Stereotypy In Rats Research Articles

Heightened reward response is associated with HCN2 overexpression in the ventral tegmental area in morphine-sensitized rats.

Morphine sensitization is associated with increased locomotion and stereotypies in rats. This persistent condition has been proposed as a model of manic-like symptoms. Modifications in reward threshold are considered a central feature of mania and have been related to changes in mesocorticolimbic dopaminergic transmission. Thus, to further characterize this model, we investigated reward responses in morphine-sensitized male rats and the mechanisms underlying the behavioral phenotype. In particular, we examined the possible involvement of hyperpolarization-activated cyclic nucleotide-gated channels as they play a critical role in regulating the excitability of dopaminergic neurons. Rats were trained to self-administer sucrose to study whether morphine sensitization affected motivated behavior. Next, the dopaminergic response to sucrose was examined in the nucleus accumbens shell by in vivo microdialysis. To investigate the possible mechanisms underlying the increased dopaminergic transmission in morphine-sensitized rats, HCN2 channel expression levels in mesocorticolimbic regions were analyzed by immunoblotting. Sensitized rats showed an enhanced motivation to work for sucrose that was accompanied by an increased dopaminergic response to sucrose consumption in the nucleus accumbens shell. Moreover, HCN2 expression levels were increased in the ventral tegmental area, suggesting that their increased expression may underpin the enhanced motivation for sucrose reward and nucleus accumbens shell dopaminergic response in sensitized rats. The modified behavioral and dopaminergic reward response observed in sensitized rats supports the suggestion that the condition of morphine sensitization can be regarded as a model of manic symptoms.

IN VIVO STUDY OF THE ACTION MECHANISM OF THE RAPITALAM PHARMACEUTICAL SUBSTANCE

The aimis to study the action mechanisms of the Rapitalam pharmaceutical substance using Parkinsonian syndrome models.Materials and methods.Various effects of a new pharmacological substance, N-chlorophenylmethyl-dihydro-methoxy-methylphenyl-oxopyridazine carboxamide (Rapitalam), were studied in male laboratory mice and rats. During the experiment, the various models of the Parkinsonian syndrome were reproduced: the simulation of the Parkinsonian syndrome by administering 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) neurotoxin, the simulation of haloperidol-induced catalepsy, the simulation of apomorphine-induced stereotypy and the simulation of oxotremorine-induced tremor followed by tests. The following tests were carried out in order to determine the Rapitalam efficacy with regard to symptoms manifested after the MPTP administration in animals: the open field test, the rotarod performance test, as well as the evaluation of the grip strength and the degree of rigidity using the stride length. When simulating the haloperidol-induced catalepsy, a horizontal bar test was performed. After the administration of apomorphine, the severity of stereotypy was assessed in scores. A simulation of oxotremorine-induced tremor in rats was used to study the cholinergic link. After the administration of oxotremorine, the severity of tremor was assessed against the background of administration of the test compounds.Results.During the analysis of the data obtained in the open field and rotarod tests as well as the stride length and the grip force when simulating the Parkinsonian syndrome by introducing MPTP, no intergroup statistical differences were found. Thus, the tested Rapitalam substance in doses of 2 mg/kg, 6 mg/kg and 20 mg/kg and the Levodopa reference drug at a dose of 60 mg/kg had no effect on the indices of motor activity and motor coordination in mice when administered orally for 10 days. Rapitalam in doses of 1 mg/kg, 3 mg/kg and 10 mg/kg as well as the Levodopa reference drug at a dose of 50 mg/kg, did not affect the severity of haloperidol-induced catalepsy and apomorphine-induced stereotypy in rats. Under the administration of oxotremorine to laboratory animals, a statistically significant decrease in the severity of tremor was observed during the Rapitalam administration in doses of 3 mg/kg and 10 mg/kg.Conclusion.Rapitalam is established to have no effect on motor impairment due to dopaminergic mechanisms. The tested substance is characterized by a pronounced cholinoblocking effect at doses of 3 mg/kg and 10 mg/kg.Conflict of interest: the author declares no conflict of interest.

