Stimulation Of Motor Activity Research Articles

Onset of antidepressant activity: reexamining the structure of depression and multiple actions of drugs.

The question of when antidepressant drugs (AD) initiate significant clinical actions in depressed patients is still unsettled. Findings from early studies on whether there is a lag in the onset of therapeutic actions were in disagreement. More recent results with the selective serotonin reuptake inhibitors (SSRIs) and other new ADs indicate that clinical actions occur within the first 2 weeks. In this paper, evidence from efficacy studies with the ADs is reviewed and the methodologic and conceptual obstacles to achieving definitive results about the onset issue are analyzed. Depression, formerly viewed as a homogenous disorder, is now seen as heterogenous and multifaceted in structure. Such major structural components as anxiety and disturbed psychomotor functioning can be as significant to the core of the disorder as depressed mood itself. Further, the ADs have been shown to act initially on different facets of the clinical disorder which then result in multiple clinical actions, e.g., an initial reduction in anxiety followed by stimulation of motor activity. Data from the NIMH Collaborative Study of the Psychobiology of Depression are used to illustrate: (1) the componential structure of severe depressive disorder; (2) the sequence of change in the major behavioral components of the disorder associated with the tricyclic drugs; (3) the consequent "multiple" onsets of clinical actions; and (4) measurement of the clinical significance and visibility of the early behavioral changes. Recent results describing new behavioral and methodological approaches, the use of early clinical changes to predict outcome, and strategies for designing sound studies of onset are discussed.

Vagus-Dependent and Vagus-Independent Mechanisms of Action of the Erythromycin Derivative EM574 and Motilin in Dogs

The motor-stimulating action of de(N-methyl)-N-isopropyl-8,9-anhydroerythromycin A 6,9-hemiacetal (EM574) on the upper gastrointestinal tract was studied in fasted conscious dogs using chronically implanted force transducers and compared with those of porcine motilin and cisapride. EM574 induced gastric phase Ill-like migrating contractions and increased the plasma motilin levels slightly. The gastric motility induced by low doses of EM574 and motilin was abolished by a 5HT3-receptor antagonist ondansetron and acute vagal blockade, whereas under these conditions, high doses of both agents induced contractions, which were abolished by atropine. Cisapride-induced gastric motility was inhibited by atropine and acute vagal blockade, but not by ondansetron. EM574 did not stimulate gastric secretion in the basal state. These results indicate that EM574- and motilin-induced gastrointestinal motility is attributable mainly to motor-stimulating vagal cholinergic neurons, and 5HT3-receptors are probably involved in the process. At high doses, EM574 and motilin also appear to stimulate cholinergic neurons in a non-vagal pathway, probably the enteric nervous system.

Effects of intracerebroventricular administration of pituitary adenylate cyclase-activating polypeptide (PACAP) on the motor activity and reserpine-induced hypothermia in murines

We investigated the effects of i.c.v. administration of pituitary adenylate cyclase-activating polypeptide (PACAP) on the spontaneous motor activity and reserpine-induced hypothermia in murines. The administration of PACAP (1 or 2 nmol) caused a dose-dependent increase in both spontaneous motor activity and rearing behavior in the rat. The peptide (0.1 or 0.2 nmol) counteracted reserpine-induced hypothermia in a dose-dependent manner in mice. On the other hand, i.c.v. injection of vasoactive intestinal polypeptide, which is structurally similar to PACAP, at a dose similar to that of PACAP (2 nmol in rats, 0.2 nmol in mice) did not show a significant effect on either behavior or body temperature. Therefore, the stimulating effect of PACAP observed here may be mediated by PACAP-specific (type I) receptors. PACAP was more potent and longer-lasting than a known potent stimulating peptide, thyrotropin-releasing hormone, in both stimulating motor activity and counteracting reserpine-induced hypothermia. Results of the present study, in combination with those of previous studies identifying endogenous PACAP in the brain, suggest that PACAP may play an important role in the CNS as a stimulant in regulating motor activity and body temperature.

