Low doses of naloxone and MIF-1 peptides increases fluid consumption in rats

Three studies were done with albino rats to determine the effects of low doses of opiate antagonists on fluid intake. In Experiment 1, male rats were deprived of water for 12 hr and then randomly injected IP with 0.0, 0.01, 0.1, 1.0 or 10.0 mg/kg of naloxone. Ten min later they were given free access to a 20% sucrose solution and consumption was measured for the next 30 and 60 min on 2 consecutive days. Only animals injected with 1.0 or 10.0 mg/kg drank significantly less than controls. The other doses were not reliably different from controls but on Day 1 animals injected with 0.01 mg/kg of naloxone drank slightly more than controls. Experiment 2 followed the same procedure with lower doses of 0.0, 0.001, 0.01, and 0.1 mg/kg of naloxone. Although the effect of 0.1 mg/kg of naloxone was again not significant, this time animals injected with 0.001 and 0.01 mg/kg of naloxone consumed reliably more fluid than controls. Experiment 3 extended the findings to a peptide with opiate antagonistic properties and its analogs. Male and female rats were randomly assigned to receive an IP injection of 0.0, 0.01, 0.1, or 1.0 mg/kg of naloxone, MIF-1 (Pro-Leu-Gly-NH₂), the pGlu analog (pGlu-Leu-Gly-NH₂), or Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH₂). Measurement of intake occurred every 30 min or 600 min. Consumption was significantly increased. Rats injected with MIF-1 drank the most, followed in order by those injected with the pGlu analog, naloxone, Tyr-MIF-1, and controls. Dose was also reliable in a dose-dependent fashion, with animals receiving the lowest dose of 0.01 mg/kg drinking the most. None of the groups drank less than the controls. Sex was also significant in interactions with substance and dose. The results suggest that in some situations low doses of opiate antagonists may facilitate fluid consumption even though high doses are known to suppress the same behavior. The data also support the role of MIF-1 and MIF-1 analogs as opiate antagonists.     

Conditioned saccharin aversions in rats as a result of cutaneous nicotine or intraperitoneal nicotine administered in divided doses

Nicotine base was used in a conditioned taste aversion (CTA) paradigm to avert male Sprague-Dawley rats to saccharin solution (0.1%, w/v). Experiments investigated different dose routes of nicotine administration and duration of action as determinants in nicotine-induced CTA. In Experiment 1 nicotine was injected intraperitoneally (IP) at doses of 0.5, 1.0, or 3.0 mg/kg 30 min after drinking saccharin solution. Using a two-bottle choice test, no CTA was observed, although all nicotine animals showed obvious symptoms of malaise including seizures in the highest dose group. Experiment 2 showed dose-related CTA when nicotine (10.0, 30.0, or 50.0 mg/kg) was cutaneously applied 30 min following saccharin drinking. Experiment 2B showed that the aversions were due to associative rather than nonassociative factors such as sensitization or enhanced neophobia. In Experiment 3, the following group treatments were begun 30 min after saccharin drinking to distribute identical total nicotine doses over an extended period of time: One IP injection of 2.0 mg/kg nicotine (in a saline vehicle) and four injections of saline solution, three injections of 0.67 mg/kg nicotine and two injections of saline, five injections of 0.40 mg/kg nicotine, or five injections of saline. All injections were spaced 30 min apart. Compared with saline-injected controls, CTA occurred in the rats receiving either three or five injections of nicotine but the group receiving one injection did not differ from the control group. There was no difference in CTA between the groups receiving three or five injections.     

Antagonism of morphine-induced aversive conditioning by naloxone.

In Experiment 1, 4 doses of morphine and 4 doses of naloxone were tested for their ability to induce a conditioned aversion to saccharin in rats. Morphine was much more potent than naloxone which had only weak effects at the highest dose (12.96 mg/kg). Based on the determinations of Experiment 1, doses of 0.096, 0.96 and 0.6 mg/kg of morphine in a second experiment. The highest dose of naloxone was an effective antagonist of morphine-induced aversion. The antagonism was incomplete, but this may have reflected the particular dose combinations that were employed. Although 12.96 mg/kg of naloxone induced only a weak conditioned aversion to saccharin in Experiment 1, 9.6 mg/kg had a substantial effect in Experiment 2. Thus naloxone was itself an agent of aversive conditioning at a dose which significantly antagonized the aversive effects of morphine. Because of the successful demonstraion of antagonism, it was suggested that there may be common pharmacological mechanisms involved in both positive reinforcement and aversive conditioning by drugs of the opiate class.     

