The relationship between vascular expansion of the aorta and pulmonary artery and the genesis of the impedance cardiogram using the technique of sonomicrometry.

PRIMARY OBJECTIVE: This prospective animal study aims to evaluate the contribution of the pulmonary artery (PA) and aorta on the morphology of the impedance cardiogram using sonomicrometry. METHODS: Impedance electrodes were placed around the thorax, aorta and in the oesophagus of five dogs. Sonomicrometry crystals were mounted on the PA and aorta for tracking vascular distension while a Doppler flow probe measured aortic blood flow. RESULTS: No significant differences (p > 0.05) were recorded between the onset of aortic expansion, aortic blood flow and the start of the impedance dZ/dt signal. Significant differences (p > 0.001) were recorded between the onset of PA expansion and the dZ/dt signal. PA expansion began 41.6 +/- 6.0 ms, 60.7 +/- 7.2 ms and 42.2 +/- 4.9 ms respectively, before surface, aortic and oesophageal impedance recordings. CONCLUSION: The genesis of the impedance cardiogram is attributed to volumetric expansion of the aorta.

An analysis of the utility of differential outcome procedures in drug discrimination research.

In differential outcomes procedures, the correlation of unique reinforcers with distinct discriminative stimuli can decrease the amount of time needed for response acquisition and improve terminal accuracy of responding. The drug discrimination assay is widely used to categorize psychoactive drugs as similar or dissimilar and to describe underlying neurochemical changes associated with drug administration. Because the drug discrimination assay relies heavily upon initial response acquisition and continuing terminal accuracy, a procedure successful at shortening acquisition time and improving terminal accuracy would be beneficial. The present studies examined differences in acquisition of drug stimulus control between rats exposed to differential outcome procedures and rats exposed to the outcomes, in a non-systematic way, in two experiments. The first experiment examined acquisition of control by (+/-)-3,4-methylenedioxymethamphetamine (MDMA), D-amphetamine and saline; the second examined control by MDMA, (+)-lysergic acid diethylamide (LSD) and saline. Neither initial acquisition nor terminal accuracy was influenced by differential outcomes in either experiment. Although the differential outcome effect has been demonstrated in many situations, it does not appear to be useful in the drug discrimination assay. Possible reasons for the lack of an observed effect are discussed.

Common discriminative stimulus properties in rats of muscarinic antagonists, clozapine and the D3 preferring antagonist PNU-99194a: an analysis of possible mechanisms.

Dopamine D3 receptors have been implicated in the aetiology of schizophrenia and the actions of antipsychotic drugs. The initial studies reported here assessed the involvement of such receptors in the in vivo actions of the atypical antipsychotic clozapine and the putative D3-preferring antagonist PNU-99194A in drug discrimination assays. Rats trained to discriminate clozapine consistently generalized to PNU-99194A in two separate studies. However, four other putative D3-preferring antagonists (PD 152255, (+)-S14297, nafadotride and (+)-AJ 76) did not induce generalization to clozapine. In rats trained to discriminate PNU-99194A, which has been suggested to induce a stimulus mediated specifically by D3 antagonism, the D3-preferring antagonist (+)-UH 232 and clozapine both induced full generalization. However, the PNU-99194A-trained animals also generalized fully to the muscarinic antagonists scopolamine and trihexyphenidyl. A possible explanation for the symmetrical generalization observed between clozapine and PNU-99194A is that these drugs have common muscarinic antagonist actions, since muscarinic antagonists have been reported to substitute for clozapine in numerous prior studies. However, in vitro receptor binding studies with M1-M5 receptors indicated that (with the possible exception of the M4 receptor), no muscarinic receptor subtype had high affinity for both clozapine, PNU-99194A and scopolamine. In addition, other binding studies indicated that whereas clozapine and PNU-99194A had high affinity for the D3 receptor, scopolamine did not. It is therefore concluded that: (1) The generalization seen between clozapine, PNU-99194A and muscarinic antagonists may be mediated by common effects 'downstream' from either muscarinic or D3 receptors; (2) D3 antagonism does not play a critical role in the clozapine stimulus (since D3-preferring antagonists did not consistently induce generalization to clozapine); (3) although D3 antagonism plays a role in the PNU-91994A stimulus (since the D3-preferring antagonist (+)-UH 232 induced full generalization, in accord with results from prior studies with other D3-preferring antagonists, the PNU-99194A stimulus also has commonalities with that induced by muscarinic antagonists and clozapine. The in vivo differences observed between PNU-99194A and other D3-preferring antagonists should be borne in mind when this agent is used as a tool to study D3 receptor functioning in vivo. The similarities between the PNU-99194A and clozapine stimuli suggest tentatively that compounds with a profile like PNU-99194A may have antipsychotic actions similar to clozapine. Some preclinical data are suggestive of such effects of PNU-99194A.

