Effects of anti-phencyclidine and anti-(+)-methamphetamine monoclonal antibodies alone and in combination on the discrimination of phencyclidine and (+)-methamphetamine by pigeons.

RATIONALE: Drug-specific monoclonal antibodies against phencyclidine (PCP) and (+)-methamphetamine [(+)-METH] should bind to these drugs to block their discriminative stimulus effects. OBJECTIVES: To determine if mouse monoclonal antibodies against PCP and (+)-METH can block the discriminative stimulus effects of the drugs in pigeons. MATERIALS AND METHODS: Pigeons were trained to discriminate among intramuscular injections of saline, 1 mg/kg PCP, and 2 mg/kg (+)-METH. After responding stabilized, cumulative dose-response curves were obtained for PCP and (+)-METH. Doses of an anti-PCP antibody at 620 mg/kg (anti-PCP mAb6B5) with a K (D) of 1.3 nM for PCP and no measurable affinity for (+)-METH and 1,000 mg/kg doses of anti-(+)-METH antibody (anti-METH mAb6H7) with a K (D) of 41 nM for (+)-METH and no measurable affinity for PCP were subsequently administered, first alone and later in combination after which the dose-response curves were redetermined. RESULTS: When the antibodies were given alone, the anti-PCP antibody blocked the discriminative stimulus effects of PCP, but not those of (+)-METH, and the anti-(+)-METH antibody blocked the discriminative stimulus effects of (+)-METH, but not those of PCP. The anti-PCP antibody shifted the PCP dose-response curve further to the right and for a longer time than the anti-(+)-METH antibody shifted the dose response curve for (+)-METH. When the anti-PCP and anti-(+)-METH antibodies were administered on the same day, the discriminative stimulus effects of both drugs were completely blocked 1 day after antibody administration. CONCLUSIONS: These experiments demonstrate the high specificity of the antibodies for the drugs to which they bind and show that monoclonal antibodies can be combined to antagonize the effects of more than one drug.

Effects of murine-derived anti-methamphetamine monoclonal antibodies on (+)-methamphetamine self-administration in the rat.

Two murine-derived anti-methamphetamine monoclonal antibodies were studied as potential pharmacokinetic antagonists of (+)-methamphetamine self-administration by rats. Intravenous administration of a 1 g/kg dose of the lower affinity [antibody equilibrium dissociation constant (K(d)) = 250 nM] monoclonal antibody (mAb) designated mAb6H8, 1 day before the start of several daily 2-h self-administration sessions produced effects that depended on the dose of (+)-methamphetamine. mAb6H8 increased the rate of self-administration of a unit dose of 0.06 mg/kg (+)-methamphetamine, had little effect on the rate of self-administration of a unit dose of 0.03 mg/kg (+)methamphetamine, and lowered the rate of self-administration of a unit dose of 0.01 mg/kg (+)-methamphetamine to a level similar to that after saline substitution. mAb-induced changes in rates of self-administration occurred very early in self-administration sessions and lasted for 3 to 7 days. Intravenous administration of a 1 or a 0.6 g/kg dose of a higher affinity (K(d) = 11 nM) mAb designated mAb6H4, 24 h before the first of several self-administration sessions, produced very similar effects to the lower affinity mAb, despite the more than 20-fold greater affinity for (+)-methamphetamine. It is proposed that these anti-methamphetamine antibodies bind some of the self-administered (+)-methamphetamine before it can penetrate into brain, thereby reducing the amount of free drug available to function as a reinforcer. Although neither of these mAb medications are optimal antibodies for treating (+)-methamphetamine abuse, the experiments demonstrate that anti-(+)-methamphetamine monoclonal antibodies can attenuate the self-administration of the drug and suggest the potential of using monoclonal antibodies as pharmacokinetic antagonists of (+)-methamphetamine.

Pharmacokinetic antagonism of (+)-methamphetamine discrimination by a low-affinity monoclonal anti-methamphetamine antibody.

