Behavioral effects of xylamine-induced depletions of brain norepinephrine: interaction with LSD

Male rats were treated with a combination of systemic fluoxetine and intraventricular xylamine (under ether anesthesia) to deplete brain norepinephrine (NE) in the projection areas of the locus coeruleus. Four days later, control and lesioned rats were tested following injections of either saline or 80 micrograms/kg LSD in a Behavioral Pattern Monitor which recorded the sequential patterns of their locomotor and investigatory (holepokes) responses. Liquid chromatographic measures of brain monoamines confirmed that xylamine reduced hippocampal NE by 80.8% and hypothalamic NE by 26% without affecting levels of serotonin or dopamine. Relative to controls, NE-depleted rats exhibited repetitive spatial patterns of locomotion with no alteration in the amount or rate of habituation of locomotor activity. Lesioned animals made fewer rearings and holepokes, particularly early in the hour test session. When given 80 micrograms/kg LSD, sham-lesioned rats exhibited the expected decreases in entries into and time spent in the center of the chamber, an increase in time spent in the corners, and fewer holepokes and rearings early in the session. With the exception of the effect on rearings and holepokes, the effects of LSD were diminished in rats depleted of brain NE. These results indicate that this profile of behavioral effects of LSD, which has been interpreted as a potentiation of neophobia, may be dependent upon the noradrenergic projections of the locus coeruleus.     

Spatial and temporal patterning distinguishes the locomotor activating effects of dizocilpine and phencyclidine in rats

A behavioral pattern monitor was used to assess the effects of dizocilpine (MK-801) and phencyclidine on the spatial and temporal patterns of locomotion and investigatory behavior in rats. The monitor provided both quantitative measures of crossovers, rearings and holepokes and qualitative measurement of the spatial and temporal patterns of locomotion. Dizocilpine (0.004-0.5 mg/kg) and phencyclidine (0.25-5.0 mg/kg) produced similar, dose-dependent increases in locomotor activity. At small doses, dizocilpine and phencyclidine increased investigatory holepokes, while at larger doses, both drugs significantly decreased the number of holepokes. Rearings were reduced similarly by the larger doses of each drug. Both dizocilpine and phencyclidine produced perseverative spatial patterns of locomotion, especially at larger doses. However, the locomotor patterns produced by these drugs were found to be dissimilar in spatial quality. After phencyclidine, animals frequently circled the perimeter of the monitor chamber or moved repetitively in horseshoe or figure-8 patterns. By contrast, rats given dizocilpine completed small rotations about either end of the chamber. Pretreatment with a small dose (0.02 mg/kg) of haloperidol, prior to either dizocilpine (0.5 mg/kg) or phencyclidine (5.0 mg/kg) had no effect on the increase in locomotor activity or the decreases in investigatory holepokes produced by the drugs. However, haloperidol altered the effects of phencyclidine on the spatial and temporal patterns of locomotion, suggesting that sigma receptors or other haloperidol-sensitive binding sites, may influence the quality but not the quantity of phencyclidine-induced hyperactivity.     

Locomotor effects of lisuride: A consequence of dopaminergic and serotonergic actions

The open-field test was used to study the involvement of serotonergic and dopaminergic mechanisms in the action of lisuride on locomotor activity in the rat. Lisuride produced a biphasic locomotor effect. The maximum locomotor stimulatory response of lisuride was stronger than that of apomorphine and comparable with that of apomorphine and LSD combined. Hypermotility induced by high doses of lisuride was partially suppressed by the serotonin antagonist cyproheptadine and not further enhanced by LSD. A moderate dose of lisuride potentiated apomorphine-induced hypermotility in the same manner as has been shown for LSD. Lesion of dopaminergic structures within the median raphe nucleus by 6-OHDA produced a potentiation of lisuride-induced hypermotility. This effect was suppressed by cyproheptadine. The locomotor inhibitory effect of low doses of lisuride may be related to a stimulation of presynaptic mesolimbic dopamine receptors. It is concluded that the locomotor stimulant effect of higher doses of lisuride may depend on stimulation of postsynaptic dopamine receptors and a scrotonergic action and that the locomotor effects of lisuride reflect a complex interaction at dopaminergic and serotonergic transmission systems.     

