Development Of Acute Tolerance Research Articles

Differential development of acute tolerance to analgesia, respiratory depression, gastrointestinal transit and hormone release in a morphine infusion model

To determine whether the differences in development of acute tolerance to several morphine actions correlate with the mu receptor subtype mediating them, we have examined the appearance of acute tolerance to analgesia, respiratory depression, gastrointestinal transit, and hormone release in an intravenous morphine infusion model. Analgesia, a naloxonazine-sensitive mu1 action, peaked at 2 hr after initiation of the infusions. The log dose-response relationship of the infusion rate to peak tailflick latency was linear from 10 to 50 micrograms/kg/min. By 8 hr, the tailflick latencies declined nearly to baseline levels, implying the rapid development of tolerance. Tolerance to morphine-induced prolactin release, another mu1 action, also developed rapidly over 8 hr. In contrast two mu2 actions, respiratory depression measured with arterial blood gas, determinations and gastrointestinal transit, showed no significant tolerance over a similar 8 hr infusion. We also observed no tolerance to morphine-induced growth hormone release, a non-mu1 action, over the same period. Thus, these results demonstrate that mu1 actions develop tolerance in an infusion model far more rapidly than a number of naloxonazine-insensitive (non-mu1) ones and may help explain differences in the rate of tolerance development to morphine actions.

Effect of raphe lesions on the development of acute tolerance to ethanol and pentobarbital.

The effect of electrolytic lesions in the median and dorsal raphe nuclei was tested on acute tolerance development to ethanol and pentobarbital in the rat, as measured by motor impairment on the moving belt test. Acute tolerance to ethanol (1.7 g/kg, IP) or pentobarbital (17.5 mg/kg, IP) was monitored at 12.5, 25, or 50 min in separate subgroups tested only once each. One week of recovery was allowed between ethanol and pentobarbital tests. Median raphe lesions delayed the development of acute tolerance, whereas dorsal raphe lesions produced a negligible effect. These results were seen with both ethanol and pentobarbital. The mesolimbic 5-HT pathway from the median raphe nucleus is important in the development of acute tolerance to ethanol and pentobarbital, as was shown to be the case previously for chronic tolerance.

Endogenous oxytocin inhibits morphine tolerance through limbic forebrain oxytocin receptors

It has previously been shown that endogenous oxytocin (OXT) inhibits the development of acute morphine tolerance. The role of OXT receptors in the central nervous system (CNS) was therefore studied by using a specific OXT receptor antagonist, N-acetyl-(2- O-methyltyrosin)-OXT (ACME-OXT). ACME-OXT (1 pg) was injected into the posterior olfactory nucleus, central amygdaloid nucleus, ventral hippocampus, caudate nucleus or lateral cerebral ventricle. The antagonist facilitated the development of tolerance to morphine when injected into the posterior olfactory nucleus, central amygdaloid nucleus or ventral hippocampal areas, which are known to contain OXT binding sites. When administered into the caudate nucleus (with no OXT binding sites) or the lateral cerebral ventricle, it had no effect on morphine tolerance. Our results suggest that the limbic forebrain OXT receptors play an important inhibitory role in adaptive responses to morphine.

Effects of intraperitoneal administration of apomorphine and the isomers of 3-(1-propyl-3-piperidinyl)phenol on the firing activity of substantia nigra dopamine neurons: comparison of agonist efficacies and development of acute tolerance

The effects of intraperitoneal administration of apomorphine, ( + )-3-PPP, and (−)-3-PPP on slow-(<4 spikes/sec) and fast-(>4 spikes/sec) firing dopaminergic neurons in the substantia nigra zona compacta of rats anesthetized with chloral hydrate were assessed. All compounds completely inhibited slow-firing dopaminergic neurons. When a dose-response was determined by administering each dose in a single bolus injection, apomorphine and ( + )-3-PPP produced dose-related inhibitions of fast-firing dopaminergic neurons, with the largest dose of each compound completely inhibiting nearly all cells tested. In contrast, (−)-3-PPP only partially inhibited (50%) fast-firing dopaminergic neurons. Thus, on fast-firing neurons, (−)-3-PPP had the profile of a partial agonist, while apomorphine and ( + )-3-PPP demonstrated greater efficacy than (−)-3-PPP. Pretreatment while doses of apomorphine, ( + )-3-PPP, or (−)-3-PPP that partially inhibited the activity of dopaminergic neurons antagonized the complete inhibitory effects of a dose of apomorphine that normally produced complete inhibition of neuronal firing. In addition, pretreatment with doses of ( + )-3-PPP that partially inhibited the activity of cells antagonized the complete inhibitory effects of a dose of ( + )-3-PPP that, normally produced complete inhibition of neuronal firing. From the antagonism studies alone, it was not clear if tachyphylaxis or partial agonist activity accounted for the observed antagonisms. However, since apomorphine and ( + )-3-PPP completely inhibited the activity of fast-firing DA neurons, it is proposed that they antagonize by inducing a doseand time-dependent tachyphylaxis. In contrast, (−)-3-PPP is proposed to antagonize by virtue of its partial agonist activity.

