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PubMed1983

Lack of potency of metoclopramide's metabolites in various dopaminergic models.

The dopaminergic properties of metoclopramide and four of its metabolites were determined in a series of in vivo and in vitro tests. In vivo measures included changes in dopamine turnover, serum prolactin levels and antagonism of apomorphine-induced stereotyped behavior. In each of these tests the four metabolites were either completely inactive or significantly less potent than the parent compound. The potency of metoclopramide and its metabolites in in vitro dopamine/neuroleptic receptor models was compared to the potency of standard reference compounds. In vitro results indicate that none of the four metabolites tested had antagonist activity in any of the receptor models in which they were evaluated. These findings will be discussed in light of the current understanding of receptor models as they relate to antipsychotic efficacy.

Animals↗

PubMed1977

Dopamine receptors hypersensitivity: further confirmation following drug abuse model.

Controversial multiple investigations have reported that chronic administration of amphetamine or similar drugs in different animals produces a reverse tolerance or a receptor hypersensitivity. However, most studies utilized large doses given chronically and for lengthy periods of time. Real life drug abusers ten to utilize drugs in a cyclic pattern of intermittently increasing doses and then "crashing off" depending on the availability of drugs and psychiatric treatment. In this experiment I intended to demonstrate receptor hypersensitivity with less chronic administration of drugs (in this case only six dosages) given in about two weeks, intermittently, and in increasing dosages to stimulate somewhat closer a drug abuse model. I also utilized a lengthier period of time of waiting in-between the pretreatment and post-treatment evaluation (eight weeks). The subjects were 16 Sprague-Dawley rats of initial weight of 150-200 grams, acclimated to photoelectric cell cages. They were given either D- or L-amphetamine in alternating days for two weeks and in increasing dosages. Both activity and stereotype behavior (SB) were measured. The animals were given eight weeks of rest and then retested with a subthreshold dose of the same drug previously utilized and two days later with the smallest dose of the same medication again. The results showed that the latency and the threshold was decreased and the response was maximized but this was statistically true only for SB, as it did not reach statistical significance for hyperactivity. The relationship of this phenomenon of dopamine receptor hypersensitivity and the clinical findings in dyskinetic disorders, is discussed; also some ideas for further research in this area are brought to light.

Amphetamine↗

PubMed1982

A quantitative study of cholinergic-dopaminergic interactions in the central nervous system.

The effects of cholinergic (Ach) and anti-Ach drugs on stereotyped behavior induced by apomorphine administration were studied quantitatively. Dose-response curves were constructed to apomorphine and the horizontal shifts of the experimental curves induced by the different treatments were measured at the level of ED50 of apomorphine. Treatment with both atropine sulfate and scopolamine hydrobromide induced a leftward displacement of the dose-response curve; physostigmine and oxotremorine displaced the curve to the right. Changes in stereotypy were not observed after atropine methyl nitrate. It is concluded that the activity of acetylcholine-containing neurons may exert a modulatory influence on dopaminergic systems.

Acetylcholine↗

PubMed1991

[Comparison of central stimulating effects between ephedrine and apomorphine].

The potentiation of motor activity caused by ephedrine (Eph) in mice was inhibited by prazosin but not by sulpiride. This potentiation effect caused by apomorphine (Apo) was not inhibited by prazosin. Apo produced stereotyped behavior (including sniffing, licking, and biting) in rodents, but Eph was ineffective except at the toxic dose (400 mg.kg-1 in mice, 200 mg.kg-1 in rats). Apo antagonized haloperidol-induced catalepsy in mice whereas Eph had no such effect. Severe vomiting was evoked by Apo in dogs, but not by Eph even when lethal dose (20 mg.kg-1) was used. Palpebral ptosis induced by prazosin was abolished by intracerebroventricular injection of Eph in mice, but not affected by Apo. The results suggest that the central stimulating action of Eph is mediated by alpha 1-adrenoceptors and not by dopamine receptors.

Animals↗

PubMed1981

Effects of a high-dose treatment of methamphetamine on caudate dopamine and anorexia in rats.