Effect of p-chloroamphetamine on morphine withdrawal syndrome

Adult male rats were injected four times a day with increasing doses of morphine sulfate until a dose of 405 mg/kg/day was tolerated. After 5 days of maintenance at that dose, withdrawal signs were observed at 24, 48, and 72 hr of withdrawal. Given 4 or 18 hr after last morphine injection, a single administration (3–12 mg/kg) of p-chloroamphetamine (PCA) blocked withdrawal “wet shakes” and ptosis during the following withdrawal period. Dose-dependent reduction in withdrawal hypothermia was observed only at 24 hr of withdrawal. Writhing was blocked only at higher doses. Morphine-withdrawal aggression measured at 72 hr of withdrawal and loss in body weight were not blocked by any delayed action of PCA. However, withdrawal aggression was blocked by PCA when given 1 hr before measurement at a dose of 3 mg/kg. Mice that were made morphine dependent by repeated injections of morphine given in large doses, exhibited withdrawal jumping either after cessation of morphine injections, or on injection of naloxone. PCA (3–12 mg/kg) given 2 hr before naloxone blocked this jumping in a dose-dependent manner. It also blocked withdrawal jumping in morphine-deprived mice when injected 2 hr, but not 14 or 17 hr before measurement. Jumping induced by α-naphthyloxyacetic acid (α-NOAA) was not blocked. The effect of PCA on different signs of morphine withdrawal is time dependent and may be related to its similarly time-dependent effect on brain serotonin and dopamine.     

Effect of propranolol on antinociceptive and withdrawal characteristics of morphine

Propranolol at a dose (10 mg/kg) which did not alter tail-flick latency by itself, did not alter the ED50 of morphine when given 10 min prior to the narcotic. Propranolol at doses of 10 and 25 mg/kg given 10 min prior to naloxone challenge did not significantly alter the frequency of naloxone induced jumping 72 hr after morphine pellet implantation. The ED50 of naloxone in morphine pelleted mice was not altered by treatment with propranolol at 0, 24, and 48 hr after pellet implantation. Naloxone caused hyperactivity in mice when administered 72 hr after morphine pellet implantation. An injection of 25 mg/kg propranolol 10 min prior to naloxone did not block this hyperactivity. In addition, administration of 10 mg/kg of propranolol every 8 hr to rats during withdrawal from morphine failed to alleviate the withdrawal syndrome as evidenced by changes in either body weight or water intake. These data suggest that the beta-adrenergic blocking agent, propranolol, does not alter the antinociceptive activity or lessen the withdrawal syndrome of morphine in rodents.     

The effects of morphine sulphate on ovulation in the immature rat treated with PMSG

Two experiments were carried out on the effects on ovulation of morphine sulfate administered prior to the preovulatory LH surge in the immature rat treated with PMSG. At the commencement of the experiments, rats were 30 days old. In Experiment 1 all rats were injected subcutaneously with 12 IU of PMSG at 1200 hr on day 30. Doses of 6, 12, 24 and 36 mg/kg of morphine were given IP at 1555 hr on day 32. Examination of oviducts on the morning of day 33 enabled the verification of ovulation as well as oocyte counts. Results suggest that the effect of morphine on ovulation is biphasic resulting in the stimulation of ovulation at low doses (6 mg/kg) and inhibition of ovulation at high doses (24 and 36 mg/kg). In Experiment 2, rats injected with a low dose of PMSG sufficient to result in ovarian maturation but not in a preovulatory LH surge, were injected on the eve of day 32 with either saline, 6 or 24 mg/kg morphine. The treatment of rats with 6 mg/kg morphine significantly increased mean ovulatory values compared with control and 24 mg/kg morphine conditions. Further, the percentage of 6 mg/kg treated rats ovulating was more than that of both control and 24 mg/kg morphine conditions. The failure of rats treated with 24 mg/kg morphine to display increments in ovulatory response similar to 6 mg/kg morphine injected rats suggests that increased ovulation is not due to the ability of morphine to cause adrenal progesterone release but is more probably the result of LH release at low doses of morphine.     