Acute tolerance to and distribution of hexobarbital in relation to depth and duration of anaesthesia in rats.

The development of acute tolerance to hexobarbital was investigated with an EEG-threshold method in rats. Hexobarbital was infused in a tail vein and the effect was monitored either by continuous EEG-recording (using the criterion "silent second") or by continuous observation. Anaesthesia was maintained at the level of "the silent second" for periods of up to 120 min. After different time intervals the last infusion period to the EEG-criterion was followed by decapitation and samples from blood, brain, muscle and fat were analysed for hexobarbital content. Brain concentrations at the EEG criterion increased and were notable after 10 min. but statistically significant at 30 min. when a 40% increase in concentration was needed to reach the criterion. Another group of rats kept at a lower level of anaesthesia (i.e. the righting reflex) showed a slight but not always significant increase in concentration when measured in different parts of the brain at "silent second". The dose of hexobarbital needed to maintain anaesthesia for intervals up to 120 min. increased almost linearly with time. Analysis of serum, muscle and fat tissue showed that concentration in fat tissue increased linearly during this whole interval and served as the final depot in redistribution. Muscle tissue shows an increase up to 60 min. but a very small increase thereafter, which is consistent with a function as temporary storage compartment.

Respiratory and cardiovascular effects in relation to plasma levels of midazolam and diazepam.

1. In the present study possible relationships between cardiovascular and respiratory effects and plasma concentrations were investigated after administration of midazolam and diazepam. Eight healthy volunteers were given three injections at 20 min intervals of equipotent sedative doses of midazolam (0.05 mg kg-1) and diazepam (0.15 mg kg-1) in a randomized double-blind cross-over design. Blood pressure, blood-gases and respiration measured nonivasively, were monitored throughout the experimental session of 160 min, and frequent blood samples were collected during the session. 2. Correlations between the blood pressure reduction, the increase of PaCO2 in blood, and plasma concentrations were found for both drugs. A maximal reduction of blood pressure and PaCO2 was produced after sedative doses of midazolam and diazepam. 3. A possible acute tolerance development towards the blood pressure reduction was found after the repeated administration of diazepam but not after the midazolam administration. 4. The plasma concentrations producing half the maximal effects after administration of midazolam was 50-60 ng ml-1, indicating that the influence on blood pressure and PaCO2 after drug administration is evoked at lower plasma concentrations than sedation. 5. No correlation between the respiratory effects and plasma concentrations was found for either drug.

Application of serial sampling of cerebrospinal fluid in pharmacodynamic studies with a drug active in the CNS: Heptabarbital concentrations at onset and offset of loss of righting reflex in rats

As cerebrospinal fluid (CSF) possesses unique characteristics in order to explore concentration-pharmacological response relationships of drugs active in the CNS, the practicability of serial sampling of CSF was tested in a study with heptabarbital. Concentrations in CSF and plasma were measured simultaneously in individual rats during and after an intravenous infusion for 30 min. At the end of the infusion, the distribution equilibrium was attained with a CSF/plasma concentration ratio of 0.38, roughly equal to the fraction unbound to protein. When concentrations in blood and CSF were determined at the onset and offset of loss of righting reflex concentrations in blood were significantly greater at onset (146 ± 19 mg/l) than at offset (108 ± 16 mg/l, n = 6), whereas concentrations in CSF were identical (39 ± 5 and 38 ± 5 mg/l, respectively). This confirmed the earlier observation that the CSF is pharmacokinetically indistinguishable from the site of action. When the duration of the loss of righting reflex was varied, concentrations of heptabarbital in CSF at onset and offset were similar, independent of the duration of the loss of righting reflex (1–5 hr). These findings demonstrate the absence of the development of acute tolerance and confirmed that no (inter)active metabolites interfered with the pharmacological response. In a total number of 26 rats the concentrations in CSF at onset and offset of loss of the righting reflex were compared. The interindividual variation was 13–15% and the intraindividual variation was only 4–6%. The results demonstrate the usefulness of serial sampling of CSF in pharmacodynamic studies with centrally acting drugs.