Dose-effect curves of d-methamphetamine (MA) on intake of sweetened condensed milk by rats were obtained before and after twice a day treatment for four days with either saline (control) or a high (50 mg/kg) dose of MA previously shown to decrease the dopamine levels of the caudate. The animals that were more sensitive to MA's anorexic effect during the before-treatment determination were found to be more sensitive to the lethal effects of the high-dose treatment. This treatment produced a six month decrease in brain dopamine but no change in the anorexic effect on milk intake or in the stereotypic behavior elicited by the drug. Subsequently, the daily administration of 2.5 mg/kg of MA, 15 min before presentation of the milk, to both control and treatment groups produced tolerance to the drug's anorexic effect. After 4 to 5 weeks of repeated administration of this dose there was a significant difference between the control group's intake of milk and treatment group's intake as well as body weight. These differences indicate an effect on the treatment upon the formation of tolerance to the anorexic effects of MA.

Animals↗

PubMed2000

The effect of amphetamine on locomotion depends on the motor device utilized. The open field vs. the running wheel.

The effect of amphetamine on the level of locomotion exhibited on two different motor devices was examined in the Golden hamster. Increasing concentrations of the psychostimulant from 4 to 10 mg/kg significantly enhanced locomotor activity in hamsters exposed to an open field. A further increase to 25 mg/kg inhibited ambulatory activity to levels below the control baseline, while augmenting the occurrence of stereotypic behaviors. The activating effect of amphetamine on ambulatory activity was observed regardless of the time of testing (day or night) or lighting condition, with no apparent modulation by the circadian system. On the other hand, home-cage wheel-running activity was maximally inhibited by 10 mg/kg amphetamine, whereas a smaller dosage (1.5 mg/kg) had no effect over the wheel-running activity baseline of saline controls. Although both the running wheel and the open field quantify locomotion, the dissociation obtained shows that they measure different components of it. The results are interpreted within Lyon and Randrup's hypothesis on the actions of amphetamine (16).

Animals↗

PubMed1977

Experiences with a new ergoline (CF 25-397) in parkinsonism.

Studies on rats with unilateral nigral lesions suggest that a new ergoline, CF 25-397, is a dopaminergic agonist that might improve parkinsonism. CF 25-397 induces less stereotyped behavior than other dopaminergic agents in rats, and might therefore cause less dyskinesia than levodopa in man. We investigated the clinical actions of CF 25-397 in nine patients. During treatment, severe deterioration resulted in hypokinesia and rigidity; five patients showed marked dysphagia and dysphonia. There was statistically significant deterioration in four timed tests. Mild improvement, not statistically significant, was noted in tremor. These results indicate that clinical implication of the response to potential therapeutic agents in rodent models of parkinsonism must be interpreted with caution.

Aged↗

PubMed1988

McN-5652: a highly potent inhibitor of serotonin uptake.

McN-5652 is one of a series of substituted pyrrolo-isoquinolines that, as a group, potently inhibit the uptake of one or more of the monoamines, norepinephrine, serotonin and dopamine. McN-5652 is characterized by exceptionally high potency as an inhibitor of the uptake of serotonin by rat brain synaptosomes in vitro (Ki approximately 0.6 nM) and ex vivo (ED50 approximately 2 mg/kg p.o.). The high potency of McN-5652 as a serotonin uptake inhibitor in vivo is indicated further by the low doses required to potentiate L-5-hydroxytryptophan-induced head twitches in mice (ED50 = 0.4 mg/kg 2 hr after p.o. dosing) and the serotonin syndrome in rats (ED50 = 1.5 mg/kg 2 hr after p.o. dosing). McN-5652 also potently inhibited the synaptosomal uptake of norepinephrine (Ki approximately 3 nM) and was a moderately potent inhibitor of the synaptosomal uptake of dopamine (Ki approximately 40 nM). McN-5652 inhibited tetrabenazine-induced ptosis in rats and mice but was much less effective in blocking the sedation caused by tetrabenazine. In rats, McN-5652 did not induce the stereotyped behavior often caused by dopamine agonists and inhibitors of dopamine uptake. Receptor binding experiments indicated that McN-5652 has a weak affinity for serotonin 5-HT2 and alpha-1 adrenergic receptors (apparent Ki approximately 200 nM) and a very low affinity for dopamine D1 and D2 receptors, serotonin 5-HT1, alpha-2 adrenergic, muscarinic and gamma-aminobutyric acid-A receptors. Experiments using the guinea pig ileum indicate that McN-5652 is a weak, noncompetitive antagonist of histamine.

