVES: The present study was designed to provide information about the discriminative stimulus properties of the atypical antipsychotic olanzapine. METHODS: Rats were trained to discriminate the atypical antipsychotic olanzapine (either 0.5 mg/kg OLZ or 0.25 mg/kg OLZ, i.p.) from vehicle in a twolever drug discrimination procedure. The atypical antipsychotic clozapine fully substituted for olanzapine in both the 0.5-mg/kg OLZ group (99.3% drug lever responding [DLR]) and the 0.25-mg/kg OLZ group (99.9% DLR). The typical antipsychotic chlorpromazine also substituted for olanzapine in both the 0.5-mg/kg OLZ group (87.5% DLR) and in the 0.25-mg/kg OLZ group (98.9% DLR); whereas, haloperidol displayed partial substitution for olanzapine in the 0.5-mg/kg OLZ group (56.1% DLR) and in the 0.25-mg/kg OLZ group (76.4% DLR). The 5.0-mg/kg dose of thioridazine produced olanzapine-appropriate responding in the 0.5-mg/kg OLZ group (99.6% DLR), but only partial substitution was seen with the 0.25-mg/kg OLZ training dose (64.0% DLR). The atypical antipsychotics raclopride (53.9% DLR) and risperidone (60.1% DLR) displayed only partial substitution in the 0.5-mg/kg OLZ group. Both the muscarinic cholinergic antagonist scopolamine (90.0% DLR) and the 5-HT2A/2C serotonergic antagonist ritanserin (86.0% DLR) fully substituted for olanzapine in the 0.5-mg/kg OLZ group. CONCLUSIONS: In contrast to previous discrimination studies with clozapine-trained rats, the typical antipsychotic agents chlorpromazine and thioridazine and the serotonin antagonist ritanserin substituted for olanzapine. These results demonstrate that there are differences in the mechanisms underlying the discriminative stimulus properties of clozapine and olanzapine. Specifically, olanzapine's discriminative stimulus properties appear to be meditated in part by both cholinergic and serotonergic mechanisms.

Effects of modulation of NMDA neurotransmission on response rate and duration in a conflict procedure in rats.

N-Methyl-D-aspartate (NMDA) antagonists and gamma-aminobutyric acid agonists share a number of common pharmacological properties, including motor and anticonvulsant effects. In the present study, site-selective NMDA antagonists were evaluated for potential anxiolytic efficacy and motor impairment in a modified Geller-Seifter conflict procedure, an animal model widely used to screen drugs for anxiolytic effects. Male Sprague-Dawley rats were trained to respond for food reward under a multiple FI 30 s (food only), FR 10 (food + shock) operant schedule. Consistent with the results of previous studies, the benzodiazepines chlordiazepoxide and diazepam selectively increased punished responding and increased response durations at higher doses. The competitive NMDA antagonist CGP 37,849 increased punished responding at some doses, though not selectively, and also increased response duration in both schedule components. The glycine-site modulators milacemide, ACEA 1011 and ACEA 1021, the NR2B-selective polyamine site antagonist eliprodil and NMDA did not produce anticonflict effects at any dose and had inconsistent effects on response durations. These results suggest that the anticonflict effects of NMDA antagonists are not as reliable as those of the benzodiazepines. Further research is needed to clarify the experimental conditions under which the anxiolytic potential of NMDA antagonists is most evident.

Metabolism of halofantrine to its equipotent metabolite, desbutylhalofantrine, is decreased when orally administered with ketoconazole.