Antagonism of the discriminative stimulus effects of (+)-7-OH-DPAT by remoxipride but not PNU-99194A.

The dopamine (DA) agonist 7-hydroxy-N,N-di-n-propyl-2-amino-tetralin (7-OH-DPAT) has been used extensively as a tool to investigate the role of DA D(3) receptors in the reinforcing and discriminative stimulus properties of psychostimulant drugs. The present study examined the relative importance of D(3) vs. D(2) receptor actions in the discriminative stimulus effects of (+)-7-OH-DPAT (0.03 mg/kg, sc) in 16 male Sprague-Dawley rats trained to discriminate this compound from saline in a two-lever, water-reinforced operant procedure under a FR 20 schedule. Stimulus generalization and antagonism tests were conducted with cocaine and with various selective D(2) and D(3) receptor ligands. In contrast to previous findings that (+)-7-OH-DPAT substitutes for cocaine, the present results demonstrated that cocaine does not produce stimulus generalization in animals trained to discriminate (+)-7-OH-DPAT. Although two D(3)-preferring agonists, PD-128907 and pramipexole, produced complete stimulus generalization to the training drug, two highly selective D(3) antagonists (PNU-99194A, PD 152255) failed to block the discriminative stimulus effects of (+)-7-OH-DPAT. However, the D(2) antagonist remoxipride (3.0 mg/kg) produced a rightward shift in the (+)-7-OH-DPAT dose-response curve. These findings suggest that D(2) receptors are critically involved in mediating the cue properties of (+)-7-OH-DPAT. However, alternative interpretations that PNU-99194A is not entirely D(3) receptor selective should also be considered.

A silica-based mitochondrial DNA extraction method applied to forensic hair shafts and teeth.

The purpose of this study is to evaluate the applicability of a nonorganic DNA extraction method for use in the analysis of environmentally compromised forensic hair shaft and tooth samples. The condition of the samples included cases of water decomposition, severe incineration, and varying stages of putrefaction. Enzymatic amplification and manual sequencing of the first segment of the mitochondrial hypervariable region were performed successfully on each of the 20 autopsied individuals. The results indicate that the silica-based extraction method produces mtDNA suitable for genetic identification from forensic samples including hair shafts and teeth.

A three-choice discrimination procedure dissociates the discriminative stimulus effects of d-amphetamine and (+/-)-MDMA in rats.

(+/-)-3,4-Methylenedioxymethamphetamine (MDMA) produces subjective effects in humans that are similar to, but distinguishable from, those of psychostimulants. Drug discrimination studies in nonhumans have yielded inconsistent results regarding the similarities between MDMA and the psychomotor stimulant d-amphetamine. This study successfully used a 3-choice operant procedure to establish MDMA and d-amphetamine as discriminative stimuli in rats. Cocaine produced complete substitution for d-amphetamine, and LSD produced dose-dependent increases in MDMA-appropriate responding with nearly complete substitution (78%) for MDMA. The hallucinogen 2,5-dimethoxy-4-bromoamphetamine only partially substituted for MDMA and severely disrupted response rate. Fenfluramine and both isomers of 3,4-methylenedioxyamphetamine (MDA) all produced complete substitution for MDMA. The serotonin-receptor antagonist pirenpirone only partially blocked MDMA discrimination.