5-Hydroxytryptophan↗

PubMed1977

Lithium inhibition of norepinephrine and dopamine receptors.

Sprague-Dawley rats (150-200 g), serving as their own controls, were evaluated for hyperactivity (HyA) and stereotyped behavior (SB) produced by chronic (1 week) ip administration of different doses of drugs that have differential NE and DA " agonist" properties. Drugs utilized were d- and l-amphetamine, metamphetamine, cocaine, and the specific and direct DA receptor agonist apomorphine. This was followed by 1 week of rest after which all rats received 3 weeks of lithium chloride (Li) subcutaneously. In the last week of Li administration, each rat also was given the same drug administered previously at the same dose. In all cases, Li decreased both HyA and SB, suggesting Li effects both at the pre- and postsynaptic neuron (receptor).

Amphetamines↗

PubMed1976

Synthesis and dopaminergic activity of (+/-)-, (+)-, and (-)-2-dipropylamino-5-hydroxy-1,2,3,4-tetrahydronaphthalene.

In an effort to identify further the structural requirements for central dopamine receptor agonists, some monohydroxyl analogs of the known agonist 5,6-dihydroxy-2-dipropylamino-1,2,3,4-tetrahydronaphthalene were synthesized. They were examined for production of emesis in dogs and stereotyped behavior in rats. The most potent was 5-hydroxy-2-dipropylamino-1,2,3,4-tetrahydronaphthalene, which was more potent than apomorphine but less so than the dihydroxyl analog. The two enantiomers of the monohydroxyl analog were synthesized by conventional methods from an optically active intermediate, 2-benzylamino-5-methoxy-1,2,3,4-tetrahydronaphthalene. The resolution of this amine was performed with the aid of mandelic acid. Dopaminergic activity was found to be confined to the levo enantiomer. Requirements for both substitution and chirality in the tetralines were found to correspond closely to those known for the dopaminergic aporphines.

2-Naphthylamine↗

PubMed2000

Role of the laterodorsal tegmental nucleus in scopolamine- and amphetamine-induced locomotion and stereotypy.

Scopolamine (1.5 mg/kg; i.p.) or amphetamine (3 mg/kg; i.p.) increases locomotion and stereotyped behavior patterns in rats. Previous studies suggest that scopolamine acts via muscarinic receptors near the midbrain-pons border. In this study, unilateral microinjections in N-methyl-scopolamine (2.5-10 microg) into the laterodorsal tegmental nucleus (LDT) increased locomotion. Bilateral ibotenate lesions of the LDT attenuated scopolamine-induced locomotion by 68% 7 days postlesion, and by 35% 28 days postlesion. LDT lesions reduced scopolamine-induced stereotypy less than locomotion. The sensitization to amphetamine observed on repeated tests was attenuated by LDT lesions for stereotypy, but not for locomotion. These findings suggest that scopolamine induces locomotion largely, but not exclusively, by blocking muscarinic receptors in LDT.

Amphetamine↗

PubMed1999

Prenatal protein restriction increases sensitization to cocaine-induced stereotypy.

The present study characterized the total amount of stereotyped behavior following acute and repeated administration of cocaine in male and female prenatally protein malnourished rats. Adult offspring of female Sprague-Dawley rats fed either a low (6% casein) or adequate (25% casein) protein diet 5 weeks prior to mating and throughout their pregnancy were studied. Once every 3 days (for a total of six injections), half the rats from each nutritional treatment group (repeated exposure) were injected with cocaine (30 mg/kg, i.p.) and their total amount of stereotypy (rearing, forepaw treading, compulsive sniffing and head bobbing) monitored. The remaining rats received five saline injections followed by a cocaine injection on the last injection day (acute exposure group) and their behavioral response was also measured. Despite being slightly less sensitive to cocaine following their first injection, by the sixth injection, prenatally protein malnourished animals in the repeated-exposure group exhibited significantly greater sensitization to the psychomotor stimulant effects of cocaine than well-nourished controls. In the acute exposure groups, however, prenatally malnourished males, but not females, exhibited significantly more stereotypy than well-nourished subjects following a single cocaine injection. These findings have implications for characterizing addiction potential in the previously malnourished rats, as well as providing additional information regarding factors which can influence sensitization.