Halofantrine (Hf) is a highly lipophilic antimalarial with poor and erratic absorption. Published data indicates that the oral bioavailability of Hf was increased 3-fold in humans and 12-fold in dogs when administered postprandially; however, the proportional formation of the active desbutyl metabolite (desbutylhalofantrine, Hfm) decreased 2.4-fold in humans and 6.8-fold in dogs (Milton et al., Br. J. Clin. Pharmacol. 1989, 28, 71-77; Humberstone et al., J. Pharm. Sci. 1996, 85, 525-529). The current study was undertaken to confirm the putative involvement of CYP3A4 in the N-dealkylation of Hf to Hfm by administering Hf with and without ketoconazole (KC), a specific CYP3A4 inhibitor, and measuring the resulting plasma concentration profiles of Hf and Hfm. The plasma Hfm/Hf AUC(0-72 h) ratio after fasted oral administration of Hf without KC was 0.56, whereas the ratio after fasted oral administration with KC was less than 0.05. It is likely that both hepatic and prehepatic (enterocyte-based) CYP3A4 contributed to metabolism of Hf to Hfm after oral administration. Interestingly, the low plasma Hfm/Hf AUC ratios observed after fasted administration of Hf with KC were similar to the low values previously observed when Hf was administered postprandially (despite increased Hf absorption). The mechanism(s) by which postprandial administration of Hf led to a decrease in its metabolism are unknown, but based on the current data, could include inhibition of CYP3A4-mediated metabolism by components of the ingested meal. Other possibilities include a lipid-induced postprandial recruitment of intestinal lymphatic transport or avoidance of metabolism during transport through the enterocyte into the portal blood. Further studies are required to determine the relative contributions by which these different processes may decrease the presystemic metabolism of Hf.

The role of muscarinic cholinergic receptors in the discriminative stimulus properties of clozapine in rats.

The present study examined the role of muscarinic receptors in the discriminative stimulus properties of clozapine. One group of rats was trained to discriminate the atypical antipsychotic clozapine (CLZ, 5.0 mg/kg, i.p.) from vehicle in a two-lever drug discrimination procedure, and a second group of rats was trained to discriminate the muscarinic cholinergic antagonist scopolamine (SCP, 0.125 mg/kg, i.p.) from saline. Complete cross-generalization was obtained for SCP in the CLZ-trained rats and for CLZ in the SCP-trained rats. The M1 muscarinic antagonist trihexyphenidyl substituted completely for both CLZ and SCP; however, the M2 antagonist BIBN 99 failed to substitute for either CLZ or SCP. In other substitution tests, the tricyclic antidepressant amitriptyline, the antihistamine promethazine, and cyproheptadine (5-hydroxytryptamine [5-HT]2A/5-HT2C, histamine, and muscarinic antagonist) substituted completely for CLZ and SCP. The tetracyclic antidepressant mianserin substituted completely in the CLZ-trained rats, but did not substitute for SCP. Compounds that produced partial substitution included the tricyclic antidepressant imipramine, the anxiolytic chlordiazepoxide, and the antipsychotic thioridazine. Other compounds tested only in the CLZ-trained rats that failed to produce reliable CLZ-appropriate responding included N-methyl-D-aspartic acid (NMDA, selective agonist for glutamate receptors), metergoline (5-HT2A/5-HT2C antagonist), propranolol (beta noradrenergic antagonist), and phentolamine (alpha noradrenergic antagonist). All of the compounds that produced CLZ-appropriate responding (except for mianserin) display high binding affinities for muscarinic cholinergic receptors. The results of the present study demonstrated that muscarinic receptors (especially M1) play an important role in the mediation of the discriminative stimulus properties of CLZ in rats, and provide additional support for the importance of CLZ's anticholinergic properties as part of it's unique profile as an atypical antipsychotic.

Discriminative stimulus control with olanzapine: generalization to the atypical antipsychotic clozapine.

The present study was conducted to determine if the putative atypical antipsychotic olanzapine could be established as a discriminative stimulus in rats. Seven rats were successfully trained to discriminate olanzapine (0.5 mg/kg, IP) from vehicle in a two-lever drug discrimination procedure (mean number of acquisition sessions = 39.3). Generalization testing with olanzapine (0.0625-2.0 mg/kg) yielded an ED50 of 0.170 mg/kg (95% confidence interval = 0.118-0.246 mg/kg). The atypical antipsychotic clozapine (0.156-10.0 mg/kg) fully substituted for olanzapine in all rats at the 2.5 mg/kg dose with 99.0% drug-lever responding, in six rats at the 0.625 mg/kg dose, and in five rats at the 1.25 and 5.0 mg/kg doses (ED50 = 0.259 mg/kg, 95% confidence interval = 0.089-0.755 mg/kg). This study is the first demonstration that rats can be trained to discriminate olanzapine from vehicle in a two-lever drug discrimination procedure and that the olanzapine discrimination cue generalizes to clozapine.