MDMA and learning: effects of acute and neurotoxic exposure in the rat.

In two experiments, the effects of MDMA on the acquisition of lever-press responding of rats were examined under procedures in which water delivery was delayed by 0, 10, or 20 s relative to the response that produced it. In the first study, experimentally naive, water-deprived rats received an intraperitoneal injection of MDMA (0, 1.0, 3.2, or 5.6 mg/kg) prior to one 8-h experimental session. Response acquisition was observed under all conditions at all drug doses. MDMA increased the total number of responses emitted and the total number of water deliveries earned in dose-dependent fashion, but only when reinforcement was immediate. Under conditions of delay, MDMA had no effect on either measure. Under all reinforcement conditions, higher doses of MDMA typically produced an initial reduction in lever pressing, and in that sense interfered with learning. In the second study, rats received an MDMA injection regimen previously shown to be neurotoxic. Control rats received saline solution according to the same injection schedule. Two weeks after completing the regimen, rats were water deprived and exposed to behavioral procedures as described for the first experiment. Although MDMA significantly reduced 5-HT and 5-HIAA levels in the striatum and prefrontal cortex, mean performance of rats exposed to MDMA did not differ from that of rats exposed to vehicle. Twenty-five percent of the rats exposed to MDMA and delayed reinforcement did fail to acquire responding, which suggests that further study of the effects of neurotoxic doses of MDMA on initial response acquisition is warranted.

Analysis of D2 and D3 receptor-selective ligands in rats trained to discriminate cocaine from saline.

This study examined the role of dopamine D3 receptors in the stimulus generalization produced by 7-OH-DPAT and PD 128907 in rats trained to discriminate cocaine from saline. Twelve male Sprague-Dawley rats were trained to discriminate cocaine (10 mg/kg) from saline in a two-choice operant procedure using a FR20 schedule of water reinforcement. Stimulus generalization tests were administered with the D3-preferring agonists (+/-)-7-OH-DPAT (0.01-0.3 mg/kg), (+)-7-OH-DPAT (0.01-0.3 mg/kg), and PD 128907 (0.01-0.3 mg/kg), and the selective D2 agonist PNU-39156 (0.01-0.3 mg/kg). Complete generalization to cocaine was observed with (+/-)-7-OH-DPAT at doses that markedly suppressed response rate. Only partial stimulus generalization was observed with (+)-7-OH-DPAT and PD 128907 when these compounds were administered intraperitoneally, although subcutaneous injections of these compounds produced complete substitution. Response rate was also significantly reduced by these compounds. The selective D2 agonist, PNU-91356 also fully substituted for the cocaine cue and suppressed response rate in a dose-dependent manner. To ascertain the importance of D3 receptor actions in the stimulus generalization produced by (+/-)-7-OH-DPAT (0.1 mg/kg) and PD-128907 (0.3 mg/kg), the fairly selective D3 antagonist, PNU-99194A (2.5-20 mg/kg) was also tested in combination with these compounds. Although PNU-99194A partially attenuated the stimulus generalization produced by (+/-)-7-OH-DPAT, it failed to block PD-128907 substitution for cocaine. These results indicate at least some involvement of D3 receptors in the stimulus effects of (+/-)-7-OH-DPAT, although further investigations are clearly warranted. The present results also suggest that the cue properties of cocaine may be dissociated from the locomotor activating effects of this drug, because D3/D2 receptor agonists suppress locomotor activity but produce stimulus generalization to cocaine.

Assessment of D3 versus D2 receptor modulation of the discriminative stimulus effects of (+)-7-OH-DPAT in rats.