Opioid influence on some aspects of stereotyped behavior induced by repeated amphetamine treatment

Rats were administered repeated IP injections of dl-amphetamine (AMPH) according to a chronic escalating dose schedule (three doses per 24 hr, for four days or one day). Animals treated for four days exhibited a diminished oral stereotypy in response to a challenge of 12 mg/kg AMPH or 2 mg/kg SC apomorphine (APO), 72 hr after withdrawal. Pretreatment with 2 mg/kg IP naloxone (NAL) during the period of chronic AMPH administration prevented the reduction in oral stereotypy induced by AMPH or APO. No differences were detected among the mean of stereotypy scores from the different treatments in response to a challenge dose of 6 mg/kg AMPH. Neurochemical data showed that NAL pretreatment reversed the depletion of striatal dopamine content induced by chronic AMPH. When repeated injections of AMPH were given only one day, the diminished stereotypy response to AMPH or APO was not observed. Animals treated simultaneously with 1 mg/kg IP morphine or 5 μg/kg IP β-endorphin and repeated AMPH injections for one day, showed a reduced stereotyped response to AMPH or APO. These results suggest that opioid peptides are involved in the mechanisms underlying the decrease in oral behaviors following AMPH treatment.     

Effects of naloxone on morphine induced sedation and hyperactivity in the hamster

Three experiments investigated the effects of naloxone on morphine elicited changes in hamster locomotor activity. In Experiment 1, a prior subcutaneous injection of naloxone (0.4 mg/kg) converted morphine (15 mg/kg) elicited hypoactivity into hyperactivity: Compared with saline controls, naloxone pretreated animals were hyperactive following a subcutaneous injection of morphine. Experiment 2 investigated the effects of four doses of naloxone (0, 0.04, 0.1, 0.4 mg/kg) on morphine elicited hyperactivity. Results indicated that naloxone reversal of morphine elicited hyperactivity is directly related to dose of naloxone. In Experiment 3, naloxone (0.4 mg/kg) was administered one and two hours after a morphine injection. Compared with saline controls, morphine treated animals were hypoactive for approximately 40 minutes after each of the naloxone injections. Results are discussed in terms of a modified dual-action hypothesis.     

Hyperglycemic suppression of morphine withdrawal signs in the rat

Male Sprague-Dawley rats maintained under controlled lighting and temperature conditions were used in this experiment. Morphine dependency was induced by giving increasing doses of morphine by intraperitoneal injection (IP group) or by the ingestion of morphine through drinking water (PO group). Animals were injected with 10, 20, 30 and 50 mg/kg morphine sulfate at days 1, 2, 3 and 4, respectively. Another group of animals received increasing concentrations of morphine through drinking water from 0.1, 0.2, 0.3 to 0.4 mg/ml at 48 h intervals. Morphine dependent animals were given naloxone by the intraperitoneal route to precipitate withdrawal. Glucose (3 g/kg or 10 g/kg) was given 10 min prior to the administration of naloxone to the respective groups. Another two groups of animals were made diabetic by the administration of streptozotocin. In one group, animals received increasing concentrations of 10, 20, 30 and 50 mg/kg morphine sulfate by the IP route at days 1, 2, 3 and 4, while the other group was not treated with morphine but was assessed for withdrawal signs to serve as the control. Withdrawal signs were assessed by observing the presence of diarrhea, tremor, piloerection, hunchbacked posture, teeth chattering, salivation, erection, restless activity, territorial exploring, irritability to handling, vocalization and jumping. Results obtained indicate that glucose administration at 10 g/kg abolished most of the withdrawal signs, and we were unable to induce the same degree of morphine dependency in diabetic animals as compared to the non-diabetic groups. It was concluded from this study that hyperglycemia could suppress morphine withdrawal signs.     

Combined low dose treatment with opioid and cannabinoid receptor antagonists synergistically reduces the motivation to consume alcohol in rats