LSD-induced alterations of locomotor patterns and exploration in rats

A free exploration test was used to examine the effects of LSD on investigatory responding and locomotor activity in a novel environment. Rats were injected with 20–30 g/kg LSD or saline prior to being placed in a home cage. After 10 min, a door was opened permitting entry into a larger holeboard chamber where crossovers, rearings, hole pokes, and routes of locomotion were monitored. When administered either 10 or 30 min prior to testing, LSD reduced the time spent in the holeboard chamber only during the first half of a 1-h session, resulting in a corresponding reduction in all holeboard activity measures. In the subsequent 30 min, LSD-treated rats maintained a steady level of responding, in contrast to the continual derement exhibited by controls. Despite their initial avoidance of the holeboard, LSD-treated rats made consistently longer hole pokes into floor holes and showed a more diversified pattern of locomotion than did controls throughout the 1-h session. Most striking was the failure of LSD-treated rats to establish the stereotyped excursion routes, characteristic of controls, from the home cage to various parts of the holeboard. It is suggested that LSD potentiates both neophobic (avoidance) and investigatory responses to a novel environment by retarding the rate of behavioral habituation.     

Comparison of the effects of LSD and lisuride on A10 dopamine neurons in the rat

Extracellular single-unit recording techniques were used to compare the effects of d-lysergic acid diethylamide (LSD) and its non-hallucinogenic congener lisuride hydrogen maleate (LHM) on the activity of dopamine (DA) neurons in the A10 region of the rat ventral tegmental area. Lisuride hydrogen maleate potently suppressed the firing rates of A10 DA cells (ID₅₀ = 0.021 mg/kg). The DA antagonist haloperidol prevented, but did not reverse, the effect of lisuride. In addition, the DA agonist apomorphine was unable to suppress further the firing rates of A10 DA cells that had been partially suppressed by small doses of lisuride. These results suggest that lisuride acted as a non-competitive or irreversible DA agonist. In contrast to lisuride, LSD exerted mixed effects on A10 DA cells, partially depressing the firing rates of 54% of the cells tested, increasing the firing rates of 23% of the cells and exerting no effect on the other 23%. The response of a particular A10 DA cell to administration of LSD was dependent upon its baseline firing rate. Haloperidol readily reversed the LSD-induced partial suppression of the firing of A10 DA cells. Also, LSD effectively reversed apomorphine-induced suppression and increased the doses of apomorphine required to suppress firing of A10 DA neurons. These results suggest that, in addition to its weak DA agonist effects, LSD also exerted partial DA antagonist effects. Pharmacological and physiological manipulations of serotonergic neuronal systems failed to implicate a role for serotonin in the effects of LSD and lisuride on A10 DA neurons. These qualitative and quantitative differences between the effects of LSD and lisuride on A10 DA neurons suggest that the potent DA agonist actions of lisuride may contribute to its lack of hallucinogenic potential.     