Animal Nutritional Physiological Phenomena↗

PubMed1984

Kinetic analysis of central nervous system supersensitivity induced in rats by long-term haloperidol administration. I. pA2 determination.

A kinetic analysis of central dopamine receptors in control and in experimental rats, withdrawn from long-term haloperidol treatment was made in vivo. Using the stereotyped behavior induced by apomorphine administration as the response, the relative affinity of metoclopramide as reflected by pA2 values, was examined in normal and supersensitive rats. Metoclopramide antagonized apomorphine stereotypy in a dose-dependent and competitive manner. At each dose tested, metoclopramide produced a larger rightward shift of the apomorphine dose-response curve in the control rats than in withdrawn rats. The Schild plot resulted in a straight line, the slopes being -1.2 +/- 0.3 and -0.8 +/- 0.2 for control and experimental rats, respectively. These findings suggest a decrease in receptor affinity after long-term haloperidol treatment, a concept not demonstrated in binding studies in vitro.

Animals↗

PubMed2003

Developmental control of foraging and social behavior by the Drosophila neuropeptide Y-like system.

Animals display stereotyped behavioral modifications during development, but little is known about how genes and neural circuits are regulated to turn on/off behaviors. Here we report that Drosophila neuropeptide F (dNPF), a human NPY homolog, coordinates larval behavioral changes during development. The brain expression of npf is high in larvae attracted to food, whereas its downregulation coincides with the onset of behaviors of older larvae, including food aversion, hypermobility, and cooperative burrowing. Loss of dNPF signaling in young transgenic larvae led to the premature display of behavioral phenotypes associated with older larvae. Conversely, dNPF overexpression in older larvae prolonged feeding, and suppressed hypermobility and cooperative burrowing behaviors. The dNPF system provides a new paradigm for studying the central control of cooperative behavior.

Age Factors↗

PubMed1998

Novel antipsychotic agents with dopamine autoreceptor agonist properties: synthesis and pharmacology of 7-[4-(4-phenyl-1-piperazinyl)butoxy]-3,4-dihydro-2(1H)-quinolinone derivatives.

To develop a novel antipsychotic agent which is an agonist of dopamine (DA) autoreceptors and an antagonist of postsynaptic DA receptors, a series of 7-[4-[4-(substituted phenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2 (1H)-quinolinones was synthesized and their dual activities were examined. The postsynaptic DA receptor antagonistic activities of the compounds were evaluated by their ability to inhibit stereotypy induced by apomorphine in mice, and the autoreceptor agonist activities were determined by their effects on the gamma-butyrolactone (GBL)-induced increase in L-dihydroxyphenylalanine (DOPA) synthesis in the mouse brain. Many compounds inhibited the stereotypic behavior, and several compounds reversed the GBL-induced increase in the DOPA synthesis. Among them, 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy]-3,4-dihydro-2 (1H)-quinolinone (28, aripiprazole, OPC-14597) was found to have these two activities. This compound reversed the GBL-induced DOPA synthesis (ED50 values of 5.1 mumol/kg p.o.) and inhibited the APO induced stereotypy (ED50 values of 0.6 mumol/kg p.o.). Compound 28 induced catalepsy at 10 times higher dose than that required for the antagonism of APO-induced stereotypy (ED50 value of 7.8 mumol/kg p.o.).

4-Butyrolactone↗

PubMed1997

In vitro and in vivo characterization of the dopamine D4 receptor, serotonin 5-HT2A receptor and alpha-1 adrenoceptor antagonist (R)-(+)-2-amino-4-(4-fluorophenyl)-5-[1-[4-(4-fluorophenyl)-4-oxobutyl] pyrrolidin-3-yl]thiazole (NRA0045).