Pharmacokinetic modeling of the anticonvulsant response of oxazepam in rats using the pentylenetetrazol threshold concentration as pharmacodynamic measure.

This investigation developed strategies along which the anticonvulsant effect of oxazepam in the rat could be pharmacokinetically modeled. After determination of the pharmacokinetics of oxazepam, which could be described with a two-compartment model (half-lives of distribution and elimination 6 and 52 min, respectively), the drug was administered iv to groups of animals to achieve a serum concentration range of 0.1-2.5 mg/L at 10, 45, and 120 min after administration. At these time points pentylenetetrazol (PTZ) was infused slowly until the first myoclonic jerk occurred. The anticonvulsant response, expressed as the elevation of the serum or brain threshold concentration of PTZ, was modeled versus the serum (both total and free) and brain oxazepam concentration, according to the sigmoid Emax model. The total serum and brain oxazepam EC50 values are about 0.5 mg/L and 1.1 mg/kg, respectively, and Emax 120 mg/L PTZ. No marked differences in pharmacodynamic parameters between the three time groups were found, which indicates that serum and brain are pharmacokinetically indistinguishable from the effect compartment, that there is no (inter)activity of oxazepam metabolites and absence of development of acute tolerance during the investigated time frame. An interfering role of metabolites was also excluded by a direct radioreceptor assay of oxazepam, yielding very similar results as the specific chromatographic assay. It is concluded that the conception-anticonvulsant effect relationship of oxazepam can satisfactorily be described by the sigmoid Emax model, when utilizing the employed experimental strategies.

Development of acute tolerance to the cardiorespiratory effects of alfentanil after subsequent bolus injection in conscious rats

The cardiovascular and respiratory effects of alfentanil in conscious freely moving rats, were evaluated after initial and subsequent injections. Doses of alfentanil (50, 130, 260, and 500 ug/kg) were given to naive rats ( n = 4−5) and 1 hour later this dose was repeated. The resultant cardiovascular and respiratory effects were compared. At all doses there was a significant (p<0.05) depression of mean arterial pressure and heart rate after the initial dose of alfentanil. At doses of 50, 130, and 260 ug/kg, the second administration elicited significantly less depression of cardiovascular parameters than the initial dose. Maximum changes in respiratory parameters (PaCO 2 and PaO 2) were also significantly less after the second administration of alfentanil. This difference, in maximum respiratory depression, was not seen at the highest doses (500 ug/kg). These results indicate that tolerance, to the cardiorespiratory side effects seen after alfentanil, can occur in as little as 1 hour after subsequent bolus injections.

Development of acute tolerance to bumetanide: constant-rate infusion studies.

Bumetanide was administered intravenously to four mongrel dogs as a bolus of 8.7 micrograms/kg, immediately followed by a constant-rate infusion of 0.35 microgram/min/kg at 0.036 ml/min. Treatment A consisted of a 90-min equilibration period and first hour (Phase I) of study in which animals were maintained under euvolemic conditions. During the subsequent 3 hr of Treatment A (Phase II), animals were maintained under hydropenic conditions. These experiments were then repeated 1 week later (Treatment B) with the temporal aspects of hydration reversed (Phase III, hydropenia; Phase IV, euvolemia). Serial plasma and urine samples were assayed for bumetanide by high-performance liquid chromatography (HPLC) and for sodium by flame photometry. The bumetanide excretion rate was not significantly different during the 4 hr of Treatment A, although minor differences were observed between Phase III and Phase IV of Treatment B. The sodium excretion rate showed significant differences between euvolemic and hydropenic conditions of both treatments. A two- to threefold difference in the sodium excretion rate persisted even when slight differences (less than 20%) in bumetanide excretion rates were taken into account. These results demonstrate that an acute tolerance does develop to constant-rate infusions of bumetanide when inadequate fluid and electrolyte replacement occurs and that this tolerance can be reversed by rehydration.

