Amphetamine-induced Stereotyped Behavior Research Articles

Antipsychotic Effect of the Leaves of Stachytarpheta Cayennensis (l.C. Riche) Vahl. Verbenaceae in Mice.

The antipsychotic effect of the extracts of the leaves of Stachytarpheta cayennensis was examined following ethnomedicinal claims for its use in the management of mental illness in Nigeria, Ghana and other tropical parts of the globe. The apomorphine and amphetamine-induced stereotyped behavior models were used in this study to see if the extract or its fractions would abolish the stereotypy in mice. The method of Siqueira et al (1998) was employed in this study and the Kruskal Wallis non parametric ANOVA followed by Mann-Whitney U-test was employed for statistical analysis.The results showed that only the methanolic extract of the leaves of Stachytarpheta cayennesis but none of the fractions thereof prevented stereotyped behavior induced by amphetamine. The extract did not abolish stereotypy induced by apomorphine. The inhibition of amphetamine stereotypy also occurred at only one dose (20 mg/kg, i.p.).The inferences from this study include the fact that for the antipsychotic effect of the leaves of stachytarpheta cayennesis, fractionation would lead to loss of activity. More importantly the methanolic extract of the leaves of Stachytarpheta cayennensis possesses antipsychotic effect and this justifies its ethnomedicinal use in the management of mental illness in some regions of the world.Keywords: Antipsychotic; Stachytarpheta cayennensis; amphetamine; apomorphine; stereotypy

Amphetamine-induced stereotyped behaviour and brain concentrations of amphetamine and its hydroxylated metabolites in mice.

Amphetamine-induced stereotyped behaviour and brain concentrations of amphetamine and its hydroxylated metabolites in mice.

Stereoselective actions of substituted benzamide drugs on cerebral dopamine mechanisms.

Abstract Apomorphine-induced locomotor activity in reserpine-pretreated mice was antagonized by pretreatment with (-)-sulpiride and (-)-sultopride. The (+)-enantiomers were inactive. Apomorphine- and amphetamine-induced stereotyped behaviour in rats were antagonized by (-)-sultopride but not by the (+)-enantiomer. Neither enantiomer of sulpiride prevented the onset of the stereotyped response. Both (-)-sulpiride and (-)-sultopride induced increases in striatal and mesolimbic HVA and DOPAC concentrations; (+)-sultopride elevated striatal and mesolimbic DOPAC concentrations but not HVA, while (+)-sulpiride had no effect on HVA or DOPAC in either area. Dopamine concentrations were reduced by the enantiomers of sultopride but not by sulpiride. Low concentrations (10−9 −10−66 M) of the (-)-enantiomers of both drugs displaced [3 H]spiperone from its specific binding site in rat striatal preparations, but the (+)-enantiomers were 40 and 100 times less active. However, neither enantiomer of either drug anatagonized the dopamine-induced stimulation of adenylate cyclase in rat striatal preparations. The data suggest that the central pharmacological activity of sulpiride and sultopride resides in the (-)-enantiomers and that this activity occurs at cerebral dopamine receptors not dependent on adenylate cyclase for functional activity.

Psychopharmacological properties of an aqueous extract of Tetracarpidium conophorum Hutch. & Dalziel in mice