Although there are presently no highly selective agonists for the D3 dopamine receptor, a number of compounds reported to bind with moderate selectivity to D3 receptors are currently employed to investigate the importance of D3 receptors in the behavioral effects of psychostimulant drugs. For example, 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) has been used extensively to investigate the role of D3 receptors in the reinforcing and discriminative stimulus properties of cocaine and d-amphetamine. However, recent investigations with a relatively selective D3 antagonist, PNU-99194A, have led us to question the importance of D3 receptors in the discriminative stimulus effects of 7-OH-DPAT. In the present study, 16 male Sprague-Dawley rats were trained to discriminate (+)-7-OH-DPAT (0.03 mg/kg, subcutaneously (s.c.)) from saline in a two-choice operant procedure using a fixed-ratio 20 schedule of water reinforcement. Consistent with previous findings, PNU-99194A appeared to attenuate only partially (+)-7-OH-DPAT discrimination at a dose that disrupted responding in most subjects. Moreover, a highly selective D2 agonist, PNU-91356A, substituted completely and in a dose-dependent manner for (+)-7-OH-DPAT, while d-amphetamine produced only partial substitution for the training drug. These data indicate that D2 receptor actions appear to be more important than D3 receptor actions in exerting the discriminative stimulus effects of (+)-7-OH-DPAT. Continued efforts to determine the relative importance of D2 vs D3 receptor actions in the modulation of the discriminative stimulus effects of (+)-7-OH-DPAT are discussed.

Disruption of the discriminative stimulus effects of S(+)-3,4-methylenedioxymethamphetamine (MDMA) by (+/-)-MDMA neurotoxicity: protection by fluoxetine.

This study utilized drug discrimination procedures to assess the functional consequences of (+/-)-3,4-methylenedioxymethamphetamine (MDMA)-induced serotonin depletion, and to determine whether concomitant injections of fluoxetine averted these effects. Twelve male Sprague-Dawley rats were trained to discriminate S(+)-MDMA (1.5 mg/kg, s.c.) from saline in a two-lever, water-reinforced operant procedure. After dose generalization tests were completed, training was suspended, and subjects were administered saline injections twice daily for four days. Ten days later, tests were conducted with S(+)-MDMA (1.5 mg/kg) and saline, to ascertain that discriminative stimulus control was maintained in the absence of training over a two-week period. All subjects received two additional weeks of training. Subsequently, (+/-)-MDMA (20 mg/kg, s.c.) was administered twice daily for four days, concomitantly with either 5.0 mg/kg fluoxetine (FLX) or saline (SAL) injections, and stimulus generalization tests with S(+)-MDMA and SAL were conducted after ten days. In the rats administered (+/-)-MDMA + SAL injections, S(+)-MDMA-appropriate responding dropped from 99.24% to 44.99% during S(+)-MDMA generalization tests, and rose from 2.78% to 22.14% during SAL generalization tests. This disruption did not occur, however, in rats administered the combination of (+/-)-MDMA and FLX injections. Subsequent training reestablished discriminative stimulus control by S(+)-MDMA in the (+/-)-MDMA + SAL-treated rats. Postmortem neurochemical assays indicated that 5-HT levels were significantly reduced in the prefrontal cortices of rats given (+/-)-MDMA + SAL, compared to both drug-naive control rats and (+/-)-MDMA + FLX-treated rats. 5-HIAA levels were significantly lower in the prefrontal cortices of both (+/-)-MDMA + SAL-treated rats and (+/-)-MDMA + FLX-treated rats, relative to control. These results support previous findings that fluoxetine protects against (+/-)-MDMA-induced 5-HT depletion. Moreover, this study demonstrated that drug discrimination is a sensitive assay in which to examine behavioral correlates of (+/-)-MDMA-induced serotonergic deficits, and the protection against these deficits by fluoxetine.