Effect of xylene inhalation on fixed-ratio responding in rats

The effect of xylene inhalation was studied on operant under a fixed-ratio (FR24) schedule in rats. Experiments were performed while rats were being exposed to xylene vapor in an inhalational (flow-through) behavioral chamber. Rats were exposed succesively to three graded concentrations (113, 216 and 430 ppm) of xylene vapor each for 2 hr in range-finding studies during 6 1 4 - hr sessions. The reinforcement rate which is correlated with FR responding was shown to be decreased at hr 1, hr 3 and hr 5. However at hr 2, hr 4 and hr 6 the reinforcement rate in rats increased approaching the control level, thereby indicating development of tolerance. When rats were exposed to one of the three graded concentrations of xylene for 2 hr on separate days, they also showed a decrease in the reinforcement rate at hr 1; development of acute tolerance was also noted in this schedule. Exposure to the lowest (98.5 ppm) level of xylene used during 5-hr sessions caused no significant decrease in the reinforcement rate. This study thus attempts to identify a minimum effective concentrations of xylene and indicates the development of acute tolerance to behavioral effect of xylene.

Effects of smoking deprivation on smoking behavior and heart rate response in high and low CO absorbing smokers.

Short-term deprivation effects on smoking-induced heart rate response and smoking behavior were compared in consistently high and low CO absorbing smokers, suggested to depend differentially on smoking and/or nicotine. The subjects came to the laboratory for two afternoon sessions and smoked at 1 p.m. and at 5 p.m. both after previous free smoking and following afternoon or overnight-morning deprivation. Overnight-morning deprivation decreased presmoking heart rate in both groups similarly, but it increased heart rate response to smoking more in the high than low CO absorbers. Single cigarette tidal CO boosts concomitantly decreased in the high CO absorbers and remained at the habitually low level among the low CO absorbers. Afternoon deprivation had no effects on presmoking heart rate, presmoking tidal CO concentration and tidal CO boost, but increased the heart rate response to smoking in the high CO absorbers. Smoking need and satisfaction as well as puff volume and duration tended to increase after both deprivations slightly more among the high than low CO absorbers. These results are discussed in terms of a differential development of acute tolerance to nicotine in the two groups of smokers which dissipates during smoking abstinence periods.

Effect of Age on the Pharmacodynamics of Phenobarbital and Ethanol in Rats

The purpose of this investigation was to determine the effect of age on the sensitivity of the central nervous system (CNS) to the depressant action of phenobarbital and ethanol. For this purpose, one or the other of these drugs was administered by slow iv infusion to male rats of various ages until the animals lost their righting reflex. The drug concentrations at that time in serum, brain, and cerebrospinal fluid were determined. The results obtained in studies on 1, 9, and 18-month-old Sprague-Dawley rats and on 7, 16, and 24-month-old Fischer-344 rats showed that phenobarbital concentrations at the pharmacologic end-point decreased with increasing age, indicative of an increased sensitivity of older animals to the CNS depressant effect of the barbiturate. Similar studies with ethanol on Sprague-Dawley rats (only) showed substantially higher drug concentrations at all sampling sites in 5-weekold animals than in 9- and 12-month-old animals at the onset of loss of righting reflex, but no significant differences between the 9- and 12-month-old groups. This investigation, which was designed to exclude or account for pharmacokinetic variables and to avoid confounding secondary effects, such as hypothermia and development of acute functional tolerance, showed a substantial increase in CNS sensitivity to phenobarbital and ethanol with increasing age in rats between the age of 1 and 9months, and a less pronounced increase (phenobarbital) or no significant change (ethanol) in rats between 9 and 18 months of age.

