Light-dark phase differences in behavioral effects of moclobemide in rats

Effects of single and repeated administration of the MAO-A-inhibitor moclobemide (MOC) on the spontaneous locomotor activity and the locomotor hyper- and hypoactivity induced by d-amphetamine and clonidine, resp., in male Wistar rats were studied in both the light (L) and the dark (D) phase of the diurnal cycle (L:0700-1900 h). In the light phase, two hours after single administration, MOC (10 and 50 mg/kg po) increased the basal activity and a dose of 50 mg/kg decreased the exploratory and gross activities and enhanced the effects of amphetamine and clonidine. On the other hand, in the dark phase MOC (50 mg/kg) increased the gross activity and potentiated amphetamine hyperactivity. Only exploration was diminished to the same extent as in the light phase. After repeated administration MOC increased only the gross activity in the light phase. In the dark phase, however, MOC diminished exploration and potentiated the d-amphetamine hyperactivity. MOC, in both doses used, diminished food and water consumption and the body weight gain during the treatment period. These results demonstrate that MOC influences the behavior of rats in a phase-dependent manner after both single and repeated administration.     

Effect of clonidine,amphetamine, and their combinations on the locomotor activity of CD-1 and C57BL/6 mice

Clonidine inhibited the exploratory motor activity of C57BL/6 mice non-habituated to the testing conditions. In CD-1 mice clonidine did not depress exploratory activity but did elevate the basal locomotor activity of animals both non-habituated and habituated to testing conditions. Amphetamine increased the locomotor activity of many C57BL/6 mice and conversely inhibited the locomotion of many CD-1 mice. In both strains, amphetamine in doses up to 2 mg/kg was unable to alter effects produced by clonidine. Results suggest that the locomotor activity of C57BL/6 mice is more sensitive than that of CD-1 mice to drugs affecting the central noradrenergic system.     

Differential behavioral responses to chronic amphetamine in adult male and female rats exposed to postnatal cocaine treatment.

The impact of cocaine exposure during development on behavioral sensitization as measured by locomotor activity and stereotypy following repeated intermittent administration of amphetamine is examined. Male and female Sprague-Dawley rats were exposed to cocaine at 50 mg/kg/day during postnatal days (PND) 11-20 and, as adults (PND193-212), were administered seven daily injections of 2.0 mg/kg amphetamine. Both locomotor activity and stereotypic behavior were assessed following the first and seventh injections. Control males and females showed sensitized behavior following repeated amphetamine injections with females showing greater locomotion while males showed increased stereotypy. Male rats pretreated with cocaine failed to develop sensitized locomotor or stereotypic responses following repeated amphetamine injections consistent with dampened D(1) receptor activity. Females pretreated with cocaine did not show a sensitized locomotor response but did display sensitization of stereotypy following repeated amphetamine administration. Thus, it appears that postnatal cocaine treatment produces differential effects on the circuits mediating sensitization behavior in male and female rats.     

Effects of repeated treatment with antidepressant drugs on the 24 hour behavior in the light-dark synchronized mice

Imipramine, amitriptyline, citalopram, zimelidine and mianserin--antidepressant drugs with a different mechanism of pharmacological activity, as well as haloperidol, a neuroleptic, and diazepam, an anxiolytic, administered for 14 days, were examined in photoresistor actometers in the exploratory activity test (within the first 60 min) and in the basic locomotor activity test (the following 11 h) in the light and dark phases of the LD 12:12 cycle. Imipramine had no effect on the exploratory activity in either phase of the cycle, yet it enhanced the basic locomotor activity in the light phase. Amitriptyline stimulated only the exploratory activity in the dark phase. Citalopram enhanced the exploratory activity in both phases and did not change the basic locomotor activity in either phase of the cycle. Zimelidine increased the exploratory activity in the dark phase and inhibited the basic locomotor activity in both phases. Mianserin stimulated the exploratory activity in the dark phase and the basic locomotor activity in the light one, yet it inhibited the latter in the dark phase. Haloperidol attenuated the exploratory activity in both phases and the basic locomotor activity in the light phase. Diazepam enhanced the exploratory activity in both phases, exerting no effect on the basic locomotor activity. The results indicate that the examined antidepressant drugs administered repeatedly exert a diversified effect on the exploratory activity and the basic locomotor activity in the dark and light phases, yet the dominating feature is the increased exploratory activity in the dark phase.     