Sepsis-induced changes in behavioral stereotypy in rats; involvement of tumor necrosis factor-alpha, oxidative stress, and dopamine turnover

BackgroundSepsis-associated encephalopathy (SAE) is defined as a diffuse or multifocal cerebral dysfunction that generally occurs early during severe sepsis. The complete pathophysiology of SAE is unknown, but several mechanisms including endotoxins, inflammatory mediators, the alteration of amino acids and of neurotransmitters, apoptosis, oxidative stress, and blood-brain barrier dysfunction have been suggested. The aim of the present study was to explore the relationship between behavioral stereotypy and plasma levels of tumor necrosis factor-alpha (TNF-α) and malondialdehyde (a marker of lipid peroxidation), and brain homovanillic acid content (a marker of dopamine turnover) in a surgically induced sepsis model in rats. Materials and methodsTwenty-two adult male Sprague Dawley rats were included in the study. The cecal ligation and puncture procedure was performed to induce sepsis model. Apomorphine-induced stereotypy test was achieved 24 h after cecal ligation and puncture surgery and then, blood and brain samples were collected for biochemical measurements. ResultsSignificantly higher stereotypy score was found in sepsis group than in the sham group (P = 0.008). Furthermore, septic rats revealed significantly higher plasma TNF-α (P = 0.002) and malondialdehyde levels (P = 0.002), and brain homovanillic acid (P = 0.004) compared with sham rats. There was a significant and positive correlation between the behavioral and biochemical parameters. ConclusionsTaken together, these results demonstrate the association between inflammatory response, oxidative stress, and stereotypic behavior in an experimental sepsis model. More comprehensive experimental and clinical studies are required to clarify the specific mechanisms underlying SAE.

Modification of the amphetamine-induced stereotypy in rats following inhibition of the noradrenaline release by FLA 136.

Modification of the amphetamine-induced stereotypy in rats following inhibition of the noradrenaline release by FLA 136.

Cannabis and amphetamine-induced stereotypy in rats

Cannabis and amphetamine-induced stereotypy in rats

Psychopharmacological investigation of the monoamine oxidase inhibitory activity of molindone, a dihydroindolone neuroleptic.

24 h pretreatment with molindone enhanced the behavioural effects of L-dopa and 5-HTP, precursors of biogenic amines (catecholamines and 5-HT respectively) preferentially deaminated by MAO-A, confirming that a metabolite of molindone inhibits MAO-A. 24 h pretreatment with molindone enhanced the behavioural effects of tryptamine and antagonized reserpine-induced ptosis, and in molindone-pretreated rats L-tryptophan induced behavioural effects, probably because of the MAO-A inhibitory activity exerted by a metabolite of molindone. Since 24 h pretreatment with molindone, unlike 30 min pretreatment with clomipramine, failed to antagonize fenfluramine and p-chloramphetamine-induced behavioural syndromes, it suggests that molindone and/or its metabolites most probably do not exert 5-HT neuronal uptake blocking activity and the potentiation of 5-HTP-induced behavioural syndrome is due to a metabolite's MAO-A inhibitory activity. As 2 h pretreatment with molindone induced catalepsy and antagonized apomorphine-induced climbing behaviour in mice and stereotypy in rats, while 24 h pretreatment failed to induce catalepsy and to antagonize apomorphine-induced behaviour, it appears that, at 24 h, the tissue levels of molindone are inadequate to block postsynaptic striatal and mesolimbic DA receptors and that, though a metabolite of molindone is biologically active so far as inhibition of MAO-A is concerned, the metabolites are devoid of neuroleptic activity. Further, since 2 h pretreatment with molindone failed to enhance the behavioural effects of L-dopa, it suggests that at 2 h the degree of MAO-A inhibition induced by molindone and/or the metabolite is not sufficient to counteract the neuroleptic activity of the parent compound.