Effects of a novel opioid peptide antagonist on rat bladder motility in vivo

The agonist, and opioid antagonist, effects of intracerebroventricularly (ICV) given D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH 2 (CTP), a cyclic analogue of somatostatin octapeptide, were evaluated using the micturition reflex of the anesthetized rat as the endpoint. Antagonist effects were evaluated against equieffective doses of selective mu [D-Ala 2,NMPhe 4,Gly-ol]enkephalin (DAGO) and delta [D-Pen 2,D-Pen 5] enkephalin (DPDPE) opioid agonists. At low ICV doses, CTP preferentially antagonized DPDPE rather than DAGO; increasing the dose of CTP further effectively antagonized both mu and delta agonists, while even higher doses showed an agonist effect alone which was not blocked by adrenergic, cholinergic or opioid antagonists. Selective opioid antagonist doses of CTP failed to block the inhibition of the micturition reflex produced by pentobarbital. Possible residual somatostatin like properties of CTP were tested by using somatostatin as a possible antagonist of equieffective doses of DPDPE and DAGO; somatostatin did not antagonize these agonists. Repeated exposure to CTP resulted in the development of acute tolerance to the agonist effect, and also prevented the inhibition of the reflex by high doses of somatostatin, with the converse experiment showing a similar pattern; thus, repeated somatostatin resulted in tolerance and subsequent cross-tolerance to the agonist effects of CTP. In animals tolerant to somatostatin, CTP nevertheless behaved as an opioid antagonist. The present results indicate that CTP possesses opioid antagonist properties in vivo which are pharmacological in nature but nevertheless retains residual somatostatin-like activity at higher doses.

Effect of prolactin on tolerance and dependence to acute administration of morphine

The effect of exogenous prolactin on the development of acute tolerance to and dependence on morphine was studied. As described elsewhere, analgesia induced by prolactin was subject to tolerance. Pretreatment with prolactin enhanced the development of tolerance to analgesia induced by morphine while it effectively suppressed the withdrawal symptoms. These results indicate that prolactin behaves like an opioid agonist and suggest that it may have therapeutic implications in the management of opioid dependence.

Effects of the rate and composition of fluid replacement on the pharmacokinetics and pharmacodynamics of intravenous furosemide.

Effects of differences in the rate and composition of intravenous fluid replacement for urine loss on the pharmacokinetics and pharmacodynamics of furosemide were evaluated using the dog as a model animal. Each of six dogs received 8-hr constant intravenous infusion of 20 mg (15 mg used in one dog) of furosemide with 0% replacement (treatment I), 50% replacement (treatment II), and 100% replacement (treatment III) with lactated Ringer's solution, as well as with 100% replacement with 5% dextrose in water (treatment IV). Most pharmacokinetic parameters, such as plasma clearance, steady-state volume of distribution, mean residence time, and terminal half-life, were essentially the same in all four treatments. Renal clearances and urinary excretion rates of the drug in treatments II-IV were essentially the same, but about 20% higher than those in treatment I. In spite of the similarities in kinetic properties, diuretic and/or natriuretic effects from furosemide were markedly different among the four treatments. For example, mean 10-hr urine outputs were 646, 1046, 3156, and 1976 ml and mean 10-hr sodium excretions were 87.0, 142, 383, and 97.2 mmole for treatments I-IV, respectively. Except for treatment III, diuresis and/or natriuresis were found to be time-dependent, generally decreasing with time until reaching a low plateau during later hours of infusion. The present findings also showed that no fluid replacement and 100% replacement with 5% dextrose solution both produced the same degree of severe acute tolerance in natriuresis, indicating the insignificance of water compensation in tolerance development; in treatment II, where neutral sodium balance was achieved, the development of acute tolerance in diuresis and natriuresis can mainly be attributed to negative water balance under this special condition; at steady state the hourly diuresis and natriuresis could differ up to about ten times between treatments. Some implications for the kinetic/dynamic relationship or modeling, in the clinical use, and in the bioequivalence evaluation of dosage forms are discussed.

Pharmacokinetic and Pharmacodynamic Interactions Between Caffeine and Diazepam

The pharmacokinetic and dynamic interactions of caffeine and diazepam after single doses were investigated in six young healthy adults. Subjects received 6 mg/kg of caffeine, 0.3 mg/kg of diazepam, and their combination at 2-week intervals according to a Latin square design and a double-blind procedure. Subjects had blood samples withdrawn at 0, 5, 10, 20, 30, 45, 60 minutes and every 30 minutes thereafter until 210 minutes after treatment. A battery of behavioral tests were administered before treatment and after each blood sampling, starting with the 20-minute period. The coadministration of caffeine with diazepam resulted in a 22% reduction in diazepam plasma levels. Caffeine produced hand tremors and diazepam produced sedation and impaired memory and cognition. The two drugs did not antagonize the effects of each other except in the symbol cancellation task. There were significant correlations between the caffeine and diazepam plasma levels and performance on several tasks and evidence for the development of acute tolerance to both drugs.