Immobilization stress modifies locomotor response to catecholamine receptor agonists in rats

The effects of dopaminergic (apomorphine, nomifensine, B-HT 920) and noradrenergic (methoxamine, clonidine, salbutamol) agonists on locomotor activity were investigated in rats submitted to acute (3 h) or repeated (3 h/4 days) immobilization stress. The stress-induced functional changes were monitored by the blood level of corticosterone and the number of lymphocytes as well as the brain utilization of NA and DA. The rats subjected to acute immobilization stress displayed 30 min later an enhanced locomotor activation after apomorphine, nomifensine, or methoxamine and reduced sedative effect of clonidine, salbutamol or B-HT 920. 24 h after the repeated stress only the locomotor responses to apomorphine, nomifensine, B-HT 920 and salbutamol were modified. Spontaneous locomotor activity was not significantly changed under the influence of stressful stimuli. Increased plasma corticosterone level, strong reduction of blood lymphocytes and enhanced NA and DA utilization in the brain of rats after acute stress, together with above mentioned results, suggest that short-lasting stress evokes (30 min later) significant functional changes not only in the blood but also in the brain: enhanced CA neurons activity as well as the increased alpha 1-adrenergic and DA-post-synaptic receptors responsiveness in parallel with reduced alpha 2 - and beta-adrenergic and DA-presynaptic receptors reactivity. On the other hand, 24 h after last session of repeated stress CA brain neurons activity was not changed, however DA and beta-adrenergic responsivity was farther modified. It is postulated that the stress conditions produce in NA and/or DA brain systems a state of readiness to locomotion activating stimuli.     

Interaction between ethanol and diazepam in mice: chronobiological aspects

The mechanism of action of benzodiazepines and ethanol demonstrates that these agents can synergistically affect the central nervous system (CNS). The effects of both ethanol and diazepam are likely to depend on the time of the day when they were administered. Diazepam influence on ethanol-induced sleeping and hypothermic activity in mice as well as the influence of combined administration of these agents on spontaneous locomotor activity and coordination in mice (rota-rod) were investigated. Experiments were carried out in the light phase (10:00-12:00 h) and the dark phase (22:00-24:00 h). It was shown that ethanol-induced sleeping time was longer in the dark phase than the light phase, and that ethanol increased spontaneous locomotor activity both in the light and the dark. Ethanol-induced hypothermia was lower in the dark than in the light. Diazepam decreased locomotor activity more strongly in the dark phase than by day. It impaired the hypothermic action of ethanol in the light phase, but did not have such an effect in the dark phase. Diazepam prolonged ethanol-induced sleep in the light phase, enhanced its action on locomotor coordination and decreased the stimulating effect of ethanol on spontaneous locomotor activity in mice. The chronobiological effect of the interaction between diazepam and ethanol seems to be of practical importance (sleep and motor coordination).     

Amphetamine modulation of paced mating behavior

The present study evaluated the effects of acute and repeated, intermittent amphetamine administration on paced mating behavior in ovariectomized (OVX) rats primed with estrogen and progesterone. In Experiment 1, female rats were tested for paced mating behavior following acute administration of amphetamine (1.0 mg/kg). Amphetamine increased the likelihood that a female would withdraw from a male following a mount or an intromission. Although this dose of amphetamine did not alter sexual receptivity or the latency to return to a male after sexual stimulation, locomotor activity was increased significantly. Experiment 2 evaluated the dose response characteristics of acute amphetamine (0.5, 1.0 and 2.0 mg/kg) administration on paced mating behavior. In agreement with Experiment 1, amphetamine at all doses increased the likelihood that a female would withdraw from a male following sexual stimulation. In Experiment 3, female rats were tested for partner preference (sexually active male vs. estrous female) following acute amphetamine administration. Amphetamine treatment augmented both social and sexual preferences. In Experiment 4, female rats were administered estrogen (20 microg/kg) and amphetamine (1.0 mg/kg) for 3 weeks and tested for paced mating behavior 1 and 4 weeks later, amphetamine free. Repeated intermittent exposure to amphetamine shortened the latency to return to a male after receiving a mount on the test conducted 1 week after the final drug injections. Collectively, these results suggest that the acute effects of amphetamine on paced mating behavior may reflect a reduction in social and sexual behaviors and an increase in locomotor activity, whereas the effects of repeated exposure may reflect a change in incentive motivation.     