Motor actions of 7-OH-DPAT in normal and reserpine-treated mice suggest involvement of both dopamine D 2 and D 3 receptors

In non-habituated mice, 7-hydroxy- N,N-di- n-propylaminotetralin (7-OH-DPAT, 0.04–10 mg/kg s.c.) potently and rapidly suppressed species-typical behaviours and induced frozen postures, with only occasional evidence of weak behavioural stimulation occurring at 5–10 mg/kg. This inhibitory effect was reversed by the dopamine D 1 receptor agonist 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1 H-3-benzazepine hydrochloride (SKF 38393, 10 mg/kg i.p.). 7-OH-DPAT (3–10 mg/kg) did not reinstate locomotion in 4 h habituated mice, either when administered alone or in conjunction with a threshold dose of SKF 38393 (3 mg/kg). By contrast, 7-OH-DPAT (0.2–10 mg/kg) dose-dependently reversed the akinesia of 24 h reserpine-treated mice. This response was blocked by the dopamine D 2 receptor antagonist raclopride (10 mg/kg i.p.), but not by the dopamine D 1 receptor antagonist ( R)-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1 H-3-benzazepine-7-ol hemimaleate (SCH 23390, 0.05 mg/kg i.p.), and was potentiated synergistically by coinjection of SKF 38393 (3 mg/kg). These and earlier data suggest the motor inhibitory effects of 7-OH-DPAT (low doses) in normal animals are mediated by dopamine autoreceptors (D 2 and/or D 3), whilst its motor stimulant actions in normal (high doses) and in dopamine-depleted, supersensitive animals, are mediated by dopamine D 2 receptors.

Synergistic interactions between COMT-/MAO-inhibitors and L-Dopa in MPTP-treated mice.

Four experiments were performed to investigate the anti-akinesia effects of combining a sub-threshold dose (5 mg/kg, s.c.) of L-Dopa with different doses and combinations of COMT and MAO inhibitors upon the hypokinesia observed in MPTP-treated mice. Ro 40-7592 (1 and 3 mg/kg, s.c.), a novel COMT inhibitor, 60 min before L-Dopa reinstated both locomotion and rearing during a 2-hr interval after L-Dopa in MPTP mice; control mice were unaffected. The combination of Ro 40-7592 (3 mg/kg, s.c.) and pargyline (5 mg/kg, s.c.), a MAO inhibitor, with L-Dopa produced increases in both the peak effect and duration of action indicating a distinct potentiation of the effects of Ro 40-7592 by pargyline. L-Deprenyl, a MAOB inhibitor, together with L-Dopa, restored locomotion and rearing behaviour at all three doses applied (1, 3 and 10 mg/kg, s.c.); in control mice, motor activity was stimulated at the higher doses (3 and 10 mg/kg, s.c.), independent of L-Dopa administration. Combining L-Deprenyl (3 mg/kg, s.c.) with Ro 40-7592 (3 mg/kg, s.c.) one hr before L-Dopa to MPTP mice potentiated the restorative effects of each compound by itself, although no increase in peak effect was obtained. In the control mice, L-Deprenyl plus Ro 40-7592 or L-Deprenyl, by itself, stimulated motor activity following injection of L-Dopa. Marked dopamine (DA) depletions in the striatum of MPTP-treated mice were evident. The present results demonstrate that the effects of the COMT/MAO inhibitors in combination, and in conjunction with L-Dopa (at a dose that was without effect by itself), were well in excess of a summation of their individual effects. It was concluded therefore that a synergism of the restorative, anti-akinesic action of these compounds in MPTP-treated mice could offer a broader therapeutic spectrum in the treatment of Parkinson's disorder.

Potentiation of dopamine-dependent locomotion by clonidine in reserpine-treated mice is restricted to D2 agonists.