The extract of the nut of Tetracarpidium conophorum (TC), commonly known as African walnut, is widely used to relieve pain, increase sperm count, enhance sexual performance in males and as a nerve tonic in ethnomedicine. This study describes the psychopharmacological properties of the aqueous extract of the nut of TC in mice. The spectrum of activities studied were the effects of TC on the duration of immobility in the forced swim test of the behavioural despair model of depression; prolongation of the duration of sleep produced by thiopentone; amphetamine-induced stereotyped behaviour; and on pain episodes produced by acetic acid and by formalin. Orally administered TC (50-200mg/kg) produced a significant and dose-related decrease in the duration of immobility in the forced swim test in mice. TC also exhibited analgesic property, as shown by its ability to reduce the frequency of abdominal constrictions induced by acetic acid and to inhibit the nociceptive responses produced by formalin. However, at the tested oral doses of 50-200mg/kg, TC did not prolong the duration of sleep produced by thiopentone nor alter the pattern of the stereotyped behaviour induced by amphetamine. This investigation provides evidence that may support the ethnomedicinal applications of the extract of the nut of TC in the treatment of pain. The study also revealed that TC seems to demonstrate antidepressant-like activity, as evidenced by its ability to shorten the period of immobility in the forced swim test; however, further studies are necessary to clearly define the role of TC in depression.

Functional reactivity of the dopaminergic system following acute and chronic ketamine treatments

This study examined the effects of acute (15 mg/kg, i.p.) and chronic subanesthetic (15 mg/kg, i.p., t.i.d, for 6 days) doses of ketamine [a noncompetitive N-methyl-D: -aspartate (NMDA) receptor antagonist] on amphetamine (presynaptic dopamine releasing agent; 10 mg/kg, i.p.) and apomorphine (a D(2) receptor agonist; 1 mg/kg, i.p.)-induced stereotyped behaviors. The effect of acute and chronic ketamine on haloperidol (a D(2) receptor antagonist; 1.6 mg/kg, i.p.)-induced catalepsy was also examined. Acute ketamine and chronic ketamine pretreatment increased amphetamine-induced stereotyped sniffing and locomotion compared with control groups. Acute ketamine significantly increased apomorphine-induced stereotyped sniffing. However, chronic ketamine had no significant effect on apomorphine-induced stereotyped sniffing. Acute, but not chronic ketamine treatment abolished haloperidol-induced catalepsy. The increase in amphetamine-induced stereotyped behaviors and the reversal of haloperidol-induced catalepsy by acute ketamine suggest that blockade of NMDA receptors by ketamine facilitates dopaminergic transmission. The absence of significant effect of chronic ketamine on apomorphine-induced stereotyped sniffing and haloperidol-induced catalepsy suggests that chronic ketamine does not modulate postsynaptic dopaminergic D(2) receptors. It is suggested that chronic ketamine increased amphetamine-induced behaviors by causing hypersensitivity of presynaptic dopamine releasing mechanisms on dopaminergic terminals.

Evaluation of antipsychotic and anti-diarrhoeal activities of ethanolic extract of roots of Rubia cordifolia Linn

The objective of the present study was to assess the antipsychotic and antidiarrhoeal activities of ethanolic extract of roots of Rubia cordifolia in mice and rats. The antipsychotic activity of ethanolic extract of roots of Rubia cordifolia (ERC) was evaluated by observing its effect on amphetamineinduced stereotyped behavior in mice. Effect of ERC was also studied on motor coordination and locomotion in mice. The antidiarrhoeal activity was evaluated using castor oil-induced diarrhoea and excretion of sodium and potassium ions in the intestinal secretion in rats and gastrointestinal transit in mice. The ERC inhibited amphetamine-induced stereotyped behaviour, diminished locomotion and impaired motor coordination. ERC inhibited castor oil-induced diarrhoea, decreased both sodium and potassium excretion in the intestine and decreased gastrointestinal transit. Thus the present study confirms the anti-diarrhoeal activity of Rubia cordifolia. Further studies are necessary to evaluate the potential of Rubia cordifolia as an antipsychotic.