(R)-(+)-2-Amino-4-(4-fluorophenyl)-5-[1-[4-(4-fluorophenyl)-4-oxobutyl]+ ++pyrrolidin-3-yl]thiazole (NRA0045), a novel thiazole derivative, has high affinities for the human cloned dopamine D4.2, D4.4 and D4.7 receptors, with Ki values of 2.54, 0.55 and 0.54 nM, respectively. NRA0045 is approximately 91-fold more potent at the dopamine D4.2 receptor, compared with human cloned dopamine D2L receptor. NRA0045 also has high affinities for the serotonin (5-HT)2A receptor (Ki = 1.92 nM) and alpha-1 adrenoceptor (Ki = 1.40 nM) but weak affinities (IC50 values are approximately 1 microM) for six other neurotransmitter receptors (adenosine1, 5-HT1A, 5-HT1C, dopamine transporter, alpha2A and alpha2A) and negligible affinities (IC50 values are over 10(-5) M) for 42 other receptors, including neurotransmitters and hormones, ion channels and second messenger systems. Locomotor hyperactivity induced by methamphetamine (1 mg/kg i.p.) in mice was dose-dependently antagonized by NRA0045 (ED50 = 0.5 mg/kg i.p. and 1.9 mg/kg p.o., respectively). Methamphetamine (10 mg/kg i.p.)-induced stereotyped behavior in mice was dose-dependently antagonized by NRA0045, whereas NRA0045 did not exceed 50% inhibition even at the highest dose given (30 mg/kg i.p.). Catalepsy was dose-dependently and significantly induced by NRA0045 in rats, whereas NRA0045 did not exceed 50% induction even at the highest dose given (30 mg/kg i.p.). Thus NRA0045 blocks behaviors associated with activation of the mesolimbic/mesocortical dopaminergic neurons more selectively than behaviors associated with nigrostriatal dopaminergic neurons. In rats, tryptamine-induced clonic seizure, a 5-HT2 receptor-mediated behavior, was also dose-dependently inhibited by NRA0045 (ED50 = 1.7 mg/kg i.p.). Norepinephrine-induced lethality is regarded as being induced through the alpha-1 adrenoceptor. NRA0045 dose-dependently antagonized norepinephrine-induced lethality in rats (ED50 = 0.2 mg/kg i.p.). Thus NRA0045 may have a unique antipsychotic activity with regard to dopamine D4 and 5-HT2A receptors and alpha-1 adrenoceptor antagonistic activities, without producing the extrapyramidal side effects.

Adrenergic alpha-1 Receptor Antagonists↗

PubMed1980

On the mechanism of action of 2-amino-4-methylpyridine, a morphine-like analgesic.

2-Amino-4-methylpyridine (2-AMP), when implanted into the ventral lateral thalamus of rats, does not cause stereotyped behavior. On the other hand, when compulsive biting and gnawing was evoked by thalamic implants of morphine (via stimulation of type 1 opiate receptors, which activate a dopaminergic mechanism) or of apomorphine, systemic application of 2-AMP suppressed this response. The anti-gnawing effect of 2-AMP was abolished by naloxone, indicating that the inhibitory action of 2-AMP involves activation of another, viz. type 2 receptor. The antagonistic influence of 2-AMP could also be suppressed by pretreatment of the rats with p-chlorophenylalanine. It is concluded that 2-AMP has only a weak effect on type 1 opiate receptors, linked to a dopaminergic mechanism, but it possesses high affinity to type 2 opiate receptors, which are connected with serotonergic pathways.

Analgesics↗

PubMed1995

The effect of MK-801 and SCH23390 on the expression and sensitization of morphine-induced oral stereotypy.

Repeated high doses of morphine sulfate, administered in a 24-36 h period, stimulates the expression of oral stereotypy in rats. Sensitization to this effect of morphine is demonstrated by the reexpression of the stereotypy by the administration of 4.0 mg/kg of morphine one week following the original exposure. To investigate the role of N-methyl-D-aspartic acid (NMDA) and D1 dopamine (DA) receptors in the acute expression and sensitization of morphine-induced oral stereotypy, rats were administered four injections of morphine (10.0 mg/kg) one injection every 12 h and observed for the expression of stereotypic behaviors following pretreatment with selective antagonists. Pretreatment with the NMDA antagonist, MK-801 (0.7 mg/kg), before each of the four morphine injections antagonized both the initial expression of oral stereotypy and the development of sensitization. In contrast, the DA D1 receptor antagonist SCH23390 (40.0 micrograms/kg) administered during the four high-dose treatments with morphine antagonized the initial expression of oral stereotypy and not the development of sensitization. These findings implicate glutamate's action at the NMDA receptor in both the acute expression of morphine-induced oral stereotypy, and the development of sensitization of this morphine effect, whereas DA D1 receptors may only be involved in the acute expression of the stereotypy.

Animals↗