The atypical antipsychotic drug, aripiprazole, reverses amphetamine‐induced focused stereotypy in rats

Although the dopamine D2 partial agonist and atypical antipsychotic drug (AAPD), aripiprazole (ARPZ), has been shown to antagonize apomorphine‐induced behaviors in rats, it is unknown whether ARPZ antagonizes amphetamine (AMPH)‐induced behaviors in this species. Accordingly, this study examined effects of ARPZ on AMPH‐induced focused stereotypy in rats. Clozapine was included as a comparison AAPD. Rats were first sensitized to AMPH by 5 treatments (5.0 mg/kg, ip.) each separated by 72 hr. Subsequently, AMPH treatments continued but were followed 30 min later by ARPZ (6, 12, and 18 mg/kg, po.) or clozapine (5, 10, 20 mg/kg, po.). Focused stereotypy and locomotor activity were quantified with force‐plate actometers in 4‐hr recording sessions. Clozapine prolonged AMPH‐induced focused stereotypy and slowed the rats’ rhythmic head movements. On the other hand, ARPZ significantly reversed the expression of focused stereotypy and left intact intermediate amounts of locomotion. Thus, ARPZ behaviorally antagonized the effects of the indirect‐acting dopamine agonist AMPH, and this effect is consistent with ARPZ's D2 partial agonist properties. Supported by MH043429 & HD002528.

Circadian-dependent effect of melatonin on dopaminergic D 2 antagonist-induced hypokinesia and agonist-induced stereotypies in rats

Although a melatonin/dopamine relationship has been well established in nonmotor systems wherein dopamine and melatonin share an antagonist relationship, less clear is the role melatonin may play in extrapyramidal dopaminergic function. Therefore, the purpose of the present experiments was to examine the relationship between melatonin and the dopaminergic D 2 receptor system and behavior. Hypokinesia was induced in male Sprague–Dawley rats with fluphenazine (D 2 antagonist, 0.4 mg/kg ip) and stereotypies with apomorphine (D 2 agonist, 0.6 mg/kg sc) during the light (1200 h) and dark (2200 h) phases. As expected, fluphenazine induced severe hypokinesia during the light phase (482±176 s); however, unexpectedly, fluphenazine-induced hypokinesia during the dark was almost nonexistent (25±6 s). Furthermore, melatonin treatment (30 mg/kg ip) produced a strong interaction with fluphenazine in that it reduced fluphenazine-induced hypokinesia by nearly 80% in the light (112±45 s) but paradoxically increased the minimal fluphenazine-induced hypokinesia in the dark by more than 60% (70±17 s). Melatonin also reduced apomorphine-induced stereotypies by nearly 40% in the light but had no effect in the dark. Taken together, these data show (1) a strong and unexpected nocturnal effect of fluphenazine on hypokinesia and (2) provide support for an antagonistic melatonin/dopaminergic interaction in the context of motor behavior and D 2 receptor function which appears to be critically dependent on the light/dark status of the dopaminergic system.

Nociceptin inhibits acquisition of amphetamine-induced place preference and sensitization to stereotypy in rats

Nociceptin (also called orphanin FQ), a 17-amino-acid peptide, is the natural ligand of the nociceptin opioid peptide (NOP) receptor. This peptide shows similarities, in its structure, to opioid peptides, mainly to dynorphin A. However, unlike opioid peptides, it does not produce a conditioned place preference or aversion but inhibits rewarding effect of drugs of abuse. The present study was designed to examine the ability of nociceptin to block the acquisition of amphetamine-induced place preference, and the development of amphetamine-induced sensitization to stereotypy in rats. Our experiments indicated that repeated administration of nociceptin at increasing doses during conditioning significantly attenuated the reinforcing effect of amphetamine in conditioned place preference paradigm. Nociceptin did not change the acute effect of amphetamine-induced stereotypy but prevented the development of sensitization to stereotypy measured on the challenge day. Our results suggest the involvement of nociceptin in long-lasting neuronal adaptation after repeated amphetamine treatment.

Dopaminergic profile of new heterocyclic N-phenylpiperazine derivatives.