Serotonergic and dopaminergic effects on yawning in the cat

The serotonergic agents LSD (0.01–0.05 mg/kg) and lisuride (0.025 and 0.05 mg/kg) elicited a high frequency of limb flicking in the cat after IP doses; LSD, but not lisuride, elicited a significantly increased frequency of yawning as well. In combination, LSD plus lisuride (0.25 mg/kg each) gave additive frequencies of limb flicking, but the frequency of yawning was half that after LSD alone. The dopamine agonist apomorphine had no significant effect on either yawning or limb flicking over the dose range 0.006 to 3.2 mg/kg. Pretreatment of cats with 1.0 mg/kg of apomorphine (but not with 0.05 mg/kg) significantly reduced the frequency of yawning elicited by 0.01 or 0.025 mg/kg of LSD, but had no effect of limb flicking. The dopamine antagonist haloperidol had no effect on limb flicking at doses from 0.008 to 0.512 mg/kg, but produced a significantly increased frequency of yawning at 0.256 mg/kg, an effect antagonized by lisuride administration. Given that lisuride has more potent dopamine agonist properties than LSD, these results are consistent with serotonergic elicitation of yawning, dopaminergic inhibition of yawning, and with their concomitant interaction in the expression of drug-induced yawning in the cat. The behavioral pharmacologies of limb flicking and yawning are different in this species.     

Dissociation of multiple effects of acute LSD on exploratory behavior in rats by ritanserin and propranolol

Rats tested for 1 h in the Behavioral Pattern Monitor (BPM) after injection of the mixed serotonergic agonistd-lysergic acid diethylamide (LSD) exhibit a behavioral profile similar to that produced by various hallucinogenic 5HT-2 agonists. The characteristic effects of the hallucinogens include suppression of locomotor and exploratory behavior and a preferential decrease in entries into the center of the BPM during the initial half of the test session. After LSD, the initial suppression of responding is followed by a subsequent increase in locomotor activity that is not observed with other serotonergic agonists. In the present studies, the 5HT-1 andβ-adrenergic antagonistd,1-propranolol and the 5HT-2 antagonist ritanserin were administered individually or in combination prior to the acute administration of LSD to test for the involvement of these receptor subtypes in the mediation of the effects of LSD in the BPM paradigm. Propranolol (20 mg/kg) abolished the initial suppression of activity induced by 60 μg/kg LSD without affecting the subsequent increase in locomotion. Conversely, 2.0 mg/kg ritanserin failed to block the initial suppressive effects of 60 or 120 μg/kg LSD, but attenuated the LSD-induced increases in activity during the second half of the session. The combination of propranolol and ritanserin prevented both these effects of LSD. By contrast, the more selective 5HT-2 agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) (0.27 mg/kg) produced an initial suppression of activity in the BPM that was blocked by 2.0 mg/kg ritanserin and was not followed by a subsequent increase in activity. These findings suggest that the initial suppressive effects of LSD in the BPM paradigm are dissociable from the subsequent increases in locomotion and that the two effects are mediated via different serotonergic orβ-adrenergic receptors.     

Effect of lisuride and LSD on monoamine synthesis after axotomy or reserpine treatment in rat brain

Summary The effect of d-lysergic acid diethylamide (LSD) and lisuride on the synthesis of monoamines was evaluated in rat brain regions using an in vivo method in which the accumulation of dopa and 5-hydroxytryptophan (5-HTP) is measured after inhibition of the aromatic amino acid decarboxylase by means of 3-hydroxybenzylhydrazine.LSD (50–1000 g/kg i.p.) caused a dose-dependent increase in dopa formation and a slight elevation of tyrosine and tryptophan concentrations in the intact rat forebrain; moreover, it reduced the accumulation of 5-HTP.The increase in dopa formation in the terminal system of the rat forebrain following an axotomy of the ascending monoaminergic fiber system was antagonized by LSD at a dose of 0.5 mg/kg i.p. Haloperidol (2 mg/kg i.p.) counteracted the effect of LSD.The increase in dopa formation in c. striatum and the dopamine-rich part of the limbic system following treatment with reserpine was antagonized by lisuride as well as by LSD. However, lisuride was at least 10 times as potent as LSD. In reserpinized animals LSD counteracted the inhibitory effect on dopa accumulation of the direct dopamine receptor stimulant apomorphine while lisuride did not. The data suggest that LSD is a weak agonist at dopamine receptors in vivo with partial receptor blocking properties at higher doses, while the action of lisuride on dopamine receptors is a potent, purely agonistic one.with technical assistance of Ruth NeumeisterPart of this paper has been presented at the Spring Meeting 1977 of the German Pharmacological Society at Mainz (Kehr, 1977b)     