Animals were trained to discriminate 5 or 10 mg/kg cocaine (rats), or 3 mg/kg (+)-amphetamine (pigeons) from saline, after which dose-response curves were determined for (+)-methamphetamine and other drugs before and after administration of a (+)-methamphetamine-specific monoclonal antibody (K(D) =250 nM). In rats trained to discriminate 10 mg/kg cocaine from saline, intravenous (+)-methamphetamine was about three times more potent as a discriminative stimulus than intraperitoneal (+)-methamphetamine. Also in these rats, intraperitoneal (+)-methamphetamine and (+)-amphetamine were about equipotent as discriminative stimuli, and were about three times more potent than intraperitoneal cocaine. In pigeons trained to discriminate 3 mg/kg intramuscular (i.m.) (+)-amphetamine from saline, (+)-methamphetamine and (+)-amphetamine were nearly equipotent, while cocaine was slightly less potent. In rats trained to discriminate 5 or 10 mg/kg cocaine from saline, intravenous administration of 1 g/kg of the antibody shifted both intravenous and intraperitoneal dose-response curves for (+)-methamphetamine discrimination approximately threefold to the right at 1 or 4 days after administration of the antibody. In pigeons trained to discriminate 3 mg/kg intramuscular (+)-amphetamine from saline, a similar shift of the (+)-methamphetamine dose-response curve to the right also lasted for 4-7 days. However, the antibody did not affect the (+)-amphetamine dose-response curve (pigeons), or the cocaine (rats) dose-response curve. The data show that a low affinity anti-(+)-methamphetamine-specific antibody can produce a specific antagonism of an effect of (+)-methamphetamine that is closely associated with its abuse.

Drug discrimination under concurrent variable-ratio variable-ratio schedules.

Pigeons were trained to discriminate 5 mg/kg pentobarbital from saline under concurrent variable-ratio (VR) VR schedules, in which responses on the pentobarbital-biased lever were reinforced under the VR schedule with the smaller response requirements when pentobarbital was given before the session, and responses on the saline-biased key were reinforced under the VR schedule with the larger response requirements. When saline was administered before the session, the reinforcement contingencies associated with the two response keys were reversed. When responding stabilized under concurrent VR 20 VR 30, concurrent VR 10 VR 40, or concurrent VR 5 VR 50 schedules, pigeons responded almost exclusively on the key on which fewer responses were required to produce the reinforcer. When other doses of pentobarbital and other drugs were substituted for the training dose, low doses of all drugs produced responding on the saline-biased key. Higher doses of pentobarbital and chlordiazepoxide produced responding only on the pentobarbital-biased key, whereas higher doses of ethanol and phencyclidine produced responding only on this key less often. d-Amphetamine produced responding primarily on the saline-biased key. When drugs generalized to pentobarbital, the shape of the generalization curve under concurrent VR VR schedules was more often graded than quantal in shape. Thus, drug discrimination can be established under concurrent VR VR schedules, but the shapes of drug-discrimination dose-response curves under concurrent VR VR schedules more closely resemble those seen under interval schedules than those seen under fixed-ratio schedules. Graded dose-response curves under concurrent VR VR schedules may relate to probability matching and difficulty in discriminating differences in reinforcement frequency.

Discrimination of pentobarbital doses and drug mixtures under fixed-ratio and fixed-interval reinforcement schedules.

Pigeons were trained to discriminate among 5 mg/kg pentobarbital, 10mg/kg pentobarbital, and saline, under either fixed-interval (FI) or fixed-ratio (FR) reinforcement schedules. When baseline responding stabilized, a higher percentage of responses occurred on the key that produced the reinforcer under the FR schedule than under the FI schedule. After low doses of pentobarbital, responding shifted from the saline key to the 5 mg/kg pentobarbital key; at higher doses of pentobarbital responding shifted to the 10mg/kg pentobarbital key under both schedules. After low doses of ethanol and chlordiazepoxide, responding shifted from the saline key to the 5 mg/kg pentobarbital key, but after high doses of these drugs, responding continued to occur on the 5 mg/kg pentobarbital key under both reinforcement schedules. A 5 mg/kg dose of pentobarbital increased responding on the 10 mg/kg pentobarbital key when it was combined with pentobarbital, ethanol or chlordiazepoxide. Phencyclidine and D-amphetamine produced responding largely on the saline key under both reinforcement schedules. Under the FR schedule, pentobarbital dose-response curves were usually quantal, whereas under the FI schedule the pentobarbital dose-response curves usually were graded.