Mice treated with reserpine (5 mg/kg IP), 24 h beforehand, were completely akinetic. Fluent locomotion was reinstated with the D1-selective agonist SKF 38393 (3-30 mg/kg IP), the D2-selective agonist RU 24213 (0.5-5 mg/kg SC) and the mixed D1/D2 agonist apomorphine (0.025-0.5 mg/kg SC). Clonidine (0.03125-1 mg/kg IP) caused a dose-dependent sedation in dopamine-intact mice, but had no effect by itself on the locomotor activity of monoamine-depleted mice. In drug interaction experiments, clonidine did not modify the motor stimulant action of SKF 38393, but greatly enhanced the motor responses to RU 24213 and apomorphine. These results support the hypothesis that alpha-adrenoceptor agonists facilitate dopamine D2 but not dopamine D1 motor responding in the reserpine-treated mouse model of Parkinson's disease.

Influence of naloxone upon motor activity induced by psychomotor stimulant drugs.

Naloxone, an opioid receptor antagonist, attenuates a wide range of behavioral effects of d-amphetamine, such as the stimulation of motor activity. To investigate the pharmacological selectivity of the naloxone/amphetamine interaction, we assessed the effects of naloxone (5.0 mg/kg SC) upon motor activity induced in rats by a range of psychomotor stimulant drugs with a mechanism of action either similar to or different from that of d-amphetamine. Each of the drugs tested caused dose-dependent increases in both gross and fine activity. Naloxone attenuated the gross but not the fine activity response to d- and l-amphetamine, but had no influence upon the other catecholamine-releasing drugs, methamphetamine and phendimetrazine. In contrast, naloxone increased the gross but not the fine activity response to the catecholamine uptake inhibitors cocaine and mazindol, but had no effects upon the motor response to methylphenidate. The responses to other stimulant drugs (apomorphine, caffeine, scopolamine) were unaffected by naloxone pretreatment. The present findings extend the range of conditions under which naloxone and, by inference, endogenous opioid systems, modulate the behavioral response to psychomotor stimulants. However, the differential effects of naloxone upon the motor response to individual stimulant drugs support previous suggestions of fundamental differences in mechanisms of action among these compounds.

Stimulating action of KW-5139 (Leu13-motilin) on gastrointestinal motility in the rabbit.

1. The gastrointestinal motor stimulating action of the motilin analogue, KW-5139 (Leu13-motilin), was investigated both in the anaesthetized rabbit and in rabbit isolated smooth muscle tissues. 2. KW-5139 (0.3-10 micrograms kg-1, i.v.) produced motor stimulating actions in the gastric antrum, ileum and descending colon, the excitatory responses of which were initiated at the same time but declined with different time courses. The rank order of the excitatory response was: descending colon > or = gastric antrum >> ileum. 3. Atropine (1-3 mg kg-1, i.v.) or naloxone (1 mg kg-1, i.v.) completely suppressed the excitatory response to KW-5139 in the gastric antrum, but only partially attenuated that in the descending colon. This suggests that the mechanism of the excitatory response is different in the gastric antrum and the descending colon, and that cholinergic neural pathway is involved in the response of the gastric antrum. 4. KW-5139 (0.1 nM-1 microM) caused concentration-dependent contractions of the gastric antrum, duodenum, jejunum, ileum and the descending colon in vitro. In the rabbit intestine, the contractile response to KW-5139 was strongest in the duodenum and weakest in the ileum. 5. The contractile response to KW-5139 in the intestinal segments were not affected by tetrodotoxin, but were decreased by verapamil, or pretreatment with a high concentration of porcine motilin, confirming the involvement of motilin receptors in the response to KW-5139. 6. The present results suggest that the rabbit is a suitable species for the investigation of motilin on gut motility, because of the high responsiveness of the descending colon as well as the upper gastrointestinal tract.