Dopamine agonists increase pallidal unit activity: Attenuation by agonist pretreatment and anesthesia

Intravenous administration of a single bolus dose of 1 μ mol/kg of the dopamine agonists, pergolide and lisuride, caused marked increases in the unit activity of globus pallidus neurons in awake, paralyzed, locally anesthesized and artificially respired rats. These agonist effects were similar to those observed after administration of 1 μ mol/kg apomorphine to awake, paralyzed rats; in rats anesthetized with chloral hydrate, however, responses to apomorphine were markedly attenuated. Subsequent administration of haloperidol reversed the effects of pergolide and pretreatment with haloperidol blocked the effects of lisuride. LSD (1 μ mol/kg i.v.) did not effectively stimulate pallidal neuronal activity, suggesting that the ability to stimulate pallidal firing rates correlates better with dopamine, as opposed to serotonin, agonist potency. The ability of a non-excitatory dose of apomorphine to attenuate responses of pallidal neurons to a normally excitatory 1 μ mol/kg dose of this agonist administered subsequently, was reconfirmed. Pretreatment with this ‘priming’ dose of apomorphine also attenuated the rate increases produced by d-amphetamine (8.7 μ mol/kg) and enhanced the rate inhibitory effects of haloperidol. The ‘priming’ effect appears related to the dopamimetic effects of apomorphine; a non-excitatory dose of a second dopamine agonist, lisuride (0.07 μ mol/kg i.v.), similarly blocked the effect of excitatory doses of lisuride (1 μ mol/kg i.v.) on pallidal activity     

Activity of a non-hallucinogenic ergoline derivative,lisuride, in an animal behavior model for hallucinogens

The behavioral effects of IP administration of lisuride, a non-hallucinogenic iso-lysergic acid amide analog structurally related to d-lysergic acid diethylamide (LSD), were examined in 15 cats. Ten animals were given saline or 6.25, 12.5, 25, 50, or 100 g/kg of lisuride and observed for 1 h by a rater blind to dose. There was a statistically significant effect of lisuride dose on the frequency of occurrence of the behaviors limb flicking, grooming, and abortive grooming. A time-course study with five cats at the most effective lisuride dose, 50 g/kg, revealed that the frequencies of occurrence of these behaviors reached a maximum during the first 2 h post dose, and were comparable to frequencies after saline by 6 h post dose. An acute tolerance study with four cats scored for 90 min post dose revealed no significant tolerance to a 50 g/kg lisuride test dose administered 6, 24, or 72 h after an initial 50 g/kg dose. Acute cross tolerance studies with four cats scored for 90 min after an initial dose of 50 g/kg of LSD or of lisuride, followed 24 h later by 50 g/kg of lisuride or LSD, revealed no significant cross tolerance. The potency of lisuride relative to LSD was evaluated in six cats that were scored for 60 min following 25 and 50 g/kg of LSD and of lisuride. On a molar basis, scores after lisuride were 51% and 67% those after LSD for limb flicking and grooming. These results indicate that lisuride, a non-hallucinogenic iso-lysergic acid derivative, is a false positive in the animal behavior model for hallucinogens.     

Re-evaluation of lisuride pharmacology: 5-hydroxytryptamine1A receptor-mediated behavioral effects overlap its other properties in rats