Schedule control of quantal and graded dose-effect curves in a drug-drug-saline discrimination.

Pigeons were trained to discriminate among 5 mg/kg pentobarbital, 5 mg/kg morphine, and saline when responding was maintained under fixed-interval (FI) or fixed-ratio (FR) reinforcement schedules. After the discrimination was established, other drugs were substituted for the training drugs. After low doses of pentobarbital and chlordiazepoxide, responding shifted from the saline key to the pentobarbital key under both FR and FI schedules. After low doses of morphine and methadone, responding shifted from the saline key to the morphine key under both reinforcement schedules. After all doses of d-amphetamine, responding occurred largely on the saline key under both schedules. Responding also was confined largely to the saline key after phencyclidine administration under the FR schedule, but under the FI schedule, responding shifted from the saline key to the pentobarbital key at high doses of phencyclidine. When responding was maintained under the FR schedule, the dose-response curves for drugs that generalized to the training drugs were quantal in shape, while under the FI schedule, the dose-response curves for drugs that generalized to the training drugs were graded. These data extend observations that FR schedules generate quantal dose-response curves, and FI schedules generate graded dose-response curves to complex three-key drug discriminations.

Drug discrimination in rats under concurrent variable-interval variable-interval schedules.

Eight rats were trained to discriminate pentobarbital from saline under a concurrent variable-interval (VI) VI schedule, on which responses on the pentobarbital-biased lever after pentobarbital were reinforced under VI 20 s and responses on the saline-biased lever were reinforced under VI 80 s. After saline, the reinforcement contingencies programmed on the two levers were reversed. The rats made 62.3% of their responses on the pentobarbital-biased lever after pentobarbital and 72.2% on the saline-biased lever after saline, both of which are lower than predicted by the matching law. When the schedule was changed to concurrent VI 50 s VI 50 s for test sessions with saline and the training dose of pentobarbital, responding on the pentobarbital-biased lever after the training dose of pentobarbital and on the saline-biased lever after saline became nearly equal, even during the first 2 min of the session, suggesting that the presence or absence of the training drug was exerting minimal control over responding and making the determination of dose-effect relations of drugs difficult to interpret. When the pentobarbital dose-response curve was determined under the concurrent VI 50-s VI 50-s schedule, responding was fairly evenly distributed on both levers for most rats. Therefore, 6 additional rats were trained to respond under a concurrent VI 60-s VI 240-s schedule. Under this schedule, the rats made 62.6% of their responses on the pentobarbital-biased lever after pentobarbital and 73.5% of their responses on the saline-biased lever after saline, which also is lower than the percentages predicted by perfect matching. When the schedule was changed to a concurrent VI 150-s VI 150-s schedule for 5-min test sessions with additional drugs, the presence or absence of pentobarbital continued to control responding in most rats, and it was possible to generate graded dose-response curves for pentobarbital and other drugs using the data from these 5-min sessions. The dose-response curves generated under these conditions were similar to the dose-response curves generated using other reinforcement schedules and other species.

Effect of drugs on response-duration differentiation VII: response-force requirements.