Rationale Opioid and cannabinoid CB₁ receptor antagonists reduce the motivation to consume alcohol when taken individually but their effectiveness in combination is not yet known.Objective The effects of naloxone/naltrexone and SR 141716 alone and in combination were examined on beer consumption in rats.Methods In a progressive ratio paradigm rats were trained to lick at a tube for either beer (4.5% ethanol v/v) or near-beer (beer containing <0.5% ethanol v/v) under a progressive ratio schedule of reinforcement. They were then tested with naloxone (0.3, 0.6 or 1.2 mg/kg IP), SR 141716 (0.15, 0.3 or 0.6 mg/kg IP) and their combination. In a continuous access paradigm, other rats were given beer or near-beer in their home cages for several weeks and the effects of repeated (4 day) administration of naltrexone (0.3, 0.6 or 1.2 mg/kg), SR 141716 (0.15, 0.3 or 0.6 mg/kg) and their combination were assessed.Results In the progressive ratio paradigm SR 141716, naloxone and their combination were more effective in reducing the break points for beer rather than near-beer. The two lowest dose combinations produced a synergistic reduction in break points. The highest dose combination reduced break points for both beer and near-beer and effects were more additive than synergistic. In the continuous access paradigm, the low doses of the drugs selectively reduced beer consumption in a synergistic fashion with higher doses having a less selective and more additive effect.Conclusions The combined, low dose treatment has possible clinical efficacy in treating alcohol craving in humans.     

The effects of choline on soman-induced analgesia and toxicity

The effects of acute choline (Ch) administration on the hot plate (HP) analgesia produced by soman and by morphine and on the toxicity produced by soman were examined in male rats. Morphine (9.0 mg/kg, IP) and soman (80 micrograms/kg, SC), but not Ch (60 mg/kg, IP), produced HP analgesia. Pretreatment with Ch (100 mg/kg, IP; given 20 min earlier) reduced morphine and soman analgesia by 68% and 38% respectively. Ch (LD50 = 405.8 mg/kg, IP) at doses above 200 mg/kg rapidly produced signs of cholinergic stimulation which disappeared by one hr. A fixed dose of Ch (100 mg/kg) altered neither the expression of toxic cholinergic signs produced by varying doses (from 75.9 to 151.4 micrograms/kg) of soman, nor the 24-hr LD50 (124.0 micrograms/kg, SC) of soman. Doses of Ch ranging from 213.8 to 269.2 mg/kg when given 40 min prior to a fixed dose (93.3 micrograms/kg) of soman resulted in persistent signs of cholinergic hyperstimulation, but again, did not affect the mortality produced by soman. The results demonstrate that acute Ch pretreatment increased the severity of cholinergic stimulation and reduced the HP analgesia, but were not accompanied by potentiation or antagonism of the lethal action of soman.     

Effect of naloxone and amphetamine on acquisition and memory consolidation of active avoidance responses in rats

Pretraining IP injection of naloxone (0.3 mg/kg) or amphetamine (2 mg/kg) enhanced performance during acquisition, but did not improve retention of active avoidance responses in rats. Naloxone (0.1 or 3 mg/kg) had no effect on acquisition or on retention. The combination of naloxone (0.3 mg/kg) plus amphetamine (2 mg/kg) did not produce the facilitation observed when each of the two drugs was administered alone. Pretreatment with the higher dose of naloxone (3 mg/kg) blocked the facilitative effect of amphetamine on acquisition. Post-training administration of naloxone (0.3 mg/kg) or amphetamine (2 mg/kg) improved retention. Naloxone (0.1 or 3 mg/kg) had no effect. When naloxone and amphetamine were combined, at respective doses of 0.3 mg/kg and 2 mg/kg, the improvement did not occur, i.e., the higher dose of naloxone prevented the facilitative effect of amphetamine. In addition, an ineffective dose of amphetamine (0.5 mg/kg), given either pre-or post-training together with the lower dose of naloxone (0.1 mg/kg), produced a significant enhancement of acquisition or consolidation, respectively. The results are consistent with the possibility that naloxone might exert its facilitative action on acquisition and memory consolidation through the release of catecholaminergic systems from inhibitory influences of opioids.     