The dopamine D3 receptor antagonist PNU-99194A fails to block (+)-7-OH-DPAT substitution for D-amphetamine or cocaine.

The present study examined the role of dopamine D3 receptor actions in the stimulus generalization produced by (+)-7-OH-DPAT in rats trained to discriminate either D-amphetamine or cocaine from saline. Twelve male Sprague-Dawley rats were trained to discriminate D-amphetamine (1.0 mg/kg) and 12 rats were trained to discriminate cocaine (5.0 mg/kg) from saline in a two-choice, water-reinforced operant procedure. Stimulus generalization tests were administered with the D3 receptor-preferring agonist, (+)-7-hydroxy-N, N-di-n-propyl-2-aminotetralin ((+)-7-OH-DPAT, 0.01-1.0 mg/kg) as well as the D3-preferring antagonist, 5,6-di-methoxy-2-(dipropylamino)indan-hydrochloride (PNU-99194A, 5-40 mg/kg). PNU-99194A (10-40 mg/kg) was also administered in combination with the training dose of D-amphetamine or cocaine to test for antagonism of each training drug cue. Finally, to assess the role of D3 receptor actions in the stimulus generalization produced by (+)-7-OH-DPAT (0.1 mg/kg), PNU-99194A (10, 20 mg/kg) was tested in combination with this compound in each training group. The results showed complete stimulus generalization with (+)-7-OH-DPAT in rats trained to discriminate D-amphetamine, although only partial stimulus generalization was observed with this compound in rats trained to discriminate cocaine. PNU-99194A produced partial substitution for both training drugs, and failed to block the discriminative stimulus effects of either D-amphetamine or cocaine. Moreover, this compound failed to block the stimulus generalization produced by (+)-7-OH-DPAT in rats trained to discriminate D-amphetamine. These results question the importance of D3 receptor actions in the discriminative stimulus effects of psychostimulants and their similarities to (+)-7-OH-DPAT.

Discriminative stimulus properties of the dopamine D3 antagonist PNU-99194A.

It was recently documented that the relatively selective dopamine D3 receptor antagonist, PNU-99194A, is capable of establishing discriminative stimulus control in rats and that the discriminative cue associated with this compound is not similar to that produced by psychostimulants. The present experiment further characterized the discriminative stimulus properties of PNU-99194A by examining several other dopaminergic agents for stimulus generalization in 23 male Sprague-Dawley rats trained to discriminate 10 mg/kg PNU-99194A (SC, 15 min) from vehicle in a two-choice discrimination procedure under an FR10 schedule of food reinforcement. Rats achieved a criterion of ten consecutive sessions with correct lever choice after a median of 35.5 sessions (range 23-78). In substitution tests, the non-selective D2 receptor antagonist, haloperidol (0.01- 0.1 mg/kg), and the mixed D2/D3 antagonists, amisulpiride (3.2-32 mg/kg) and sulpiride (32-200 mg/kg), failed to produce stimulus generalization, while the D3-preferring antagonists, (-)-DS121 (1-10 mg/kg) and (+)-AJ76 (3.2-32 mg/kg), produced complete stimulus generalization. Direct and indirect DA agonists, including apomorphine (0.01-0.32 mg/kg) and d-amphetamine (0.1-1 mg/kg), the D1 agonist SKF38393 (10-100 mg/kg), the D2 selective agonist PNU-95666E (0.32-3.2 mg/kg) and the D3-preferring agonist pramipexole (0.032-1 mg/kg), all produced non-significant amounts of drug-appropriate responding and significantly reduced response rate. It is concluded that PNU-99194A produces a distinctive subjective cue which is probably based on D3 receptor antagonism.

Time course analysis of the discriminative stimulus effects of the optical isomers of 3,4-methylenedioxymethamphetamine (MDMA).