Rats were trained to press a lever for at least 1 s but for less than 1.3 s. The force required to press the lever was then increased or decreased by 10, 15, or 20 g. Increases in the force requirements for lever pressing decreased timing accuracy, but decreases in the force requirement had the opposite effect. Accuracy decreases at increasing force requirements were characterized by an increase in the relative frequency of responses that were too short to meet the reinforcement criterion. In contrast, increases in accuracy when the force requirements were decreased were characterized by increases in response durations that met the reinforcement criterion and decreases in the relative frequency of responses that were too short to produce the reinforcer. Phencyclidine (PCP) and methamphetamine produced dose-dependent decreases in accuracy that were associated primarily with increases in the relative frequency of short response durations, although methamphetamine also produced increases in long response durations at some doses. When the effects of PCP were determined with the force requirement increased by 10 g or decreased by 15 g, the cumulative response-duration distribution shifted toward even shorter response durations. When the effects of methamphetamine were determined with the force requirement on the lever increased by 10 g, the cumulative frequency distribution was shifted toward shorter response durations to about the same extent as it had been before force requirements increased; however, when the force required to press the lever was decreased by 15 g, these shifts toward shorter response durations almost completely disappeared. These results show that increases and decreases in the force requirements for lever pressing have different effects on the accuracy of temporal response differentiation.

Drug discrimination under a concurrent fixed-interval fixed-interval schedule.

Pigeons were trained to discriminate 5.0 mg/kg pentobarbital from saline under a concurrent fixed-interval (FI) FI schedule of food presentation on which, after pentobarbital administration, responses on one key were reinforced with food under an FI 60-s component and responses on the other key were reinforced under an FI 240-s component. After saline administration, the schedule contingencies on the two keys were reversed. After both pentobarbital and saline, pigeons responded more frequently on the key on which responses had been programmed to produce the reinforcer under the FI 60 component of the concurrent schedule. The schedule was changed to concurrent FI 150 FI 150 s for drug-substitution tests. In each bird, increasing doses of pentobarbital, ethanol, and chlordiazepoxide produced increases in the proportion of responses on the key on which responses had been reinforced under the FI 60 component after pentobarbital administration during training sessions. The proportion of responses on that key was slightly lower for ethanol than for chlordiazepoxide and pentobarbital. At a dose of pentobarbital higher than the training dose, responding decreased on the key that had been reinforced under the FI 60 component during training sessions. Phencyclidine produced less responding on the key programmed under the FI 60-s component than did pentobarbital. Methamphetamine produced responding primarily on the key on which responses had been reinforced under the FI 60-s component after saline administration.

Discriminative stimulus effects and antipunishment effects of drugs measured during the same session.

The effects of pentobarbital, diazepam, phencyclidine, buspirone and methamphetamine on drug discrimination and on responding under a variable-interval variable-interval with punishment schedule were studied in pigeons trained to discriminate 5.0 mg/kg pentobarbital from saline. Pentobarbital produced dose-dependent increases in the proportion of responses on the drug key and on rates of punished responding. Diazepam had very similar effects except that the dose-effect curve for punished responding turned over at the highest dose level. Phencyclidine produced only partial responding on the drug key and weakly increased punished responding. Buspirone produced small increases in punished responding, but in the drug discrimination experiments buspirone did not cause responding on the drug key. Methamphetamine did not produce responding on the drug key, nor did it increase rates of punished responding. These experiments are among the first to demonstrate that drug discrimination and other behaviors can be studied within single test sessions in the same animals and they suggest that there is a close correspondence between the discriminative stimulus effects of some drugs and their anti-punishment activity.

Effects of drug discrimination history on the generalization of pentobarbital to other drugs.

In pigeons trained to discriminate between pentobarbital and saline, pentobarbital, amobarbital and diazepam substituted for pentobarbital, whereas phencyclidine (PCP) substituted in part for pentobarbital and d-amphetamine, morphine and drug vehicles did not substitute. After morphine replaced pentobarbital as the training drug (group A), morphine, pentobarbital and diazepam substituted, PCP substituted in part, but not d-amphetamine, haloperidol and vehicles. After d-amphetamine replaced pentobarbital as the training drug (group B), d-amphetamine, pentobarbital and diazepam substituted, PCP substituted in part, but not haloperidol, morphine and vehicles. Next, morphine and d-amphetamine were reversed as training drugs for the two groups. In group A, morphine, d-amphetamine, pentobarbital and diazepam substituted, PCP substituted in part, but not haloperidol and vehicles. Similar effects were observed in group B. Next, birds in group A were reinforced for responses on the drug key (red key) after d-amphetamine and on the previous saline key (green key) after pentobarbital. In group B, morphine continued as the training drug for the red key, whereas responses on the green key were reinforced after pentobarbital. In group A, d-amphetamine, morphine, d-pentazocine and to some extent PCP, produced responding on the red key, whereas pentobarbital, diazepam, haloperidol and the vehicles produced responding on the green key. Similar results were obtained in group B. Finally, responses were reinforced on the green key after pentobarbital and on the red key after saline. Group B did not learn this discrimination. In group A, responding occurred on the red key after d-amphetamine, morphine, haloperidol and vehicles, in part after d-pentazocine, but not after pentobarbital, diazepam and PCP. These experiments show that drug stimuli can continue to exert stimulus control over behavior for long periods, even when training with several other drug stimuli intervenes between tests, and the experiments also show that through sequential training procedures multiple drugs can serve as discriminative stimuli for the same response, even when these drugs are from different phamacological classes.