Assessment of SNC 80 and naltrindole within a conditioned taste aversion design

Although compounds with relative selectivity for the mu and kappa opiate receptors subtypes have been reported to condition taste aversions, it is not known whether systemically administered delta compounds have the ability to produce aversions. To that end, female Long-Evans rats were adapted to water deprivation and were given pairings of a novel saccharin solution and various doses of the selective delta agonist SNC 80 (0.32-10.0 mg/kg; Experiment 1) or the selective delta antagonist naltrindole (1.0-18.0 mg/kg; Experiment 2). For comparison, the relatively selective mu agonist morphine (Experiment 1) and mu antagonist naloxone (Experiment 2) were assessed under identical conditions. Both SNC 80 (Experiment 1) and naltrindole (Experiment 2) were effective as unconditioned stimuli within this design, inducing dose-dependent taste aversions with repeated conditioning trials. Although at no dose did animals injected with SNC 80 differ from those injected with morphine, aversions induced by SNC 80 were acquired at a faster rate than those induced by morphine. Subjects injected with naloxone drank significantly less than those injected with naltrindole at the 10 mg/kg dose, and aversions induced by naloxone at 5.6 and 10 mg/kg were acquired at a faster rate than those induced by naltrindole. Although the basis for opioid agonist- and antagonist-induced taste aversions is not known, the differences between aversions induced by SNC 80 and naltrindole and those induced by morphine and naloxone, respectively, may be a function of their relative selectivity for specific opiate receptor subtypes.     

The influence of various experimental conditions on the expression of naloxone-induced withdrawal symptoms in mice

• 1.1. Physical dependence was induced in mice by repeated injections of increasing doses of morphine for either 4 or 7 days.
• 2.2. Withdrawal symptoms induced by naloxone (1 mg/kg, i.p.) given 3 hr postmorphine were more severe in mice treated for 7 than for 4 days.
• 3.3. In mice that developed a similar degree of dependence, various doses of naloxone (0.1–10 mg/kg) given 3 hr postmorphine produced withdrawal symptoms of different intensities.
• 4.4. Withdrawal jumping was maximal at naloxone (1 mg/kg) but declined with further increases in the dose of the antagonist.
• 5.5. “Wet dog” shakes progressively increased with increasing doses of naloxone (0.1–10 mg/kg).
• 6.6. Variation in the temporal time interval between the last dose of morphine and that of naloxone (1 mg/kg) influenced the intensity of withdrawal symptoms.
• 7.7. In male and female mice that developed a similar degree of dependence, no major differences were observed in the severity of withdrawal symptoms-induced by naloxone (1 mg/kg) given 3 hr postmorphine.

     

Time-related facilitation and suppression of drinking by muscarinic anticholinergic drugs in water non-deprived rats

Effects of tertiary anticholinergic drugs, atropine (1.3, 2.5, 5 and 10 mg/kg, s.c.) and scopolamine (0.13, 0.25, 0.5 and 1 mg/kg, s.c.), and a quaternary anticholinergic drug, methylatropine (1.3, 2.5, 5 and 10 mg/kg, s.c.), on the drinking behavior were investigated in water non-deprived rats that were housed in a 12-hr light-dark situation (light period: 6:00-18:00) with a free access to food. Atropine, 5 mg/kg, and scopolamine, 0.13 and 0.25 mg/kg, administered at 12:00, significantly increased the drinking during the 12:00-18:00 period. Furthermore, lower to medium doses of atropine increased the drinking during the 18:00-6:00 period. In contrast, the drinking did not change during the 12:00-18:00 period, but decreased during the 18:00-6:00 period in a dose-dependent manner after administration of methylatropine at 12:00, whereas the drinking during the 18:00-24:00 period decreased in a dose-dependent manner when both the tertiary and quaternary drugs were administered at 18:00. However, the drinking during the 24:00-6:00 period increased in the rats that were administered atropine at the dose of 5 or 10 mg/kg at 18:00, while the drinking still decreased after methylatropine at the same time. The present results suggest that in water non-deprived rats, central muscarinic cholinergic blockade is effective for both increasing and decreasing drinking behavior, depending on the doses, when the drug is administered, and time span between the drug administration and the behavior observation. It is also suggested that peripheral cholinergic blockade monotonously suppresses the drinking behavior.     

Dissociation of prey killing and prey eating by naloxone in the rat

Mouse killing rats matched for killing latency and prey eating were injected (IP) with 0.5, 2.0, or 5.0 mg/kg naloxone or 0.9% saline. Naloxone did not significantly inhibit prey killing or alter prey killing latency at any dose but did reduce prey eating by 50% at the two higher doses. The dissociation of prey killing and prey eating by naloxone is consistent with other evidence that these two behaviors are separate components of predation in rats.     