Anti-dopaminergic effect of the methanolic extract of Morus alba L. leaves

Objective:To evaluate the effect of methanolic extract of Morus alba L. leaves on dopaminergic function.Materials and Methods:The effect of the methanolic extract of Morus alba L. leaves was evaluated on haloperidol and metoclopramide induced catalepsy, foot shock-induced aggression, amphetamine-induced stereotyped behavior and phenobarbitone induced sleeping in mice. In each of these tests, the extract was administered in doses of 50, 100 and 200 mg/kg, i.p., 30 min before performing the test in mice. Further, the inhibitory effect of the extract on dopamine was studied using isolated rat vas deferens.Results:The extract produced significant dose dependent potentiation of haloperidol (1 mg/kg, i.p.) and metoclopramide (20 mg/kg, i.p.) induced catalepsy in mice. The extract significantly reduced number of fights and increased latency to fights in foot shock-induced aggression; it also decreased amphetamine (1 mg/kg, i.p.) induced stereotyped behavior in a dose dependent manner. The sleeping time induced by phenobarbitone (50 mg/kg, i.p.) too was prolonged. The extract inhibited contractions produced by dopamine on isolated rat vas deferens.Conclusion:The results suggest that the methanolic extract of Morus alba L. possesses antidopaminergic activity. Further neurochemical investigation can explore the mechanism of action of the plant drug with respect to antidopaminergic functions and help to establish the plant as an antipsychotic agent.

P.5.028 Sensitization of amphetamine-induced stereotyped behaviour during the acute response and possible role of environmental conditioning in mice

Some designer drugs (such as MDMA) can be detected by amphetamine immunoassays, but many cannot. Examples of drugs of abuse that cannot be detected by routine testing include amphetamine analogs (and the recently introduced bath salts), synthetic marijuana (spices), and the date rape drug gamma-hydroxybutyric acid (GHB). This chapter will discuss these designer drugs with an emphasis on what can be done to detect them in suspected urine specimens.

Gender, Estrogen, and Schizophrenia

Most of the evidence to support an association between estrogen and psychosis is indirect and comes from clinical studies of gender differences in schizophrenia and from studies of fluctuating levels of psychopathology in different phases of the menstrual cycle. Our data, as well as those of other investigators, suggest a significantly later age at onset of schizophrenia in women than in men. There is somewhat more direct evidence from animal studies indicating that estrogen modulates dopamine systems in a manner similar to neuroleptics, although there are some inconsistencies in the literature. Few studies have examined the effects of estrogen administration in conjunction with neuroleptics on psychotic symptoms. We present a case report of a postmenopausal woman with schizophrenia who had an improvement in positive symptoms with estrogen replacement therapy. Long-term double-blind treatment studies are needed to investigate the effects of estrogen on psychotic symptoms in women with schizophrenia.

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.

Sensitization of Stereotyped Behavior to Amphetamine Is Context and Response Dependent

The present study was designed to determine whether the environmental context in which amphetamine is administered plays a role in the development of sensitization to the stereotyped behavioral effects of amphetamine in mice. In male CF-1 mice, the dose–response curve for stereotyped behavior elicited by amphetamine was shifted 1.9-fold to the left 48 h after pretreatment with 14 mg/kg amphetamine. Behavioral sensitization only developed in mice that were pretreated in the same or a similar environment as that of the test environment. In addition, when mice were placed in an environment that attenuated the acute expression of stereotyped behavior elicited by the pretreatment dose of amphetamine, sensitization never developed. A further experiment showed that 96% of the mice that expressed stereotypy after the ED 50 pretreatment dose of 10 mg/kg amphetamine showed a stereotyped behavioral response to the lesser dose of 7 mg/kg 48 h later, indicating sensitization. In contrast, mice that did not express stereotypy after the ED 50 dose of amphetamine failed to show a significant stereotyped behavioral response to amphetamine challenge compared to vehicle-pretreated controls. Therefore, the results indicate that preexposure to a single high dose of amphetamine produces context- and response-dependent sensitization to amphetamine-induced stereotyped behavior.