Dopamine constitutes about 80% of the content of central catecholamines and has a crucial role in the etiology of several neuropsychiatric disorders, including Parkinson's disease, depression and schizophrenia. Several dopaminergic drugs are used to treat these pathologies, but many problems are attributed to these therapies. Within this context, the search for new more efficient dopaminergic agents with less adverse effects represents a vast research field. The aim of the present study was to report the structural design of two N-phenylpiperazine derivatives, compound 4: 1-[1-(4-chlorophenyl)-1H-4-pyrazolylmethyl]-4-phenylhexahydropyrazine and compound 5: 1-[1-(4-chlorophenyl)-1H-1,2,3-triazol-4-ylmethyl]-4-phenylhexahydropyrazine, planned to be dopamine ligands, and their dopaminergic action profile. The two compounds were assayed (dose range of 15-40 mg/kg) in three experimental models: 1) blockade of amphetamine (30 mg/kg, ip)-induced stereotypy in rats; 2) the catalepsy test in mice, and 3) apomorphine (1 mg/kg, ip)-induced hypothermia in mice. Both derivatives induced cataleptic behavior (40 mg/kg, ip) and a hypothermic response (30 mg/kg, ip) which was not prevented by haloperidol (0.5 mg/kg, ip). Compound 5 (30 mg/kg, ip) also presented a synergistic hypothermic effect with apomorphine (1 mg/kg, ip). Only compound 4 (30 mg/kg, ip) significantly blocked the amphetamine-induced stereotypy in rats. The N-phenylpiperazine derivatives 4 and 5 seem to have a peculiar profile of action on dopaminergic functions. On the basis of the results of catalepsy and amphetamine-induced stereotypy, the compounds demonstrated an inhibitory effect on dopaminergic behaviors. However, their hypothermic effect is compatible with the stimulation of dopaminergic function which seems not to be mediated by D2/D3 receptors.

The medial prefrontal cortex mediates 3-methoxytyramine-induced behavioural changes in rat

l-3,4-Dihydroxyphenylalanine ( l-DOPA) remains a common treatment for Parkinson's disease; however, side effects (i.e., dyskinesia and hallucinations) also remain problematic. We recently reported that the dopamine metabolite 3-methoxytyramine causes stereotypy in rats via dopamine receptors, raising the possibility that 3-methoxytyramine is involved in the adverse side effects of chronic l-DOPA treatment. Thus, the present study examined the sites of 3-methoxytyramine action in the rat brain. After intracerebroventricular administration of 3-methoxytyramine, significantly more neurones expressed c-Fos in mesocortico-limbic dopamine areas including frontal cortex, medial prefrontal cortex, parietal cortex, piriform cortex, the nucleus accumbens shell, and ventral tegmental area. 3-Methoxytyramine injection into the medial prefrontal cortex specifically resulted in behavioural changes characteristic of those elicited by the more general intracerebroventricular injection of 3-methoxytyramine. This suggests that the medial prefrontal cortex mediates the 3-methoxytyramine-induced behavioural changes and that a reduction of its action there may alleviate the adverse effects of chronic l-DOPA treatment.

Behavioral activity and stereotypy in rats induced by l-DOPA metabolites: a possible role in the adverse effects of chronic l-DOPA treatment of Parkinson’s disease