Pentobarbital discrimination and generalization to other drugs under multiple fixed-ratio fixed-interval schedules.

Pigeons were trained to discriminate 5mg/kg pentobarbital from saline under several multiple fixed-ratio fixed-interval schedules of food presentation. The following schedules were studied: multiple fixed-ratio 40 fixed-interval 18s (mult FR40 FI18), mult FR10 FI18s, mult FR10 FI180s and mult FR90 FI10s. After responding stabilized under each multiple schedule, generalization curves were determined for pentobarbital, amobarbital, diazepam, phencyclidine and d-amphetamine. Pentobarbital generated dose-dependent increases in responding under all schedule components; however, there was more responding on the drug key after low doses of pentobarbital under FI components than under FR components, except for the FR90 component of the mult FR90 FI10 schedule. This tendency for more responding on the drug key after low doses of pentobarbital under FI components than under FR components generally was observed for low doses of all of the drugs. Examination of data from individual subjects revealed that there was a greater tendency for birds to distribute responding on both keys (mixed responding) under FI components than under FR components, where responding after each dose was confined largely to one of the two response keys. Analysis of local rates of responding within the FI component of the schedules showed that responding under the FI components developed the typical FI scallop at all FI-component durations. These data suggest that FI schedules with values between 10 and 180s generate similar dose-effect curves with higher rates of responding on the drug key after low doses of drugs than under FR schedules with low response requirements; however, under schedules with higher FR requirements, the dose-effect curves for some drugs begin to look more like those under FI schedules.

Effects of access to a running wheel on food, water and ethanol intake in rats bred to accept ethanol.

Rats from the University of Indiana lines bred to accept ethanol (P rats) and not to accept ethanol (NP rats) were divided into two groups of 3 rats per group. The first group of P and NP rats was given free access to food, water and 5% (w/v) ethanol 24 h a day. After food, water and ethanol intake stabilized, a running wheel was introduced into the cage. Access to the running wheel decreased ethanol intake and increased water intake in P rats. When the running wheel was locked in place, ethanol intake by P rats increased, but when the wheel was unlocked again, no decrease in ethanol intake occurred. Access to the running wheel did not affect food, water or ethanol intake in NP rats. The decrease in ethanol intake when the running wheel was introduced was replicated in the second group of P rats exposed to 5% ethanol and later to 10% ethanol. The decreases in ethanol consumption produced by the introduction of a running wheel for this genetic model of alcohol consumption are similar to those previously reported using schedule-induced polydipsia to induce ethanol intake.

Effects of drugs on response duration differentiation. III. Acute variation of reinforced duration.

Rats trained to hold a lever down for at least 1.0 s but less than 1.3 s could differentiate the reinforced response duration on about 50% of the trials. The response duration frequency distribution was a normal distribution with a peak near the minimum reinforced response duration. Dose-effect curves were determined for the effects of phencyclidine (PCP) and methamphetamine. Subsequently, rats continued to be trained for 3 days a week with responses between 1.0 and 1.3 s reinforced, but on days when injections were given either the maximum reinforced duration was increased to 2.3 s, or the minimum reinforced duration was lowered to 0.5. When the maximum duration was increased to 2.3 s, the percentage of reinforced responses increased to 60% and when the minimum reinforced duration was decreased to 0.5 s, the percentage of reinforced responses increased to 89%. Despite the increased percentage of reinforced responses when the time window was widened, the effects of PCP and methamphetamine were not changed. These data suggest that the effects of drugs on response duration differentiation are not greatly influenced by transient changes in reinforcement frequency.