Sensitization of amphetamine-induced stereotyped behaviors during the acute response: role of D 1 and D 2 dopamine receptors

During the response to an injection of amphetamine, rapid changes occur in the ability of the drug to induce stereotyped behaviors. This enhanced responsivity does not involve changes in the caudate–putamen or nucleus accumbens extracellular dopamine response, but appears to require activation of dopamine receptors. In the present studies we examined the role that D 1 and D 2 dopamine receptors might play in the development and expression of the enhanced stereotypy response. In one series of experiments we used the dopamine agonists, SKF 82958 and quinpirole as relatively selective probes at D 1 and D 2 dopamine receptors, respectively, to test for changes in dopamine receptor sensitivity following a pretreatment (`priming') with 4.0 mg/kg amphetamine. Doses of both SKF 82958 and quinpirole which were sub-threshold to induce perseverative behaviors in control animals, promoted stereotyped behaviors in amphetamine-primed animals, suggesting an enhanced sensitivity of both D 1 and D 2 receptors. In a second series of experiments, we sought to determine whether priming with these relatively selective dopamine receptor agonists, as well as the mixed D 1/D 2 agonist, apomorphine, would result in an enhanced stereotypy response to the subsequent administration of non-stereotypy producing doses of amphetamine (0.5–1.5 mg/kg). Priming with the dopamine receptor agonists each resulted in an enhanced amphetamine-induced stereotypy response. These results indicate that both D 1 and D 2 dopamine receptors contribute to both the development and the expression of the altered stereotypy responsivity, though several dose- and time-related observations suggest that other mechanisms likely contribute as well. Because these changes are apparent during the amphetamine response, they may have important implications for the evolving behavioral alterations which result when stimulants are administered in a binge pattern of drug abuse.

Mixed D 2/5-HT 2 Antagonism Differentially Affects Apomorphine- and Amphetamine-Induced Stereotyped Behavior

Evidence supports the hypothesis that psychostimulant stereotypy is mediated through postsynaptic dopamine receptors. Given the recent findings of behavioral, neurochemical and electrophysiological studies showing 5-HT 2 modulation of dopamine systems, a series of experiments were undertaken to assess the ability of D 2 and 5-HT 2 antagonists to reverse apomorphine and amphetamine stereotypy in the rat. Haloperidol reduced stereotyped behavior induced by d-amphetamine (50% reduction with 0.162 mg/kg) and apomorphine (50% reduction with 0.112 mg/kg) MDL 28,133A, a mixed D 2/5-HT 2 antagonist, also reduced stereotypy in the apomorphine group (50% reduction with 3.89 mg/kg) but was much less effective in antagonizing the effects of d-amphetamine (not even a 25% reduction with 9.0 mg/kg). MDL 100,907, a selective 5-HT 2 antagonist, was ineffective at reducing stereotyped behavior induced by either stimulant. Thus, 5-HT 2 modulation of dopaminergic activity was not demonstrated in the case of psychostimulant stereotypy. Furthermore, 5-HT 2 antagonism did not induce stereotypy, as has been proposed in some models. These findings provide further support for the hypothesis that antipsychotic medications with high affinity for 5-HT 2 receptors do not interfere with the regulation of the nigrostriatal dopaminergic system and, therefore, would be less likely to produce extrapyramidal side effects.

Changes in behavior and monoamine levels in microdialysate from dorsal striatum after 6-OHDA infusions into ventral striatum

Long-Evans rats received bilateral 6-hydroxydopamine infusions into the nucleus accumbens and were tested immediately (1 and 2 days) or after a recovery period (14 and 15 days) for changes in extracellular levels of dorsal striatal monoamines using in vivo microdialysis. Compared to controls, the monoamine metabolites 3,4-dihydroxyphenylacetic acid, homovanillic acid and 5-hydroxyindoleacetic acid were generally enhanced when tested immediately after 6-hydroxydopamine treatment, including spontaneous levels and those following depolarizing infusions of potassium (60 mM, 20 min) through the microdialysis probes. Following 2 weeks recovery, dopamine metabolite levels were depressed and the serotonin metabolite levels remained enhanced. D-Amphetamine sulfate (1.5 mg/kg, SC) stimulated dopamine overflow was enhanced 2 days after 6-hydroxydopamine administration, but not after 2 weeks recovery. In contrast, potassium increased dopamine overflow to the same extent as control animals regardless of recovery period following 6-hydroxydopamine. The immediate changes in striatal monoamine activity were accompanied by a potentiation of amphetamine-induced stereotyped behaviors. We suggest that transient presynaptic changes within the dorsal Striatum following disruption of the ventral Striatum may mediate some general aspects of loss and recovery of behavior related to the time course of 6-hydroxydopamine neurotoxicity.