Repeated pretreatment with amphetamine sensitizes increases in cortical acetylcholine release

RATIONALE: Previous studies on the attentional effects of repeated psychostimulant administration in rats suggested the possibility that these effects are mediated via increases in the efficacy of psychostimulants to stimulate cortical acetylcholine (ACh) release. Furthermore, neurochemical data have raised the possibility that increases in nucleus accumbens (NAC) dopamine (DA) release trans-synaptically increase the excitability of basal forebrain corticopetal cholinergic projections, thereby supporting speculations about relationships between the effects of repeated psychostimulant administration on NAC DA and cortical ACh release. OBJECTIVES: To determine whether repeated exposure to amphetamine would potentiate the stimulating effects of the drug on cortical ACh and NAC DA efflux. METHODS: Rats were implanted with microdialysis guide cannula in the medial prefrontal cortex and the shell region of the ipsilateral NAC. Amphetamine (2.0 mg/kg i.p.) or saline (0.9%) was administered every other day for 10 days, for a total of five injections. ACh and DA efflux and locomotor activity were measured on the day of the first and last injections of this pretreatment regimen. All animals were retested following a challenge dose of amphetamine (2.0 mg/kg i.p.) given 10 and 19 days after the last pretreatment injection. RESULTS: The initial injections of amphetamine stimulated ACh and DA efflux and locomotor behavior in both groups. The pretreatment with amphetamine potentiated the ability of the drug to stimulate cortical ACh efflux on day 19 of the withdrawal period. The pretreatment with amphetamine also increased the effects of the challenge dose on motoric activity on day 10. Pretreatment with amphetamine did not result in a significant augmentation of the amphetamine-induced increase in DA efflux in the NAC. CONCLUSIONS: Pretreatment with amphetamine sensitizes the ability of amphetamine to stimulate cortical ACh efflux. These results support the hypothesis that sensitized release of cortical ACh mediated the previously observed hyperattentional impairments in amphetamine pretreated rats. Sensitized cortical ACh release following repeated exposure to psychostimulants may mediate the overprocessing of addictive drug-related stimuli, thus contributing to repeated compulsive addictive drug use.     

Differential effects of nicotine and amphetamine on locomotor activity and maze exploration in two rat lines

Separate groups of two different rat breeding lines, Roman High Avoidance (RHA/Verh.) and Roman Low Avoidance (RLA/Verh.), treated with either saline, nicotine (0.2 mg/kg), or amphetamine (0.4 mg/kg) were compared for exploratory efficiency and for exploratory locomotion by using two different mazes on alternate testing days. The RHA/Verh. rats generally showed more locomotion but less intermaze transfer of exploratory efficency than the RLA/Verh. rats. Nicotine did not alter exploratory efficiency but stimulated locomotor activity in the RHA/Verh. rats, while it did not significantly alter either category of behavior in the RLA/Verh. rats. Amphetamine stimulated locomotor activity in both rat lines but this stimulation was weaker in comparison with that of nicotine. In contrast to nicotine, amphetamine impaired exploratory efficiency in the RHA/Verh. rats. Like nicotine, amphetamine did not significantly affect exploratory efficiency in the RLA/Verh. rats. The results demonstrate that, when the two lines of rats are compared, there is a dissociation of the two categories of behavior and a further differentiation between nicotine and amphetamine effects.     