Abstract Rationale. There is substantial evidence that lisuride can produce effects linked to 5-HT_1A receptor occupancy. Nevertheless, this action has generally been ignored in the mechanism of action of lisuride, in favor of an exclusive role for dopamine receptors in considering its antiparkinsonian effects, or an exclusive role of 5-HT_2A/2C receptor activation in hallucinogenesis. These conclusions are surprising when one considers that the potent interaction of lisuride with 5-HT_1A receptors has been demonstrated in several different laboratories and that activation of 5-HT_1A and 5-HT_1B receptors can modulate dopaminergically mediated responses. Objective. The lack of full substitution of lisuride for lysergic acid diethylamide (LSD) in drug discrimination experiments and induction of a pronounced 5-HT syndrome by this compound at relatively low doses convinced us to execute two series of experiments that might explain the primary mechanism responsible for lisuride-mediated biological effects and its paradoxical classification as a dopamine agonist in the literature. Results. In drug discrimination studies, lisuride fully mimicked the 5-HT_1A agonist LY 293284, only partially substituted for LSD and DOI, and failed to substitute for (+)-amphetamine. Lisuride produced a significant dose-related increase in flat body posture, forepaw treading, and lower-lip retraction which reflect a modulation of behavior by action at central 5-HT_1A receptors. Only pMPPI [4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridynyl-benzamide hydrochloride], a selective 5-HT_1A antagonist, was effective in inhibiting all 5-HT syndrome behaviors produced by lisuride, whereas pMPPI was without effect on any behavior induced by LSD. Lisuride dose dependently decreased body temperature in rats with a potency similar to that of the selective 5-HT_1A agonist LY 293284. The hypothermic effect of lisuride was prevented by pre-injection of pMPPI, but not by ketanserin or haloperidol. Conclusion. We have demonstrated that the behavioral effects of low doses of lisuride are clearly mediated by stimulation of 5-HT_1A receptors. Electronic Publication     

Dopaminergic and serotonergic mediation of the discriminable effects of Ergot alkaloids

The involvement of dopamine (DA) and serotonin (5-HT) neuronal systems in the discriminative stimulus effects of various ergot derivatives was assessed by administering four ergots to 36 rats which had been trained to discriminate either apomorphine (APO) or d-lysergic acid diethylamide (LSD) from saline. Lergotrile, lisuride and LSD substituted for APO (0.25 mg/kg) while bromocriptine and ergonovine (ergometrine) did not; only lisuride mimicked LSD (0.08 mg/kg). Antagonism tests showed that the DA antagonist haloperidol but not the 5-HT antagonist BC-105 (pizotifen) blocked the APO cue; both the LSD cue and the substitution of LSD for APO were blocked by BC-105 but not by haloperidol. It was concluded that DA receptor activation plays a prominent role in the discriminative stimulus effects of lergotrile and lisuride as well as APO and a secondary role in the LSD cue; 5-HT seems to be of major importance in the mediation of the effects of LSD and, to a lesser extent, lisuride. The functions of the two monoamines in the discriminable effects of bromocriptine and, particularly, ergonovine are less clear.     

Behavioral effects of intracerebroventricular administration of LSD, DOM, mescaline or lisuride

The effects on a fixed ratio-40 (FR-40) operant behavior of intracerebroventricular (ICV) administration of the hallucinogens lysergic acid diethylamide (LSD), 2,5-dimethoxy-4-methylamphetamine (DOM), mescaline or the non-hallucinogenic LSD-analogue lisuride were compared with intraperitoneal (IP) administration. Infusion of LSD (8.5 to 34 micrograms) into the left lateral ventricle produced a dose-dependent decrease in reinforcers and an increase in 10-sec periods of non-responding (pause intervals). The time-course of LSD showed a shorter latency to onset after ICV than IP administration. The ED50 for doses increasing pause intervals by ICV administration was 15 micrograms. This disruption was greater than that produced by IP administration of equivalent doses of LSD (IP ED50: 19 micrograms). DOM (40 to 120 micrograms) infused into the lateral ventricle also produced a dose-dependent disruption of FR-40 behavior. ICV DOM also showed a rapid onset to peak effects, but a slower offset than LSD, and was 3 times more potent than systemic administration (ED50s: 58 micrograms ICV vs. 153 micrograms IP). Mescaline was much more potent in disrupting FR-40 behavior by the ICV route than by IP administration. The ICV ED50 for doses of mescaline increasing pause intervals was 74 micrograms, in contrast to an ED50 following systemic administration of 2251 micrograms, demonstrating a 30-fold difference in potency. Lisuride administered via the ICV route was no more potent than by IP administration with ED50s of 4 micrograms ICV and 4 micrograms IP. Lower doses of lisuride administered by both routes had a similar effect over time on pause intervals.(ABSTRACT TRUNCATED AT 250 WORDS)     