Glutamate antagonists modify the motor stimulant actions of D1 and D2 agonists in reserpine-treated mice in complex ways that are not predictive of their interactions with the mixed D1/D2 agonist apomorphine.

In 24h reserpine-treated mice, the locomotion induced by the D1 dopamine agonist SKF 38393 (30 mg/kg IP) was facilitated by the NMDA antagonists MK 801 (0.4 mg/kg IP), CPP (1 mg/kg IP), CGP 40116 (1 mg/kg IP) and HA 966 (2 mg/kg IP), and by the AMPA antagonist NBQX (0.2 mg/kg IP). By contrast, CPP, CGP 40116 and NBQX had no effect on, while MK 801 and HA 966 suppressed, the locomotion elicited by the selective D2 agonist RU 24213 (5 mg/kg SC). When these same doses of glutamate antagonists were tested against the locomotion induced by a threshold (0.025 mg/kg SC), intermediate (0.1 mg/kg SC) or large dose (0.5 mg/kg SC) of the mixed D1/D2 agonist apomorphine, CPP, CGP 40116 and HA 966 were found to have no significant effect, whilst MK 801 was strongly inhibitory and NBQX potentiated the response to 0.1 mg/kg apomorphine only. It is evident from these data that the behavioural interaction profiles between glutamate antagonists and dopamine agonists are complex and depend on the receptor selectivities of the drugs concerned. The manner of the interaction between these glutamate antagonists and selective D1 or D2 agonists, is not predictive of the way that blockade of glutamate transmission interferes with the actions of drugs which have combined D1 and D2 motor stimulant properties.

A comparison of the motor-activating effects of acute and chronic exposure to amphetamine and methylphenidate

Acute exposure to methylphenidate (0.0, 5.0, 10.0, or 20.0 mg/kg) or amphetamine (0.0, 0.5, 1.0, 2.0, or 4.0 mg/kg) dose-dependently increased horizontal activity. The amphetamine-induced increase in activity was progressively augmented with repeated exposures over 7 days. In contrast, methylphenidate (20.0 mg/kg)-induced increases in activity became smaller with repeated exposures. Subthreshold doses of methylphenidate (1.0 or 5.0 mg/kg) were ineffective in stimulating motor activity even after 7 daily exposures. These findings suggest that, although sensitization develops with chronic amphetamine treatment, the consequence of chronic exposure to methylphenidate is tolerance. These data are discussed in terms of the different mechanisms through which methylphenidate and amphetamine affect central dopamine release.

In Vitro Effects of the New Calcium Antagonist Lacidipine

Stimulatory effects of HSR-803 on intestinal motor activity in vitro were studied in guinea pig ileum. HSR-803 (1 x 10(-6)-1 x 10(-4) M) increased the amplitude of longitudinal muscle contractions and increased the frequency of peristalsis in isolated segments of guinea pig ileum. The stimulatory effect in amplitude and not frequency was abolished by 1 x 10(-6) M atropine. In the Magnus method with ileal segments, HSR-803 (1 x 10(-7) - 1 x 10(-4) M) produced contractions concentration-dependently, which were inhibited by atropine (1 x 10(-8) and 3 x 10(-8) M) and 3 x 10(-7) M tetrodotoxin (TTX). In the [3H]-quinuclidinyl benzilate (QNB) binding experiment with ileal smooth muscle, HSR-803 had low affinity for acetylcholine (ACh) receptors (pKi = 4.47 +/- 0.04). In addition, HSR-803 failed to increase the spontaneous release and the electrical stimulation-induced [3H]ACh release in ileal smooth muscle. On the other hand, HSR-803 (1 x 10(-5) M) enhanced contractions induced by ACh, but had no effect on contractions induced by carbachol, which is not hydrolyzed by acetylcholinesterase (AChE). In conclusion, HSR-803 stimulated ileal motor activity. However, HSR-803 had low affinity for ACh receptors and had no influence on ACh release. It is likely that HSR-803 stimulated motor activity mainly due to prevention of ACh hydrolysis.