Effects of serotonergic manipulations on the behavioral sensitization and disinhibition associated with repeated amphetamine treatment

This study investigated the effects of repeated amphetamine treatment on locomotor activity and behavioral inhibition in the elevated plus-maze, and the influence of serotonin (5-HT) neurotransmission on these behaviors. Acute administration of amphetamine (1.0 mg/kg subcutaneously [SC]) stimulated locomotor activity, which was attenuated by acute citalopram (5.0 mg/kg SC) pretreatment. Repeated daily treatment with amphetamine (15 days) sensitized the rats to the amphetamine-induced locomotor stimulation. Acute pretreatment with the 5-HT precursor l-5-hydroxytryptophan (5-HTP; 25 mg/kg IP) or chronic treatment with the selective 5-HT reuptake inhibitor citalopram (5.0 mg/kg SC, twice daily), did not alter the expression of amphetamine-induced locomotor sensitization. In the elevated plus-maze, animals subjected to repeated amphetamine treatment expressed behavioral disinhibition after amphetamine exposure (1.0 mg/kg SC; -35 min), which was antagonized both by acute 5-HTP and chronic citalopram treatment. In summary, these findings suggest that behavioral sensitization to amphetamine is associated with amphetamine-induced behavioral disinhibition, and that acute 5-HTP as well as chronic citalopram treatment counteract the expression of amphetamine-induced behavioral disinhibition, but not locomotor sensitization. It appears likely that the antagonistic effects of 5-HTP and citalopram on behavioral disinhibition derive from a drug-induced facilitation of brain 5-HT neurotransmission.     

可乐定的利尿作用研究

可乐定对家兔和大鼠均有利尿作用,对大鼠作用强。这种作用比双氢克尿噻强50倍。脑室注射可乐定、甲氧胺和NE均有利尿作用。这种作用可被α-受体阻断剂(酚妥拉明和酚苄明)对抗,而不被组织胺H₂-受体阻断剂(甲氰咪胍)对抗。脑室注射异丙肾上腺素,激动β-受体则呈抗利尿作用。可见可乐定对大鼠的利尿作用可能与其激动中枢α-受体有关。     

Involvement of central histaminergic systems in modafinil-induced but not methylphenidate-induced increases in locomotor activity in rats

Modafinil is a novel wake-promoting drug used for the treatment of narcolepsy, the mechanism of action of which remains unclear. Previous studies have shown that modafinil produces a different pattern of c-Fos activation in the brain to the classical stimulants amphetamine and methylphenidate. Modafinil, given i.p. to urethane-anesthetized rats, is associated with an increase in histamine release from the anterior hypothalamus, indicating that its behavioral actions may involve histaminergic systems. In the present study, the effects of modafinil on histamine release using in vivo microdialysis and locomotor activity in freely moving rats were examined, and compared with those of the classical psychostimulant methylphenidate. Modafinil (75 and 150 mg/kg, i.p.) increased both histamine release and locomotor activity, significantly. Methylphenidate (3 mg/kg, i.p.) also increased locomotor activity to the same extent as modafinil (150 mg/kg, i.p.) without stimulating histamine release. Depletion of neuronal histamine using alpha-fluoromethylhistidine abolished the effect of modafinil on locomotor activity in mice but had no effect on methylphenidate-induced locomotion. Examination of the effects of modafinil and methylphenidate on locomotor activity in the dark phase at doses that produced comparable effects in the light phase showed that the effect of modafinil in the dark phase was less than that of methylphenidate, a possible indication that modafinil-induced locomotor activity may be partly related to its wake-promoting actions. These findings suggest that the locomotor effects of modafinil but not of methylphenidate, involve the central histaminergic systems.     

Acute and chronic behavioral interactions between phencyclidine (PCP) and amphetamine: evidence for a dopaminergic role in some PCP-induced behaviors

Amphetamine and phencyclidine (PCP) are both proposed to exert effects on unconditioned behavior through dopaminergic mechanisms. However, a relatively complete characterization of their effects in rats reveals markedly different response profiles. Furthermore, whereas acute co-administration of amphetamine and PCP resulted in an increase in one component of stereotypy, repetitive head movements, two measures of locomotor activation, i.e., ambulation and nonfocused sniffing, were unchanged, and rearings were reduced. In addition, the response alterations which occur with repeated administration of these drugs did not display cross-sensitization. Thus, although repeated daily injections of amphetamine, which produced progressive locomotor augmentation, sensitized animals to the locomotor-stimulating effects of PCP, repeated PCP treatment, which also resulted in locomotor augmentation, decreased the locomotor response to a challenge injection of amphetamine. These findings suggest significant differences in the mechanisms underlying the effects of acute and repeated administration of PCP and amphetamine.     