The 5HT2 antagonist pirenperone reverses disruption of FR-40 by hallucinogenic drugs

Indolealkylamine and phenethylamine hallucinogens disrupted responding maintained under a fixed-ratio 40 (FR-40) schedule of reinforcement. LSD, DMT, mescaline and DOM produced dose-dependent decreases in number of reinforcers and increases in 10-sec periods of non-responding (pause-intervals). The 5HT agonist quipazine, as well as the LSD congener lisuride, altered response patterns in a similar manner. The effects of these drugs were examined after pretreatment with pirenperone, an antagonist with specificity toward the 5HT2 receptor with reference to the 5HT1 receptor. The dose-response curves for the phenethylamine hallucinogens were shifted significantly to the right and to a greater degree than were those for the indolealkylamine hallucinogens. Pirenperone also antagonized the effects of quipazine to a degree similar to that observed with the phenethylamine-type hallucinogens. Pirenperone did not significantly shift the dose-response pattern to lisuride. These data suggest that the behavioral disruption induced by these hallucinogens and quipazine relates at least in part to an effect on 5HT2 receptors, while the effects of lisuride do not involve a significant interaction at the 5HT2 receptor.     

LSD but not lisuride disrupts prepulse inhibition in rats by activating the 5-HT2A receptor

Rationale

Compounds that activate the 5-HT_2A receptor, such as lysergic acid diethylamide (LSD), act as hallucinogens in humans. One notable exception is the LSD congener lisuride, which does not have hallucinogenic effects in humans even though it is a potent 5-HT_2A agonist. LSD and other hallucinogens have been shown to disrupt prepulse inhibition (PPI), an operational measure of sensorimotor gating, by activating 5-HT_2A receptors in rats.

Objective

We tested whether lisuride disrupts PPI in male Sprague–Dawley rats. Experiments were also conducted to identify the mechanism(s) responsible for the effect of lisuride on PPI and to compare the effects of lisuride to those of LSD.

Results

Confirming a previous report, LSD (0.05, 0.1, and 0.2 mg/kg, s.c.) reduced PPI, and the effect of LSD was blocked by pretreatment with the selective 5-HT_2A antagonist MDL 11,939. Administration of lisuride (0.0375, 0.075, and 0.15 mg/kg, s.c.) also reduced PPI. However, the PPI disruption induced by lisuride (0.075 mg/kg) was not blocked by pretreatment with MDL 11,939 or the selective 5-HT_1A antagonist WAY-100635 but was prevented by pretreatment with the selective dopamine D₂/D₃ receptor antagonist raclopride (0.1 mg/kg, s.c).

Conclusions

The effect of LSD on PPI is mediated by the 5-HT_2A receptor, whereas activation of the 5-HT_2A receptor does not appear to contribute to the effect of lisuride on PPI. These findings demonstrate that lisuride and LSD disrupt PPI via distinct receptor mechanisms and provide additional support for the classification of lisuride as a non-hallucinogenic 5-HT_2A agonist.     