Mianserin as a discriminative stimulus in rats: asymmetrical cross-generalization with scopolamine.

The present study was conducted to determine if the tetracyclic antidepressant mianserin could be established as a discriminative stimulus in rats. One group of rats was trained to discriminate mianserin (4.0 mg/kg, IP) from saline in a two-lever drug discrimination procedure, and a second group of rats was trained to discriminate the muscarinic cholinergic antagonist scopolamine (0.25 mg/kg, IP) from saline. Generalization testing with the training drugs yielded an ED50 of 0.502 mg/kg for the mianserin-trained rats and an ED50 of 0.048 mg/kg for the scopolamine-trained rats. Asymmetrical cross-generalization between mianserin and scopolamine was observed, because scopolamine produced mianserin-appropriate responding, but mianserin did not produce scopolamine-appropriate responding. This study is the first demonstration that rats can be trained to discriminate mianserin from saline and that antagonism of muscarinic cholinergic receptors is sufficient to produce mianserin-appropriate responding.

Differential effects of clozapine and pimozide on fixed-ratio responding during repeated dosing.

Previous research has shown that the differential development of tolerance to the disruption of operant responding produced by repeated dosing with pimozide (PMZ) or clozapine (CLZ) can distinguish these two drugs. In the present study, the effects of PMZ (1 mg/kg) and CLZ (10 mg/kg) on response rate and response duration in rats lever pressing for food reward under a fixed-ratio 30 (FR-30) operant schedule were examined. PMZ suppressed response rates across all 10 days of drug dosing; CLZ produced an initial response rate decrease, with partial recovery (50%) occurring within the 10 day period. Similarly, PMZ produced an increase in response duration that persisted into the postdrug vehicle-injection period, while CLZ did not significantly change response duration. The prolonged suppression of FR responding produced by PMZ is similar to the lack of tolerance to this drug in other types of operant schedules. In contrast, CLZ's effects on response rate are schedule dependent. These results suggest that changes in response duration with repeated dosing may more reliably differentiate typical and atypical neuroleptics than do changes in response rate under FR schedules.

Comparison of Chinese and Western rifapentines and improvement of bioavailability by prior taking of various meals.

Bioavailability was measured by rifapentine (RPE) serum concentrations and by the urinary ratio between RPE and creatinine, in specimens obtained 4-50 h after 600 mg RPE preceded by food. The bioavailabilities of RPEs manufactured in China and by a Western manufacturer were similar after a standard English breakfast, and serum concentrations were also similar to those obtained in an earlier Italian study following a complex meal. Although absorption of RPE was unsatisfactory after lipid-rich biscuits or shortbread, absorption after egges and toast was excellent and was nearly as good after a fast-food sandwich. The urinary measure of bioavailability at 26 h appeared as efficient as peak serum estimations at 6, 8 and 26 h. Fast-food sandwiches are being taken before RPE in a current clinical trial of Chinese RPE in Hong Kong.

Effects of four antipsychotics on punished responding in rats.

In Experiment 1, the benzodiazepine chlordiazepoxide (CDP), two typical antipsychotics, haloperidol (HAL) and chlorpromazine (CPZ), and the atypical antipsychotic clozapine (CLZ) were evaluated for antipunishment effects in rats in a modified Geller-Seifter conflict procedure [MULT fixed interval (FI) 60-s, fixed ratio (FR) 1 (food + shock)]. In Experiment 2, CDP and thioridazine (THD) were similarly tested. CLZ (2.5 and 5.0 mg/kg), but not HAL, CPZ, or THD, selectively increased punished responding, although the magnitude of effect was smaller than that observed for CDP. Possible serotonergic mechanisms for CLZ's action in this model and the possible importance of serotonergic activity for the development of other atypical antipsychotic drugs are discussed.

Differential tolerance to the behavioral effects of chronic pimozide and clozapine on multiple random interval responding in rats.