The role of the substantia nigra in the locomotor stimulant action of amphetamine

1. The electrolytic brain lesion technique was used to evaluate the role of the substantia nigra in the mediation of the locomotor stimulant effect of (+)-amphetamine in the rat. The effect upon the results of variations in strain and basal activity levels of the rats was assessed.2. In the immediate postoperative phase the lesioned animals developed spontaneous stereotyped behaviour patterns which were more intense in rats of initially high basal activity. Activity was depressed at this stage and only that of the low activity animals was stimulated by amphetamine.3. After the 2nd postoperative day rats with lesions of the substantia nigra developed hyperactivity, but this was only maintained in rats initially of low basal activity. During this stage the locomotor stimulant effect of amphetamine (1.0 mg/kg) was apparent and after the 9th postoperative day animals generally displayed an increased sensitivity to the drug effect.4. The involvement of the substantia nigra with the control of locomotor activity is indicated but its integrity would not appear essential for the mediation of the locomotor stimulant effects of amphetamine.     

Differences in the locomotor-activating effects of indirect serotonin agonists in habituated and non-habituated rats

The indirect serotonin (5-HT) agonist 3,4-methylenedioxymethamphetamine (MDMA) produces a distinct behavioral profile in rats consisting of locomotor hyperactivity, thigmotaxis, and decreased exploration. The indirect 5-HT agonist α-ethyltryptamine (AET) produces a similar behavioral profile. Using the Behavioral Pattern Monitor (BPM), the present investigation examined whether the effects of MDMA and AET are dependent on the novelty of the testing environment. These experiments were conducted in Sprague-Dawley rats housed on a reversed light cycle and tested during the dark phase of the light/dark cycle. We found that racemic MDMA (RS-MDMA; 3 mg/kg, SC) increased locomotor activity in rats tested in novel BPM chambers, but had no effect on locomotor activity in rats habituated to the BPM chambers immediately prior to testing. Likewise, AET (5 mg/kg, SC) increased locomotor activity in non-habituated animals but not in animals habituated to the test chambers. These results were unexpected because previous reports indicate that MDMA has robust locomotor-activating effects in habituated animals. To further examine the influence of habituation on MDMA-induced locomotor activity, we conducted parametric studies with S-(+)-MDMA (the more active enantiomer) in habituated and non-habituated rats housed on a standard or reversed light cycle. Light cycle was included as a variable due to reported differences in sensitivity to serotonergic ligands during the dark and light phases. In confirmation of our initial studies, rats tested during the dark phase and habituated to the BPM did not show an S-(+)-MDMA (3 mg/kg, SC)-induced increase in locomotor activity, whereas non-habituated rats did. By contrast, in rats tested during the light phase, S-(+)-MDMA increased locomotor activity in both non-habituated and habituated rats, although the response in habituated animals was attenuated. The finding that habituation and light cycle interact to influence MDMA- and AET-induced hyperactivity demonstrates that there are previously unrecognized complexities associated with the behavioral effects of these drugs.     

The GABAB agonist baclofen blocks the expression of sensitisation to the locomotor stimulant effect of amphetamine

The purpose of the present study was to test the possible influence of baclofen, a GABAB agonist, on the long-term sensitisation to amphetamine in rats. As expected, chronic amphetamine treatment (1.5 mg/kg i.p. daily for 10 days) led to an increased locomotor response to amphetamine (0.75 mg/kg i.p.), when the animals were challenged 20 days after the end of repeated treatment. Baclofen (2 mg/kg i.p.), administered before the test session, did not significantly modify the spontaneous locomotor activity of rats, but decreased the normal and, to a greater extent, the sensitised locomotor response to amphetamine; thus baclofen prevented the expression of sensitisation to amphetamine. Moreover a previous chronic treatment with baclofen (2 mg/kg i.p. daily for 10 days) attenuated the amphetamine-induced locomotor activity in sensitised, but not in control animals. This effect was observed 20 days after the last baclofen administration. In conclusion, the present results demonstrate that GABAB receptors play an important role in the expression of the sensitised behavioural response to amphetamine and further support a potential role of GABAB agonists in the treatment of psychostimulant addiction.     