l-3,4-Dihydroxyphenylalanine ( l-DOPA) is a common and effective treatment for Parkinson’s disease, but dyskinesia continues to be a serious adverse effect with chronic use. Evidence suggests that l-DOPA induces increases in dopamine, which then binds to supersensitive dopamine receptors, resulting in dyskinesia. We have shown previously that l-DOPA directly causes stereotypy in rats, suggesting that chronic l-DOPA-induced dyskinesia is also caused by l-DOPA itself. This raises the possibility that other l-DOPA metabolites have a role in dyskinesia. We examined the behavioral effects of five l-DOPA metabolites (3-methoxytyramine, 3-MT; 3,4-dihydroxyphenylalanine, DOPAC; dopamine; homovanillic acid, and 3- o-methyl-DOPA) in rats. A unilateral, intracerebroventricular injection of 3-MT (10–200 μg, 40 μl) over 30 min, dose-dependently increased behavioral activity and stereotypy. This effect was suppressed by the dopamine D1/5-receptor antagonist SCH 23390, but not by the dopamine D2/3/4-receptor antagonist sulpiride. Dopamine denervation resulted in behavioral supersensitivity to 3-MT. Neither dopamine nor DOPAC levels increased in the striatum after 3-MT administration, as measured using in vivo voltammetry. The behavioral changes paralleled a rise in 3-MT in the contralateral striatum. DOPAC also caused behavioral changes and stereotypy, but to a smaller degree than 3-MT. Dopamine-denervated rats did not exhibit a supersensitive response to DOPAC, however. Other l-DOPA metabolites did not cause behavioral effects. These data suggest that 3-MT directly induced dopamine-D1/5-receptor-mediated behavioral changes in rats, and that 3-MT may have a role in dyskinesia due to chronic l-DOPA treatment in Parkinson’s disease patients.

Cholecystokinin modulation of apomorphine- or amphetamine-induced stereotypy in rats: opposite effects

Stereotyped behavior can be induced by the dopamine agonist apomorphine or by the releasing agent amphetamine. Cholecystokinin influence on dopamine-mediated behaviors has been extensively studied but a real controversy remains. Our purpose was to further characterize the dopamine-cholecystokinin interaction in apomorphine- and amphetamine-induced stereotyped behavior using sulphated cholecystokinin octapeptide (CCK8) and cholecystokinin tetrapeptide (CCK4) treatments. The results showed that CCK8 decreases apomorphine-induced stereotyped behavior and CCK4 has no effect. CCK4 and CCK8 increased the amphetamine-induced stereotyped behavior; CCK4 was more effective. The results confirm the opposite modulation of apomorphine or amphetamine-induced stereotyped behavior by CCK. These data suggest that this modulation is mediated by both CCK receptors on apomorphine-induced and only by CCK 2 receptors on amphetamine-induced stereotyped behavior.

Interactions between iboga agents and methamphetamine sensitization: studies of locomotion and stereotypy in rats.

The phenomenon of sensitization has been theoretically implicated in mediating various aspects of drug addiction. Recent dose-response studies demonstrated that pretreatment with the putative antiaddictive agent, ibogaine (IBO), and a synthetic iboga alkaloid congener, 18-methoxycoronaridine (18-MC), increase the potency of cocaine to elicit behavioral sensitization, an effect proposed to contribute, in part, to their ability to attenuate drug self-administration. As abuse of the methylated amphetamine derivative, methamphetamine (METH), is a growing public health concern, the present study determined the interactions between IBO and 18-MC and the expression of METH-induced behavioral sensitization. The effects of pretreatment with 18-MC (40 mg/kg, IP, 19 h earlier) on the expression of METH-induced locomotion (0, 0.25, 0.5, 1 and 2 mg/kg, IP) and the effects of pretreatment with either IBO or 18-MC on the expression of METH-induced stereotypy (2 and 4 mg/kg, IP) were assessed in rats treated chronically with either METH (4 mg/kg daily for 7 days) or saline. Compared to vehicle-pretreated controls, 18-MC produced an overall enhancement in METH-induced locomotion in rats treated chronically, but not acutely, with METH. In addition, both iboga agents increased the stereotypic response to METH. Iboga agents augment both the locomotor and stereotypic effects of METH in a manner consistent with previous reports for cocaine. Thus, it appears that iboga agents interact in a similar manner with the neural mechanisms mediating motor hyperactivity induced by the chronic administration of stimulant drugs.