Effects of a kappa receptor agonist, ethylketocyclazocine, on water consumption in water-deprived and nondeprived rats in diurnal and nocturnal tests

In 24 hr water-deprived male hooded rats, ethylketocyclazocine (EKC), 0.1-3.0 mg/kg, dose-dependently suppressed water intake. Within the first 30 min access to water, drinking was virtually abolished by 1.0 and 3.0 mg/kg EKC. Significant reductions in the level of water intake were found after 0.1 mg/kg EKC. After 2 hr access to water, the suppressant effect was attenuated indicating some recovery. The antidipsogenic action of EKC in water-deprived rats was comparable in its effect for both daytime and nocturnal testing. Circadian variation may not be an important modulator of the antidipsogenic action. Naloxone, an opiate receptor antagonist, when administered in a dose of 0.3 mg/kg also significantly reduced drinking in deprived animals. EKC (0.3 mg/kg) and naloxone (0.3 mg/kg) when administered together displayed mutual antagonism. Drinking was at control levels. In nondeprived male rats, EKC exerted some dipsogenic action, most noticeably during diurnal testing. Within 30 min access to water, 0.1 mg/kg EKC significantly elevated the level of water intake. This effect did not occur during nocturnal testing, when the only immediate effect of EKC was a suppression of drinking at 1.0 and 3.0 mg/kg dose levels. After 2 hr access to water, there was a significant peak effect to enhance drinking at the 0.3 mg/kg dose level during the daytime. Effects of EKC during the night were less pronounced. The dipsogenic action of EKC (0.3 and 1.0 mg/kg) in satiated animals during the day was abolished by naloxone and Mr-2266BS, also an opiate receptor antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)     

A temporal analysis of naloxone's suppressant effect on drinking

Licking activity was monitored in water deprived rats following various doses of naloxone. It was found that naloxone, at doses ranging from 0.01 to 10.0 mg/kg, had very little effect on initial drinking. However, naloxone did slow sustained drinking after 2 to 6 min into the bout, dependent upon dose. We take these results to mean that naloxone is interfering with those processes which serve to sustain continued drinking throughout a drinking bout.     

The effects of acrylamide given acutely or in repeated doses on fore- and hindlimb function of rats.

Male, albino rats of the Fischer strain were given 50 to 250 mg/kg acrylamide orally. The LD50 (and 95% confidence intervals) was estimated to be 251 mg/kg (203–300) at 24 hr postdosing and 175 mg/kg (159–191) at 168 hr postdosing. Rats given 50, 100, and 200 mg/kg acrylamide orally were tested for muscular dysfunction at 12 and 168 hr post-dosing. At 12 hr after dosing, acrylamide produced marked deficits in hindlimb motor functioning, as measured by the hindlimb extensor test and performance on the inclined screen. Recovery of hindlimb function was complete at 168 hr after dosing. Forelimb grip strength was not affected at either test period. In a 4-week repeated dosing experiment, rats given 10 or 20 mg/kg/day, 5 days per week, showed hindlimb dysfunction at a cumulative dose of 50 to 100 mg/kg while rats receiving up to 400 mg/kg over a period of 4 weeks showed no signs of diminished forelimb grip strength. Recovery of hindlimb motor function was evident, but not complete, 2 weeks after cessation of dosing. The tests of motor function used in this study were sensitive to and capable of detecting specific motor deficits in rats treated with relatively low doses of acrylamide. The rapidity and ease with which the tests can be used in experiments involving repeated measures suggest their use in assessing other chemicals for potential neurotoxicity.     

Influence of lisuride on morphine withdrawal signs in the rat: A dopamine-mimetic effect

The influence of lisuride on naloxone-induced withdrawal signs (wet shakes, escape attempts) was studied in morphine-dependent rats. Lisuride, injected IP at doses of 12.5 and 25 g/kg, inhibited wet shakes while not significantly altering escape attempts induced by naloxone (4 mg/kg IP). At higher doses (50 and 100 g/kg IP), lisuride's inhibitory effect on wet shakes persisted while escape attempts were actually potentiated with respect to control withdrawal rats. Increases in aggressive behavior were seen at all doses, and were dose-related. Haloperidol (0.3 mg/kg IP), administered 40 min before lisuride, did not modify the antagonistic effect on wet shakes, unlike sulpiride (40 mg/kg IP 30 min before lisuride), but at the same time blocked the increase in escape attempts and aggressiveness induced by lisuride. We suggest that lisuride modulates withdrawal signs by stimulation of dopamine receptors in the CNS. The effect of the dopamine mimetic N-n-propylnorapomorphine (NPA) on the same variables is reported as well as the influence of haloperidol on NPA, and a comparison between the effects of the two drugs is made.