Pharmacodynamics of the Hypnotic Effect of Salicylamide in Rats

Salicylamide (SAM) can produce sedation and sleep in humans and animals. To explore the potential utility of the drug as a research tool for assessing disease effects on the response of the central nervous system to depressant drugs, and to obtain a better understanding of the clinically evident sedative action of SAM, studies were performed to characterize the relationship between the concentrations and hypnotic effect of this drug in rats. Female Lewis rats weighing 170–200g received SAM by intravenous infusion at a rate of 0.49, 1.22, or 2.47mg/min until the onset of loss of the righting reflex. This well-defined pharmacological endpoint occurred from 16.7 ± 2.3min (fastest infusion rate) to 110 ± 27min (slowest infusion rate) after the start of the infusion. SAM concentrations at that time in serum, serum water, brain, and cerebrospinal fluid (CSF) were similar in animals that had received the 1.22- or 2.47-mg/min infusion and lower in animals that were infused at a rate of 0.49mg/min. The slowest infusion rate group also exhibited increased serum protein binding of the drug. The SAM concentration ratio, CSF–serum water, was essentially unity in all three groups, indicative of rapid equilibration of the drug across the blood–CSF barrier. Gentisamide, the hydroxylated metabolite of SAM, was found in serum, CSF, and brain, but in low concentrations at which this metabolite alone had no hypnotic effect. When SAM was infused for some time beyond the onset of loss of the righting reflex, concentrations of the drug in serum, CSF, and the brain at recovery of the righting reflex were somewhat higher than at onset of loss of the righting reflex. The results of this investigation suggest that SAM exerts a direct effect on the central nervous sytem and that its hypnotic activity may be subject to development of acute tolerance.

STUDIES ON THE TOLERANCE TO SO2 OF GRASS POPULATIONS IN POLLUTED AREAS

SummaryThe development of acute and chronic sulphur dioxide (SO2) tolerance in lawn grass populations was studied by two approaches: the minimum time for tolerance to appear in Festuca rubra L., Lolium multiflorum Lam., L. perenne L., Phleum pratense L. and Poa pratensis L., was determined by comparison annually of plant samples from monoculture plots sown at a polluted site, with plants grown from the seed originally sown; the long term development of tolerance in F. rubra, D. glomerata L. and Agrostis tenuis Sibth. was also investigated by comparison of five lawns of different ages (1–c. 200 years) at a polluted site.Tolerance to acute SO2 injury was detected in L. perenne and Phleum pratense only three and four years after sowing, respectively. However, population samples of these two species, collected from the field three years later, showed no significant SO2 tolerance. An analysis using morphological and isozyme variation as criteria showed that the tolerant population consisted of a large number of different individual genotypes. The populations experienced a state of evolutionary flux with rapid selection first of the tolerant, and subsequently of the non‐tolerant phenotypes. The disappearance of tolerance coincided with declining ambient SO2 concentrations.The lawns of different ages were shown to represent an evolutionary series of increasing acute SO2 tolerance with age of lawn in F. rubra and A. tenuis. This demonstrated the continuing development of acute SO2 tolerance in grass populations over a prolonged period.The significance of the occurrence and rate of development of SO2 tolerance for grasslands in polluted areas is discussed.

Oxytocin and a C-terminal derivative (Z-prolyl- d-leucine) attenuate tolerance to and dependence on morphine and interact with dopaminergic neurotransmission in the mouse brain

The effects of oxytocin (OXT) and of dipeptides derived from the C-terminal portion of oxytocin (Z-prolyl-leucine and Z-prolyl- d-leucine) on the development of acute and chronic tolerance to, and dependence on morphine were tested in the mouse. Oxytocin and the dipeptides attenuated the development of acute and chronic tolerance to the antinociceptive effect of morphine and delayed the onset of the naloxone-precipitated withdrawal syndrome. Both oxytocin and Z-prolyl- d-leucine affected drug-induced behavioural responses related to dopamine (DA) in the brain. Thus, oxytocin potentiated the hypermotility induced by a large dose of apomorphine and decreased the supersensitivity of the DA receptors. Small doses of Z-prolyl- d-leucine inhibited the hypomotility elicited by a small dose of apomorphine and potentiated the hyperactivity induced by amphetamine. The data indicate that both oxytocin and Z-prolyl- d-leucine affect tolerance to and dependence on morphine. While oxytocin interacts mainly with postsynaptic DA-ergic neuronal elements, the dipeptide primarily affects DA-ergic neurotransmission at the presynaptic level.