Comparison of the Motor-Stimulating Action of EM523, an Erythromycin Derivative, and Prostaglandin F2α in Conscious Dogs

The effect of EM523 [de(N-methyl)-N-ethyl-8,9-anhydroerythromycin A 6,9-hemiacetal], an erythromycin derivative, on gastrointestinal motility was investigated using conscious dogs in the fasting state, and it was compared with those of motilin and prostaglandin F2 alpha (PGF2 alpha). EM523 and motilin given as i.v. infusions induced strong contractions in the stomach that migrated along the intestine. On the other hand, PGF2 alpha stimulated intestinal contractions, but its effect on gastric motility was weak. EM523 had 1/50 the potency of motilin and 6 times the potency of PGF2 alpha for stimulation of intestinal motility. Atropine at 0.1 mg/kg, i.v. strongly inhibited gastrointestinal contractions induced by EM52 EM523 or motilin and partly inhibited PGF2 alpha-induced intestinal motility. ICS-205-930, a 5HT3-receptor antagonist, at a dose of 1 mg/kg, i.v. strongly inhibited EM523 or motilin-induced gastric contractions but did not affect the action of PGF2 alpha. Infusion of EM523 at 100 micrograms/kg/hr induced strong migrating contractions even when motility was depressed by dopamine infusion or laparotomy. Infusion of PGF2 alpha at 300 micrograms/kg/hr stimulated intestinal but not gastric motility under these conditions. The results of this study indicate that the cholinergic pathway and 5HT3 receptors are involved in EM523 and motilin-induced migrating gastrointestinal contractions, whereas the cholinergic pathway seems to be only partly involved in PGF2 alpha-induced intestinal contractions.

Mechanism of the motor-stimulating action of motilin and motilide (EM523) in the dog

Mechanism of the motor-stimulating action of motilin and motilide (EM523) in the dog

Cholecystokinin's role in regulation of colonic motility in health and in irritable bowel syndrome

Colonic motor activity and plasma concentrations of cholecystokinin (CCK) both increase after oral intake of a meal. Thus, CCK had been thought to mediate the postprandial increase in colonic motor activity, which is termed gastrocolonic response. The present study used the substance loxiglumide, which acts as a specific antagonist at the CCK-A receptor, to evaluate this hypothesis. In the first set of experiments, eight healthy subjects were studied four times on separate days. A multilumen catheter was endoscopically placed with its tip lying in the descending colon. Motor activity was recorded by a low-compliance perfusion manometry system at six locations 60-45 cm from the anus. Basal activity was recorded for at least 2 hours to achieve steady-state conditions. The order of the following four experiments was randomized: (a) intravenous infusion of the CCK analogue cerulein at increasing doses (7.5, 15, 30, and 60 ng/kg · h, each given for 30 minutes); (b) intravenous cerulein plus 5 mg/kg · h loxiglumide; (c) a 1000-kcal solid/liquid meal consisting of regular German food; and (d) a meal plus 5 mg/kg · h loxiglumide. In the second set of experiments, eight patients with irritable bowel syndrome were studied twice on two separate days, and two experiments were performed in randomized order: (a) a 1000-kcal solid/liquid meal consisting of regular German food; or (b) a meal plus 5 mg/kg · h loxiglumide. The motor index was calculated as the area under contractions by a computerized system. The 1000-kcal meal markedly increased colonic motor activity. This gastrocolonic response was significantly greater in patients with irritable bowel syndrome than in healthy volunteers. Cerulein stimulated motor activity only at pharmacological doses (30–60 ng/kg · h), which resulted in plasma CCK levels markedly exceeding postprandial values. Loxiglumide abolished the effects of cerulein even at pharmacological doses. However, loxiglumide did not inhibit the gastrocolonic response to a regular meal either in healthy volunteers or in patients with irritable bowel syndrome. Loxiglumide also failed to alter the interdigestive colonic motor activity. Therefore, effects mediated by the CCK-A receptor do not play a major physiological role in the regulation of the interdigestive and postprandial motility of the left colon.