Agonist activity of LSD and lisuride at cloned 5HT2A and 5HT2C receptors

Evidence from studies with phenylisopropylamine hallucinogens indicates that the 5HT_2A receptor is the likely target for the initiation of events leading to hallucinogenic activity associated with LSD and related drugs. Recently, lisuride (a purported non-hallucinogenic congener of LSD) was reported to be a potent antagonist at the 5HT_2C receptor and an agonist at the 5HT_2A receptor. LSD exhibited agonist activity at both receptors. These data were interpreted as indicating that the 5HT_2C receptor might be the initiating site of action for hallucinogens. To test this hypothesis, recombinant cells expressing 5HT_2A and 5HT_2C receptors were used to determine the actions of LSD and lisuride. LSD and lisuride were potent partial agonists at 5HT_2A receptors with EC₅₀ values of 7.2 nM and 17 nM, respectively. Also, LSD and lisuride were partial agonists at 5HT_2C receptors with EC₅₀ values of 27 nM and 94 nM, respectively. We conclude that lisuride and LSD have similar actions at 5HT_2A and 5HT_2C receptors in recombinant cells. As agonist activity at brain 5HT_2A receptors has been associated with hallucinogenic acitivity, these results indicate that lisuride may possess hallucinogenic activity, although the psychopharmacological effects of lisuride appear to be different from the hallucinogenic effects of LSD. Received: 19 September 1997/Final version: 31 October 1997     

Chlordiazepoxide modified exploration in rats

Effects of 2.5, 3.75 and 5.0 mg/kg chlordiazepoxide on locomotion, rearing and preferences for novelty in rats were observed in an exploration box comprising a novel and a familiar half. Whereas an inverted U relationship between dose strength and locomotion was evident, rearing declined with increasing dosage. However, the two lower doses had little effect on preferences for novelty but 5.0 mg/kg produced a marked decrease to the point where the familiar half of the apparatus was preferred. It was concluded that estimates of drug effects on measures of locomotion or general activity are specific to those behaviours alone and do not necessarily relate to environmentally oriented exploration. Different views of the effects of drugs on exploratory behaviour might arise from the use of more valid indices, such as preferences for novelty.This work was supported by a research grant from the University Grants Committee (New Zealand).     

Differential effects of the dopamine antagonist remoxipride on apomorphine induced behaviour in the rat

The effects of the novel substituted benzamide remoxipride on apomorphine induced behaviour in rats was investigated by means of an automatic holeboard apparatus. The ability of remoxipride to antagonise locomotion and gnawing induced by a high dose of apomorphine (5 mg/kg) and inhibition of exploration induced by a low dose of apomorphine (0.05 mg/kg) was tested. It was found that remoxipride in moderate doses potentiate locomotion and inhibit gnawing induced by the high dose of apomorphine while higher doses of remoxipride inhibits both apomorphine induced gnawing and locomotion. The inhibition of exploration following the low dose of apomorphine was not antagonised by remoxipride pretreatment. The results demonstrated that remoxipride has an interesting and unique profile of dopamine antagonistic effects in rat behavioural models.     

Tolerance to hypoactivity and sensitization to hyperactivity after chronic treatment with a presynaptic dose of lisuride in rats.

We studied the adaptive changes of the locomotor effects of lisuride, a selective agonist for dopamine (DA) D2 receptors, and the functional state of D1 and D2 receptors after repeated administration of lisuride at a dose supposed to act preferentially on DA autoreceptors. Rats were treated daily with saline or lisuride, at a dose that causes a significant reduction in locomotor activity when given to naive rats (25 micrograms/kg i.p.), for 33 days and the effect of different challenging doses of the drug on locomotor activity was measured at different times during and after the treatment. The functional state of D1 and D2 DA receptors was evaluated by measuring SKF 82526-stimulated and LY 171555-inhibited adenylate cyclase (AC) activity in the caudatus/putamen, nucleus accumbens and substantia nigra and naive and chronically treated rats. There was a progressive decline in the ability of lisuride to decrease locomotor activity in rats given daily injections of lisuride, and there was a marked reduction in the threshold dose of lisuride for causing hypermotility. The functional state of DA receptors, positively or negatively linked to AC activity, was not modified by the treatment. The most suitable explanation of the reported adaptive behavioral changes is a down-regulation of DA autoreceptors after chronic treatment with presynaptic doses of lisuride.