Atypical antipsychotics, clozapine and sulpiride do not antagonise amphetamine-induced stereotyped locomotion.

An automated tracking system which converted an animal's path between quadrants of a circular open field into a series of trips was used to analyse stereotyped locomotion in amphetamine treated rats. Amphetamine (3.5 mg/kg) increased the horizontal distance moved and the number and proportion of thigmotaxic trips around the perimeter of the apparatus (length 4 trips). To investigate the hypothesis that classic antipsychotics, but not atypical antipsychotics, would antagonise the repetitive boundary patrolling associated with amphetamine-induced hyperactivity, animals were pretreated with haloperidol (0.01, 0.025, 0.05, 0.075 mg/kg), clozapine (5, 10, 20 mg/kg) or (+/-)sulpiride (10, 20, 50 mg/kg) 30 min before 3.5 mg/kg amphetamine. The results showed that the classic antipsychotic haloperidol antagonised both hyperactivity and the increased proportion of length 4 trips. In marked contrast, the atypical antipsychotics clozapine and sulpiride antagonised hyperactivity but did not reduce the proportion of length 4 trips. The inability of atypical antipsychotics to reduce the repetitive boundary patrolling associated with amphetamine-induced hyperactivity is consistent with the action of these drugs on other forms of amphetamine-induced stereotyped behaviour, and indicates that locomotor routes under amphetamine are stereotyped. The measurement of trip lengths provides a sensitive tool for examining drug action on the spatial distribution of open field locomotion.

Sensitization of amphetamine-stereotypy reduces plasma corticosterone: Implications for stereotypy as a coping response

The potential coping functions of amphetamine-induced stereotypy were investigated using a physiological index of stress or arousal, plasma corticosterone level. A series of five injections of d-amphetamine was used to enhance stereotyped behavior in control animals as well as in rats with bilateral dopamine-depleting lesions of the caudate-putamen. This regimen of amphetamine injections significantly increased stereotyped behavior and also reduced the normal elevation in corticosterone produced by treatment with d-amphetamine. This effect was apparent in both control and lesioned animals. These results support the hypothesis that amphetamine-induced stereotyped behavior functions to reduce stress or arousal and additionally suggest that this effect is largely independent of underlying dopaminergic mechanisms.

Hippocampal modulation of nucleus accumbens: Behavioral evidence from amphetamine-induced activity profiles

The experiments examined amphetamine-induced locomotion and stereotyped behavior in hippocampal-ablated and control rats for 30 days following surgery. Locomotor counts, stereotypy ratings, and locomotor-time profiles showed that d-amphetamine sulfate produced a selective enhancement of locomotion (cage crosses) at the expense of stereotyped behavior in hippocampal rats relative to normal control rats. This enhancement emerged over the first 2 weeks postsurgery. To examine the role of the striatum in this amphetamine-induced effect, combined hippocampal damage and 6-hydroxydopamine-induced damage of the nucleus accumbens or caudate-putamen were used. These results suggested that amphetamine-enhanced locomotion of hippocampal rats is dependent upon the integrity of the nucleus accumbens and may reflect a change of nucleus accumbens activity relative to caudate-putamen activity. Together these findings suggest that the hippocampus may participate in the control of locomotion by projections that modulate the activity of the nucleus accumbens.