A new dopamine agonist in dopamine deprived systems: FCE 23884

FCE 23884, a newly synthesized ergoline-derivative, shows a unique pharmacological profile, displaying a full dopamine (DA) antagonism in normal animals but a full DA agonism indenervated animal models. In normal animals FCE 23884, administered by different routes, showed a variety of pharmacological effects similar to those seen with standard DA antagonists (Table 1). In fact the compound potently, dose-dependently, antagonized the apomorphine-induced climbing behaviour in mice, the apomorphine-induced yawning in rats and the amphetamine-induced toxicity in grouped mice. The compound depressed per s~ spontaneous locomotor activity in both mice and rats, impaired the Sidman's avoidance in rats and completely antagonized apomorphine-induced emesis in Beagle dogs. The above reported results are all compatible with the antidopaminergic properties displayed by antipsychotic agents (Worms et al., 1983) and support that FCE 23884 acts mainly as a central D-2 antagonist in normal animals. On the contrary, in denervated animals, FCE 23884 behaves as a strong DA-ergic agent (Table 2). The compound stimulated the contralateral turning behavior in 6-OHDA lesioned rats. This effect was almost completely antagonized (81%) by the selective DI receptor antagonist SCH 23390, but slightly affected by the selective D--2 antagonist l-sulpiride. These results indicate that FCE 23884, in this context, stimulates motor activity mainly via DI receptors. In an experimental Parkinson's model, i.e. in MPTPtreated monkeys showing severe parkinsunian symptoms, FCE 23884 completely reversed the MPTPinduced akinesia and restored normal behavior. In reserpinized mice FCE 23884 reversed the induced akinesia restoring the locomotor activity. Taken as a whole, these results strongly support that FCE 23884 exerts a potent DA agonist activity in DA deprived animals. To better understand the relevance of the DA presence for FCE 23884 antagonist/agonist activity, the model of rcserpinized mice was chosen because of the reproducibility of DA depletion and the absence of the DA receptors supersensitivity (Liberini et al., 1989). Interaction studies with the DA precursor LDOPA and with the mixed or selective DI /D-2 direct agonists were performed in the model of the locomotor recovery in reserpinized mice.

Interactions between ibogaine and cocaine in rats: in vivo microdialysis and motor behavior

To investigate a possible basis for the proposed anti-addictive property of ibogaine, the effects of an ibogaine (40 mg/kg i.p.) pretreatment on in vivo neurochemical and motor effects induced by cocaine (20 mg/kg i.p.) were studied. Ibogaine, administered 19 h earlier, potentiated the increase in extracellular dopamine levels in striatum and nucleus accumbens as well as the stimulated motor activity induced by cocaine. Although high doses of cocaine can become aversive by producing an anxiogenic reaction, it is unknown whether the potentiation of cocaine's effects by ibogaine would also cause aversion and lead to a decrease in cocaine addiction.

Tolerance During Inhalation of Organic Solvents

Inhalation of several different halogenated solvents stimulated motor activity in mice. During prolonged exposure acute tolerance developed. The development of tolerance depended both on the schedule of exposure, and on the solvent. Exposure to trichloroethylene induced both stimulation and tolerance while the same degree of stimulation induced by 1,1,1-trichloroethane caused no tolerance. Thus the mechanisms which induce stimulation do not always initiate tolerance. Slow steady increases in the concentration of trichloroethylene could be maintained for several hours without any stimulation of motor activity. At the end of such exposures concentrations were reached which, if applied directly, would have induced considerable stimulation. Thus tolerance may develop without motor stimulation. Inhalation of ethanol also stimulated motor activity initially. During constant exposure the stimulation was followed by a considerable reduction in motor activity. This resulted in a hypoactive period, which in turn was followed by a second increase in motor activity, indicating the existence of not only two but several counteracting mechanisms. Development of metabolites with sedative effects counteracting the stimulating effect of the pure solvents seems to be one explanation for the results.