Orexin-induced hyperlocomotion and stereotypy are mediated by the dopaminergic system

We demonstrated involvement of the ventral tegmental area (VTA) dopaminergic system in orexin-induced hyperlocomotion and stereotypy in rats. In double-label immunohistochemical study of rat brain, we found that tyrosine hydroxylase (TH)-immunoreactive cells in the VTA received innervation from orexin immunoreactive-fibers. Orexin-A induced an increase in [Ca 2+] i in isolated A10 dopamine neurons in a dose-dependent manner. In behavioral studies, we found that orexin-A induced hyperlocomotion, stereotypy and grooming behavior when administered centrally in rats, and these effects were abolished by dopamine D 2 (haloperidol and sulpiride) or D 1 (SCH23390) antagonists. These results suggest that the orexin-induced hyperlocomotion, stereotypy and grooming behavior are mediated by the dopaminergic system and this pathway might be involved in orexin-induced emotional responses.

A measure of striatal function predicts motor stereotypy.

To identify basal ganglia circuit dysfunctions that might produce repetitive behaviors known as motor stereotypies, we applied psychomotor stimulants and a direct dopamine receptor agonist to induce different levels of stereotypy in rats. We then used a gene induction assay to measure the functional activation of neurons in the neurochemically distinct compartments of the striatum, the striosomes and the extrastriosomal matrix. The amount by which activation in the striosomes exceeded activation in the matrix predicted the degree of motor stereotypy induced by the drug treatments. These results suggest that imbalance between compartmentally organized basal ganglia circuits may represent a neural correlate of motor stereotypy.

Dopamine D 2 receptor ribozyme inhibits quinpirole-induced stereotypy in rats

The injection of a dopamine D 2 receptor hammerhead ribozyme (20 μg) once daily for 5 days into the nucleus accumbens of rats resulted in an inhibition of stereotyped sniffing and locomotor activation produced by the selective dopamine D 2 receptor agonist, quinpirole (0.4 mg kg −1 s.c.). The results suggest that ribozymes may be useful in the study of in vivo gene function in the brain.

Intracereboventricularly administered 3-methoxytyramine causes stereotypy in rats: its clinical significance

Intracereboventricularly administered 3-methoxytyramine causes stereotypy in rats: its clinical significance

Fluoxetine blocks expression but not development of sensitization to morphine-induced oral stereotypy in rats.

Repeated high doses of morphine in the rat cause stereotypic gnawing behavior that can be re-expressed by a low dose of morphine weeks and even months after the initial treatment. The determination of the role of serotonin in this sensitized morphine-induced behavior has both empirical and theoretical relevance. To determine whether the serotonin-reuptake blocker fluoxetine will block the development and/or the expression of this opiate-induced stereotypy. Rats were given four 10-mg/kg injections of morphine alone or with 5.0 mg/kg fluoxetine over a 36-h period. At weekly intervals for 6 weeks after the last of the sensitizing morphine doses, all rats were challenged with 4.0 mg/kg morphine. At week 2 and week 4, however, the morphine was co-administered with fluoxetine. Fluoxetine completely blocked the expression of the morphine-induced stereotypy; however, when the morphine/fluoxetine-treated rats were challenged with morphine alone, they expressed similar degrees of stereotypy as the rats that initially only received morphine. The results indicate that increasing synaptic serotonin will block the expression but not the development of sensitization to the oral stereotypic effects of repeated high doses of morphine. Also, despite the complete blocking of the morphine effect by fluoxetine during the sensitization phase, the presence of significant biting by these rats during the challenge with morphine alone argues that conditioning factors are not a necessary component for the morphine sensitization to develop.

Effect of MgSO4, L-DOPA, and haloperidol on delayed stereotyped behavior caused by hyperactivation of the sensorimotor cortex in rats

Repeated rhythmical electrostimulation of the right sensorimotor cortex resulted in persistent psychoaffective disorders and locomotor stereotypy in rats. Intraperitoneal or intrastriatal administration of MgSO4 did not prevent stereotyped behavior. The animals with developed syndrome exhibited sharply enhanced behavioral responses to L-DOPA and weakened cataleptic reactions to haloperidol and showed psychoaffective disorders in response to MgSO4 administration. It is suggested that dopaminergic hyperactivity and NMDA glutamate receptors are involved in the realization of delayed stereotyped behavior.