Central α1-adrenergic stimulation in relation to the behaviour stimulating effect of modafinil; studies with experimental animals

Single administration of the new drug modafinil was followed by an increase in locomotor activity in mice and in nocturnal activity in monkeys. Stereotyped behaviour in mice and rats, and potentiation of amphetamine-induced stereotyped behaviour were not observed; however, at the highest dose used, a slight potentiation of apomorphine-induced stereotyped behaviour was observed in rats. The modafinil-induced increase in locomotor activity in mice was prevented by the centrally acting α 1-adrenoceptor antagonists, prazosin and phenoxybenzamine, and by reserpine but not by the mixed dopamine D-1/D-2 antagonist, haloperidol, the dopamine D-2 antagonist, sulpiride, the peripherally acting α 1-adrenoceptor antagonist, phentolamine, the α 2-adrenoceptor antagonist, yohimbine, the β-adrenoceptor antagonist, propranolol, or by the catecholamine synthesis inhibitor, α-methyl-p-tyrosine. Likewise, the modafinil-induced increase in nocturnal activity in monkeys was prevented by prazosin. Interestingly, modafinil did not produce obvious peripheral sympathetic effects in mice and rats (no salivation, no contraction of the pilomotor muscles, slight mydriasis only at high doses). Therefore, modafinil appears to produce a strong stimulating effect in rodents and in primates. These effects could be linked to modulation (stimulation) of central α 1-adrenoceptors unaccompanied by peripheral sympathetic effects, which is unexpected.

Ontogeny of the enhanced behavioral response to amphetamine in amphetamine-pretreated rats

Repeated administration of amphetamine to adult rats results in enhanced behavioral responses to subsequent amphetamine exposure. These experiments were designed to determine the earliest age at which behavioral sensitization to amphetamine could be detected. Rats from both sexes (n = 6-8/group) at ages of 1, 7, 21 or 49 postnatal days (PNDs) were injected with either d-amphetamine sulfate (5 mg/kg) or saline, SC, twice daily for 5 consecutive days. Stereotyped behavior and locomotor activity responses to a challenge dose of d-amphetamine (2.5 mg/kg), or saline, IP, were assessed for a total of 90 min, 15 days after the last dose of pretreatment. Amphetamine-induced stereotyped behavior was significantly enhanced only when amphetamine pretreatment was initiated at PND 49, but not at the earlier ages of PND 1, 7 or 21. There was no apparent sex difference in this effect. Correspondingly, amphetamine-induced locomotor activity was reduced in both sexes of the same age group (PND 49), but not in groups pretreated earlier, when compared to the saline-pretreated rats. These results suggest that amphetamine sensitization may be a late-developing effect, one which occurs sometime after the 3rd week of postnatal life.

Low doses of corticotropin-releasing factor potentiate amphetamine-induced stereotyped behavior

Corticotropin-releasing factor (CRF) is a 41-amino acid polypeptide that is critically involved in the activation of the hypothalamic-pituitary adrenal axis during stress. In addition, it has been suggested that extrahypothalamic CRF may be important in initiating behavioral responses to stressful events. In the present experiment, we examined the effects of central administration of CRF on amphetamine-induced stereotyped behavior. Amphetamine-induced stereotyped behavior has been considered as a behavioral strategy to cope with excessive arousal. Low doses of CRF (0.02 and 0.1 micrograms), administered into the lateral ventricle (ICV), were shown to potentiate amphetamine (4.0 mg/kg; SC)-induced stereotyped behavior, as measured by the Creese and Iversen rating scale and behavioral observations. These low doses of CRF specifically enhanced the tendency for rats to sniff with their heads down 20 min after injection, and induced licking behavior later during testing. In contrast, the rats treated with a higher dose of CRF (0.5 micrograms, ICV) showed more locomotor activity throughout the test, but did not differ from the saline-treated animals in the intensity of amphetamine-induced stereotyped behavior.