The behavioral effects of 10 days of chronic administration of the typical neuroleptic, pimozide, and the atypical neuroleptic, clozapine, were compared on a schedule of multiple random interval responding for food reinforcement and on photocell activity in rats. The low doses of both neuroleptics (0.125mg/kg pimozide, 1.25mg/kg clozapine) had little effect on any of the dependent variables measured. The high doses (1.0mg/kg pimozide, 10.0mg/kg clozapine) significantly disrupted response rates and reinforcement rates and significantly increased response duration when the drugs were first administered. Chronic administration, however, resulted in different profiles for the two drugs. While tolerance developed to the disruptive effects of clozapine, tolerance did not develop to the disruptive effects of pimozide and, on some dependent measures, an increased sensitivity developed. No tolerance developed to the disruptive effects of either drug on photocell activity. The effects of the drugs depended on the reinforcement density of the operant schedule.

Serotonergic drugs do not substitute for clozapine in clozapine-trained rats in a two-lever drug discrimination procedure.

The atypical neuroleptic clozapine has been shown to have cue properties in two-lever drug discrimination procedures. Although it has been demonstrated that clozapine acts at several types of receptors in vitro and in vivo, including dopamine, serotonin [5-hydroxytryptamine (5-HT)], and acetylcholine receptors, the mechanism of action for its discriminative stimulus properties has not yet been determined. The present study examined the effects of haloperidol (D2 dopamine antagonist), ritanserin (5-HT2 antagonist), 1-alpha H,3-alpha,5-alpha H-tropan-3yl-3,5-dichlorobenzoate (MDL 72222) (5-HT3 antagonist), and buspirone (5-HT1A agonist) in stimulus substitution tests with rats trained to discriminate clozapine (5.0 mg/kg, IP) from vehicle in a two-lever drug discrimination procedure under a fixed ratio 30 schedule of food reinforcement. Analysis of the results revealed that, while clozapine produced dose-dependent responding on the clozapine lever, haloperidol and the three serotonin drugs failed to produce full substitution for clozapine at any of the doses tested. These results suggest that the discriminative stimulus properties are not mediated by D2 dopamine receptor blockade, antagonism at 5-HT2 or 5-HT3 receptors, or agonistic activity at 5-HT1A receptors. The neural basis of clozapine's discriminative stimulus properties has not yet been determined.

Pimozide mitigates excessive running in the activity-stress paradigm.

The present study investigated the role of dopamine in the maintenance of behaviors observed in the activity-stress paradigm. In Experiment 1, several doses (0, 0.125, 0.25, 0.50, and 1.0 mg/kg) of the dopamine D2-receptor blocker, pimozide, were administered to rats maintained on an ad lib feeding schedule. Results indicated that 0.25 mg/kg pimozide did not disrupt running activity when compared to control animals. In Experiment 2, injections of either 0, 0.25, or 0.50 mg/kg pimozide were given every 12 hours to rats subjected to the activity-stress paradigm. Although 0.25 mg/kg pimozide had no effect on dark-phase activity, it significantly suppressed light-phase activity and subsequently increased the number of survivors in the paradigm. It was concluded that dopamine plays a role in maintaining high running levels in the activity-stress paradigm.

Antipunishment effects of acute and repeated administration of phencyclidine and NPC 12626 in rats.

The effects of phencyclidine (PCP) and NPC 12626 on punished responding were examined using a modified Geller-Seifter procedure in rats. Both drugs are known to antagonize N-methyl-D-aspartate (NMDA) receptor mediated neurotransmission, albeit at different sites on the NMDA receptor complex. Rats were trained to lever press for food reinforcement under a multiple schedule, with responding in one component reinforced under a fixed-interval 60-sec schedule, while each response in the other component resulted in both food and brief electric shock. Both PCP and NPC 12626 produced selective increases in punished responding, although the effects were not as large as those produced by chlordiazepoxide. Repeated daily administration of each of these drugs for 6 days resulted in increases in punished responding during different portions of the treatment. A 5 mg/kg dose of chlordiazepoxide produced increases over the last 2 days of administration. PCP (2 mg/kg) produced an increase only during the second session, whereas NPC 12626 (30 mg/kg) produced increases for all but the first and fifth days of the 6-day regimen. Both competitive and noncompetitive NMDA antagonists can have antipunishment effects in this model.