Naloxone blocks anxiolytic-like effects of benzodiazepines in Swiss but not in Balb/c mice

 The ability of naloxone to block the effects of the benzodiazepines chlordiazepoxide and diazepam was evaluated in Swiss and Balb/c mice subjected to the light/dark choice test of anxiety or to a choice paradigm for measuring spontaneous exploratory behaviour. In Swiss mice, naloxone (5 or 10 mg/kg) completely or partially suppressed the anxiolytic-like effects of chlordiazepoxide (5 mg/kg) and diazepam (1 mg/kg) in the light/dark test. Naloxone alone was ineffective. None of these compounds affected locomotion in the free exploratory test. In Balb/c mice, naloxone did not reduce the anxiolytic-like action of benzodiazepines in the light/dark test. Moreover, naloxone did not antagonize the decrease in neophobia observed after anxiolytic treatment in Balb/c mice in the free exploratory paradigm. In this strain, benzodiazepines produced an increase of locomotor activity, whereas naloxone decreased it. The stimulant effects of benzodiazepines on locomotor activity were abolished by naloxone. As naloxone (2 mg/kg) reversed the morphine-induced hyperthermia both in Swiss and in Balb/c mice, differences in possible pharmacokinetic factors between the two strains can be ruled out as an explanation for the failure of naloxone to antagonize anxiolytic-like effects in Balb/c mice. Therefore, the ability of naloxone to reverse anxiolytic effects does not hold for all strains of mice. Received: 19 April 1996 / Final version: 22 November 1996     

Chronic stress alters amphetamine effects on behavior and synaptophysin levels in female rats

Previous studies show that stress cross-sensitizes with or alters amphetamine (AMPH) effects in male rats; however, few studies include females. We investigated combining daily restraint stress (21 days for 6 h/day) with chronic AMPH (10 injections every other day) on locomotor activity, exploratory activity in an open field and object recognition, a memory task, in female rats. A synaptic protein, synaptophysin, was also quantified by radioimmunocytochemistry (RICC) in brain to determine possible mechanisms for behavioral changes. Beginning at 5 days after cessation of treatments, AMPH increased locomotion, modified exploration, impaired object recognition, and increased serum corticosterone (CORT) levels. Stress did not alter these parameters but blocked AMPH effects on exploration and object recognition, potentiated AMPH-dependent locomotor effects, and did not alter increased CORT levels. AMPH treatment decreased synatophysin expression in the hippocampus. In the caudate nucleus, the AMPH group showed increased synaptophysin expression which was reversed by stress. These results in females corroborate previously shown cross-sensitizations between stress and AMPH for locomotion in males and demonstrate that chronic stress counteracts AMPH-dependent impairments in recognition memory. Stress may counteract AMPH effects on the memory task by blocking both the induction of AMPH anxiety-like effects and neuroplastic changes in the caudate nucleus of female rats.     

The influence of kolanut (cola nitida) on exploratory behaviour in rats

The effect of oral administration of an aqueous extract of kolanut ( Cola nitida ) on exploration of a Y-maze was investigated in rats. The number of entries made into all the arms of the maze and the frequency of rearing following administration of the extract was determined over 20 min, and repeated 24 h later without administration of the extract. Both the extract (400 and 800 mg/kg) and caffeine (15 mg/kg) caused significant increases in the number of entries, but reduced the frequency of rearing. The extract did not significantly reduce the number of entries after 24 h. It is suggested that kolanut stimulates exploratory locomotor activity due to its caffeine content, but does not enhance habituation.     

The Influence Of Kolanut (Cola Nitida) On Exploratory Behaviour In Rats

The effect of oral administration of an aqueous extract of kolanut ( Cola nitida ) on exploration of a Y-maze was investigated in rats. The number of entries made into all the arms of the maze and the frequency of rearing following administration of the extract was determined over 20 min, and repeated 24 h later without administration of the extract. Both the extract (400 and 800 mg/kg) and caffeine (15 mg/kg) caused significant increases in the number of entries, but reduced the frequency of rearing. The extract did not significantly reduce the number of entries after 24 h. It is suggested that kolanut stimulates exploratory locomotor activity due to its caffeine content, but does not enhance habituation.