Electroconvulsive treatment attenuates behavioral response to SKF 38393 in reserpine-treated mice

Electroconvulsive treatment (ECT) of mice, once daily for 7 days, significantly reduced the stimulation of motor activity induced by the selective dopamine (DA) D1-receptor agonist SKF 38393 (15 mg/kg IP), but significantly increased the motor stimulation by the unselective DA-receptor agonist apomorphine (1.5 mg/kg IP) in reserpine-treated (10 mg/kg IP) mice, when compared to control mice, receiving sham ECT. The results provide a functional correlate to previously observed ECT-induced down-regulation of D1 receptor sites in DA-rich regions of the rodent brain. Such an effect may be significant for clinical actions of ECT in affective disorders and, possibly, in Parkinson's disease.

Effect of amantadine on motility of reserpinized mice as a function of brain biogenic amines and mouse strains

The effect of amantadine, reserpine or both on locomotor activity and whole brain content of selected biogenic amines and major metabolites was studied as a function of mouse strain. Successive administration of small dose regimens of reserpine, 0.2 mg/kg IP, did not alter motility from corresponding saline control. Administration of amantadine, 100 mg/kg, IP, prior to each of the reserpine treatments produced either stimulation of motor activity in the albino ICR and black C57BL/6 mice or caused inhibition from reserpine in the albino BALB/C and the brown CDF-1 mouse strains. This suggests a genotype strain sensitivity to the amantadine and reserpine interaction on the motor behavior of the mouse. The amantadine treatment did not alter brain dopamine concentration but increased its immediate acid metabolite, 3,4-dihydroxyphenylacetic acid, in the C57BL/6 mice as contrasted with reduction of the same in the BALB/C mouse strain. Both BALB/C and C57BL/6 mice showed changes in brain normetanephrine levels as a consequence of the pharmacologic intervention used which suggest catecholaminergic sensitivity. The only changes produced by the agents studied in brain serotonin or 5-hydroxyindoleacetic acid levels were confined to the BALB/C mouse strain. No changes occurred in brain levels of the compounds measured from corresponding controls in the CDF-1 mice. The results indicate differential sensitivity of the serotonergic and dopaminergic systems to drug-drug interaction studied which appears to be strain dependent.

Erythromycin is a motilin receptor agonist.

Erythromycin A (EMA) is a potent stimulator of gastrointestinal motor activity. In vitro studies suggest that it mimics motilin, a peptide that stimulates motor activity in human and in rabbit via smooth muscle receptors. We have compared the in vitro contractile effect of EMA and two derivatives, 8,9-anhydro-EMA-6,9-hemiketal (EM201) and EMA N-oxide, on rabbit duodenal smooth-muscle strips with their ability to displace iodinated motilin bound to crude smooth-muscle membrane fractions. The concentrations required to induce 50% of the maximum contractile response to a supramaximal dose of acetylcholine were 5.0 x 10(-8), 2.0 x 10(-6), and 1.0 x 10(-4) M for, respectively, EM201, EMA, and EMA N-oxide. The concentrations required to displace 50% of the labeled motilin were, in the same order, 1.0 x 10(-8), 1.3 x 10(-7), and 4.0 x 10(-6) M. Both parameters were well correlated. The dose-response curve of the EMA was parallel to that of motilin and the effects of motilin and EMA were additive. Contractions induced by EMA were insensitive to pretreatment with tetrodotoxin or atropine. EMA had no effect on muscle strips of rat or dog duodenum but did induce contractions in human strips. EMA was totally ineffective on ileal preparations, which are also unresponsive to motilin and in which motilin binding is absent. EMA has therefore the same regional and species specificity as motilin. We conclude that EMA is a motilin receptor agonist.