The present study examined the discriminative stimulus effects of the MDMA optical isomers administered at different presession injection intervals. In the first experiment, male Sprague-Dawley rats were trained in a two-lever, food-reinforced operant procedure to discriminate either (+)-MDMA (1.25 mg/kg) or (-)-MDMA (3.50 mg kg) at either 20 or 90 min following injection. Animals administered (+)-MDMA or saline 90 min before training sessions failed to attain the discrimination criteria after 73 training sessions, whereas (-)-MDMA successfully established discriminative stimulus control at both the 20 min and the 90 min postinjection intervals. (+)-Amphetamine did not substitute for either isomer, although a significant amount of drug-appropriate responding occurred in animals trained to discriminate (+)-MDMA at 20 min and (-)-MDMA at 90 min. Sch 39166 partially reduced the discrimination of (+)-MDMA at 20 min and (-)-MDMA at 90 min, although this effect was not dose dependent. Sch 39166 had no effect on animals trained to discriminate (-)-MDMA at 20 min. Haloperidol did not alter the discrimination of (+)-MDMA at 20 min but partially reduced the discriminative stimulus control of (-)-MDMA at 20 min and (-)-MDMA at 90 min. Fenfluramine substituted for both isomers of MDMA. Pirenpirone completely blocked the discriminative stimulus effects of (-)-MDMA at 20 min, although (+)-MDMA at 20 min and (-)-MDMA at 90 min were only partly blocked. WAY 100,135 had little effect on drug-appropriate responding; however, the discrimination of (+)-MDMA at 20 min was partly reduced by this 5-HT1A antagonist. In a second experiment, rats trained to discriminate (+)-MDMA (1.5 mg/kg) or (-)-MDMA (3.0 mg/kg) from saline were administered substitution tests with both isomers 20, 60, 90 and 120 min after injection. Results confirmed those of the first experiment that (+)-MDMA appears to have a shorter duration of action than (-)-MDMA. These results are discussed in light of the training doses employed.

Assessment of the MDA and MDMA optical isomers in a stimulant-hallucinogen discrimination.

The phenylisopropylamine derivatives 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) have been compared to both psychostimulants and hallucinogens in drug discrimination investigations. The stereoisomers of these compounds, in particular those of MDA, appear to produce differential effects. Previous studies have demonstrated that animals trained to discriminate amphetamine from vehicle generalize to the S(+)-isomers but not the R(-)-isomers of MDA and MDMA while animals trained to discriminate LSD from saline generalize to R(-)-MDA and neither isomer of MDMA. However, animals trained to discriminate mescaline from vehicle generalize to both stereoisomers of these phenylisopropylamine derivatives. The present study consisted of two experiments in which a three-choice drug discrimination procedure was employed to compare the stereoisomers of MDA and MDMA to both amphetamine and either mescaline (experiment one) or LSD (experiment two). Sixteen male Sprague-Dawley rats were trained to discriminate S(+)-amphetamine (1.0 mg/kg) and mescaline (12.5 mg/kg) and eight rats were trained to discriminate S(+)-amphetamine (1.0 mg/kg) and LSD (0.08 mg/kg) from saline in three-choice, food reinforced drug discrimination procedures. Substitution tests were administered with the isomers of MDA and MDMA. In the second experiment, substitution tests were also administered with lower doses of each training compound and with the stimulant cocaine and the hallucinogen 2,5-dimethoxy-4-methylphenylisopropylamine (DOM). In both experiments, all of the isomers produced very few responses on the S(+)-amphetamine lever. In the first experiment, R(-)-MDA and R(-)-MDMA produced nearly complete substitution for mescaline. The results of the second experiment revealed partial substitution for LSD with both isomers of MDMA and S(+)-MDA, and nearly complete substitution with R(-)MDA for LSD. The present findings do not support previous reports that S(+)-MDMA and S(+)-MDMA substitute for S(+)-amphetamine. The three-lever drug discrimination procedure may provide a more sensitive behavioral assay in which to examine the discriminative stimulus effects of drugs with compound stimulus properties.