Attempts to establish phencyclidine and cocaine discrimination without error.

An attempt was made to train pigeons to discriminate phencyclidine (PCP) from saline using a three-key color-tracking procedure under which birds were trained under a second order schedule [FR10 (FR5)] "without errors." Training without errors was done by not lighting the side key on which responses were not reinforced during the early phases of discrimination training and then gradually increasing the light intensity on that key. Initially, this procedure prevented drug discrimination errors, but as the light intensity increased on the incorrect side key, errors began to appear and then surpassed the error rate of birds trained "with errors." When stimulus control stabilized, there were no differences in stimulus control by the phencyclidine stimulus as a function of the training procedure, as measured by error rates. Birds trained to discriminate PCP from saline with and without errors also showed no differences in the shape of the PCP stimulus generalization curve. A second attempt at training without errors under a second-order schedule was made in a second group of pigeons, using cocaine as the training drug and eliminating the use of the color-tracking procedure. The results were very similar to those with PCP. Few errors occurred in birds trained "without errors" until the incorrect key-light intensity was increased, at which time large numbers of errors began to occur, but ultimately differences in stimulus control as a function of the training procedure disappeared. There was no difference between birds trained with and without errors in the shape of the cocaine stimulus generalization curve. The pigeons trained to discriminate cocaine from saline under a second order FR 10 (FR 5) schedule showed complete generalization to d-amphetamine and partial generalization to phencyclidine and chlorpromazine. Because baseline stimulus control was deteriorating, the schedule was changed to a second order FR 4 (FR 25) and stimulus control by cocaine was reestablished. Under this schedule, partial generalization was observed from cocaine to pentobarbital and chlorpromazine before baseline stimulus control weakened again. Both the broad generalization of the cocaine stimulus and the difficulty in maintaining stimulus control with cocaine have been observed by others; such data suggest that under some conditions the cocaine stimulus may lack specificity.

Effects of drugs that bind to PCP and sigma receptors on punished responding.

Several arylcyclohexylamines and opioid benzomorphans that bind to phencyclidine (PCP) receptors were studied for their effects on punished and unpunished responding maintained under fixed-interval schedules of food presentation. All of these drugs increased both punished and unpunished responding, although higher doses decreased responding. The order of potency for increasing punished responding was MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzoa(a,d)-cyclohepten-5,1 0-imine] greater than [1-[1-(2-thienyl)cyclohexyl]piperidine] = PCP greater than (+)-N-allylnormetazocine = (-)-N-allynormetazocine. There was a high correlation (0.95) between the relative potency of these drugs in increasing punished responding and their relative affinity for PCP receptors. Because some of these drugs also bind to sigma receptors, drugs with a high affinity for sigma receptors, such as haloperidol, BD 737 [1S,2R-(-)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-N- methyl-2-(1-pyrrolidinyl) cyclohexylamine] and (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine, were also studied for their effects on punished and unpunished responding. These drugs produced only rate-decreasing effects. The correlation between the relative potency of drugs in increasing punished responding and their relative affinity for sigma receptors was low (-0.19). These data suggest that the PCP receptor is involved in some drug-induced increases in punished responding.

Phencyclidine pharmacokinetics and concentration-response relationships in the pigeon.