Assessment of the discriminative stimulus effects of the D3 dopamine antagonist PNU-99194A in rats: comparison with psychomotor stimulants.

The present study examined the discriminative stimulus effects of the D3 dopamine receptor antagonist PNU-99194A [5,6-di-methoxy-2-(dipropylamino)indan-hydrochloride] in male Sprague-Dawley rats. Eight rats were trained to discriminate cocaine (10 mg/kg, i.p.) from saline in a two-choice, water-reinforced drug discrimination procedure. In tests of stimulus generalization, PNU-99194A (1.25-40.0 mg/kg, s.c. and i.p.) did not substitute for cocaine. PNU-99194A (5.0-20 mg/kg) also did not significantly block the discrimination of cocaine (10 mg/kg), nor did it potentiate a low dose (1.25 mg/kg) of cocaine. A separate group of eight rats were trained to discriminate PNU-99194A from saline. These subjects met the discrimination criterion within an average of 68 (S.E.M. = 6.5) training sessions; the ED50 for PNU-99194A was 2.6 mg/kg. In stimulus generalization tests, cocaine (1.25-10 mg/kg) did not substitute for PNU-99194A, when administered by either i.p. or by s.c. injection. In addition, neither amphetamine (0.25-1.0 mg/kg) nor caffeine (8.0-64 mg/kg) produced stimulus generalization in these rats. These results indicate that D3 receptors do not play a critical role in the discriminative stimulus effects of cocaine. Furthermore, although PNU-99194A is capable of establishing and maintaining discriminative stimulus control in rats, the effects of this D3-preferring antagonist are dissimilar from those of psychomotor stimulants. Given the unique behavioral profile of D3 receptor antagonists, the potential utility of these agents as adjunctive treatments for psychostimulant abuse is discussed.

The application of differential outcomes to a cocaine--saline discrimination procedure.

This study examined the effects of differential outcomes on the speed of acquisition of a cocaine vs saline discrimination. Two groups of male Sprague-Dawley rats were trained to discriminate 8.0 mg/kg cocaine from saline. The experimental group was exposed to differential outcomes, where correct responses following the different injections (discriminative stimuli) were correlated with a particular outcome (either sweetened condensed milk or tap water). The control group received either sweetened condensed milk or tap water at random following cocaine and saline injections. Acquisition of schedule control and three progressively difficult testing criteria were examined. The differential outcomes group came under schedule control and reached the three progressively difficult testing criteria in significantly fewer sessions than the control group. To determine whether differential outcomes during training influenced the generalization to other doses of cocaine, substitution tests were administered with several other doses of cocaine (0.0-10.0 mg/kg) to both groups. Similar cocaine dose-response functions were observed with the differential outcome group and the control group and there was not a statistically significant effect of differential outcomes on the cocaine generalization curve.

Effects of (+)-fenfluramine on 3,4-methylenedioxymethamphetamine (MDMA) discrimination in rats.

This study examined the effects of a presumed neurotoxic dose regimen of (+)-fenfluramine on the discrimination of MDMA and (+)-amphetamine in male Sprague-Dawley rats trained to discriminate 1.5 mg/kg MDMA from saline in a two-choice operant task. Substitution tests were conducted with saline, several doses of MDMA (0.19-1.5 mg/kg), and (+)-amphetamine (0.125-1.0 mg/kg) prior to and again following the administration of (+)-fenfluramine (4.0 mg/kg twice a day for 4 days; n = 11) or a similar pattern of saline injections (n = 10). During pretreatment substitution tests, lower doses of MDMA elicited drug-appropriate responding in a dose-dependent manner, although none of these doses substituted for the training dose. Likewise, no dose of (+)-amphetamine substituted for the training drug during pretreatment substitution tests. The discrimination of MDMA was disrupted in some animals following (+)-fenfluramine treatment, but with subsequent training, discrimination criteria were met. In posttreatment substitution tests, the lowest dose of MDMA produced significantly higher drug-appropriate responding in (+)-fenfluramine treated animals but not in saline-treated animals. The amount of drug-appropriate responding during posttreatment substitution tests with (+)-amphetamine varied little from pretreatment substitution tests in saline-treated animals, but was greater at all doses in (+)-fenfluramine-treated animals; the highest dose of (+)-amphetamine substituted for MDMA subsequent to (+)-fenfluramine treatment. These results support previous findings that the long-lasting serotonergic effects of fenfluramine may have functional consequences that can be detected using a drug discrimination procedure. Specifically, serotonin depletion may unmask or strengthen the stimulant-like effects of MDMA.