Phencyclidine (PCP) pharmacokinetics and drug discrimination were examined in pigeons (n = 6 in both groups) after intramuscular doses of 1.48 mg/kg. PCP absorption was rapid with maximum measured plasma concentrations ranging from 559 to 1450 ng/ml at 10-30 min after dosing, which corresponded to the time of maximum PCP stimulus effects in the drug discrimination studies. The terminal elimination half-life was 0.88 hr (harmonic mean). Average values for the volume of distribution and total body clearance were 1.6 l/kg and 18.2 ml/min/kg, respectively. In the behavioral studies, pigeons discriminated PCP-like effects from about 2 min to 2 hr after dosing. An average value for response on the PCP-appropriate key and for PCP concentration at each time point from 2 min to 2 hr was calculated from the individual subject data. Least-squares linear regression analysis of these data showed a highly significant relationship between the ability to discriminate PCP and log PCP concentration (y = 103x - 219, r2 = .810, p less than 0.005). This analysis suggests PCP concentration is a good predictor of behavioral efficacy.

Phencyclidine pharmacokinetic scaling among species.

Interspecies pharmacokinetic parameters (y) for phencyclidine [1-(1-phenylcyclohexyl)piperidine] were correlated with body weight (B) using linear regression and the allometric equation of the form y = aBx (which also may be written as the linear regression equation, log y = x log B + log a). The data were obtained from previously reported pharmacokinetic studies in mammals (i.e., humans, monkey, dog, rat and mouse) and new pharmacokinetic data for the pigeon. The animal body weights ranged from 32.5 to 77,000 g and included 6 animal species from 2 vertebrate classes. The pharmacokinetic parameters correlated with body weight were T1/2 (T1/2 = 126B0.32, r2 = 0.799), volume of distribution (V beta = 10B0.96, r2 = 0.966) and systemic clearance (CLs = 50B0.64, r2 = 0.891). In addition, clearance values were multiplied by the maximum lifespan potential (MLP) of each animal and correlated with body weight [CLs X MLP = (3.3 X 10(5))B1.0, r2 = 0.991]. This helped normalize for species differences in systemic clearance, which correlated with species longevity. These allometric equations should provide the information for scaling phencyclidine pharmacokinetic data among diverse species.

Relationship of plasma phencyclidine levels to phencyclidine discrimination in the pigeon.

Plasma phencyclidine levels were determined in pigeons trained to discriminate 1.5 mg/kg phencyclidine from saline under a second-order schedule using a color-tracking procedure. With both cumulative and non-cumulative dosing procedures, pigeons reliably discriminated plasma phencyclidine levels above 200 ng/ml. When the time course of phencyclidine discrimination was determined and compared with the time course of phencyclidine levels in plasma in a different group of birds, a similar relationship between discrimination and plasma phencyclidine was generally observed. Plasma phencyclidine levels did not correlate well with position responding observed in some birds after lower phencyclidine doses.

The effects of triethyltin and trimethyltin in rats responding under a DRL schedule of reinforcement.

Rats were trained to respond under a schedule of reinforcement in which only those responses separated by a 10-to 14-sec period of no responding produced a feed pellet (DRL 10 to 14 sec). Each rat received a single dose of trimethyltin (TMT) (5.6, 7.5, or 10 mg/kg) or triethyltin (TET) 1, 3, 4.25, or 5.6 mg/kg). The lowest dose of TMT (5.6 mg/kg) and the lowest dose of TET (1 mg/kg) were without significant effect. At 7.5 mg/kg and 10 mg/kg TMT, the percentage of the total responses spaced 10 to 14 sec apart decreased over the first 8 to 12 days after TMT. Those rats receiving 7.5 mg/kg TMT gradually returned to control values over the next 2 to 3 weeks while those rats receiving 10 mg/kg never recovered. Rats receiving 3, 4.25, and 5.6 mg/kg TET showed a decrease in the percentage of reinforced responses immediately after receiving TET. The behavior of those rats receiving 3 mg/kg returned to control values in 24 hr. Following 4.25 mg/kg TET, the health of the rats deteriorated rapidly. They were kept alive through heroic measures, but then were killed after testing on the 12th day following TET due to their failing health. At 5.6 mg/kg, the rats were killed on the 4th day due to failing health. These results indicate that TMT and TET differ with respect to potency and time course. The behavioral deficits produced by TET parallel the time course of general toxicity while the behavioral effects of acute TMT administration can persist in time long after the general appearance of the rats has returned to normal.