Assessment of the discriminative stimulus effects of the optical isomers of ecstasy (3,4-methylenedioxymethamphetamine; MDMA).

The discriminative stimulus effects of the stereoisomers of 3,4-methylenedioxymethamphetamine (MDMA) were studied in rats trained to discriminate 1.25mg/kg of (+)-MDMA or 3.5mg/kg of (-)-MDMA from saline, in a two lever, water-reinforced, drug discrimination situation. The isomers of MDMA and 3,4-methylenedioxyamphetamine (MDA) substituted completely for both training drugs. The stimulants amphetamine and cocaine did not substitute for either MDMA isomer. The hallucinogens (+/-)-2,5-dimethoxy-4-methylamphetamine (DOM), (+)-lysergic acid diethylamide (LSD), and mescaline failed to substitute completely for (+)-MDMA. Similarly, DOM and mescaline did not substitute for (-)-MDMA; however, LSD did substitute for this isomer at a dose of 0.06mg/kg but not at higher doses. Substitution tests with 5-HT-releasing agents revealed that fenfluramine substituted partially for (+)-MDMA and completely for (-)-MDMA, while p-chloroamphetamine substituted completely for both isomers of MDMA. When given in combination with (+)-or (-)-MDMA, neither the 5-HT(2) antagonist pirenpirone nor the less selective 5-HT antagonist metergoline consistently blocked drug-appropriate responding. These results indicate that the stereoisomers of MDMA and MDA have similar discriminative stimulus properties. More importantly, the present findings suggest that 5-HT release may be important for the discriminative stimulus effects of (+)-and (-)-MDMA. Actions at 5-HT(2) receptors, however, do not appear to be critical.

Stroke volume measurement during supine and upright cycle exercise by impedance cardiography.

This study evaluated impedance cardiography (ZCG) estimates of stroke volume (SV) during exercise. Seven subjects were studied at rest and during progressive cycle exercise in supine and upright positions. SV was determined by ZCG (SVZCG) during exercise and for the first 5 cardiac cycles following exercise. SVZCG was compared with separate measurements of SV by CO2 rebreathing (SVCO2). Static blood resistivity (p) was measured at each level of exercise. No significant differences were found between supine exercise and immediate post-exercise values for the peak of the first derivative of the impedance change (dZ/dtmax), left ventricular ejection time (LVET), or SVZCG. Small differences in dZ/dtmax and SVZCG, but not LVET, were found in exercise to post-exercise cycling in the upright position. Intra-individual SVZCG and SVCO2 were moderately correlated (upright mean r = 0.64, supine r = 0.42) from rest to 70% of peak VO2. Similar correlations were found between Pulse-O2 (VO2/heart rate, used as an index to SV) and both SVZCG (upright r = 0.73, supine r = 0.57) and SVCO2 (upright r = 0.8, supine r = 0.65). The ZCG parameters dZ/dtmax and LVET correlated better with Pulse-O2 (dZ/dtmax: upright r = 0.92, supine r = 0.73; LVET: upright r = -0.9, supine r = -0.9). SVZCG calculated with the Kubicek equation performed as well as SVCO2. ZCG might be a superior method if the inversely correlated parameters, dZ/dtmax and LVET, were not expressed as a product to calculate SV.