Some central effects of brofaromine given repeatedly are phase-dependent

Effects of the MAO-A-inhibitor brofaromine (BRO), 10 mg/kg po after repeated (twice daily for 14 days) administration on the spontaneous behavior (exploratory and basal locomotor activities) and the exploratory activity modified by methoxamine, clonidine and d-amphetamine in male Wistar rats were studied in both light and dark phases of a diurnal cycle (L: 0700-1900 h). After single administration BRO in the light phase had no effects. In the dark phase BRO decreased the exploration (62% of control, p less than 0.01), increased the clonidine-evoked hypoactivity and amphetamine-evoked hyperactivity. The L-D differences occurred also after repeated administration. BRO in the light phase did not influence the exploration, decreased basal locomotor activity, did not change methoxamine and clonidine action and potentiated the action of amphetamine. In the dark phase, however, it did not influence the exploration and basal locomotor activity, intensified the methoxamine effect, and did not change the clonidine and amphetamine actions. The results demonstrate that the effects of BRO on behavior in rats: 1) differ from the effects caused by other antidepressants which are not MAO inhibitors; 2) are phase-dependent after both single and repeated administration.     

Long-term administration of d-amphetamine: progressive augmentation of motor activity and stereotypy

The competitive relationship between d-amphetamine induced stereotypy and locomotor activity indicates the importance of their concurrent evaluation, especially during chronic studies. Repeated injection of 0.5, 1.0, 2.5, 5.0, or 7.5 mg/kg d-amphetamine for 36 successive days, in rats continuously exposed to the experimental chambers, produced a progressive augmentation in stereotypy and/or locomotion (depending on dose) during the 3–4 hr interval following injections (post-injection phase). In contrast, dark phase locomotor activity (8–20 hr after each daily injection) was maximally reduced (30–40% of controls) after the first injection of either 5.0 or 7.5 mg/kg d-amphetamine and gradually declined to this level with repeated injection of 1.0 and 2.5 mg/kg. Carry-over of both the post-injection augmentation and dark phase reduction of locomotion was revealed during amphetamine retest 8 days following discontinuation of daily d-amphetamine injections. Possible mechanisms underlying these behavioral alterations are discussed.     

The interaction of clonidine with dopamine-dependent behaviour in rodents

The effect of clonidine on a number of behavioural parameters believed to be expressed through central dopaminergic mechanisms has been studied in rodents. 1. Clonidine (0.06-2 mg/kg) potentiated the circling response to standard doses of both apomorphine (0.25 mg/kg) and amphetamine (3 mg/kg) in mice with unilateral destruction of nigro-neostriatal dopamine nerve terminals. Similarly, clonidine (0.06-2 mg/kg) enhanced the locomotor effect of apomorphine in reserpinised mice. 2. Clonidine (0.5 mg/kg) was without effect on the patterns of stereotypyd behaviours induced by the dopamine agonist apomorphine (0.1-5 mg/kg) in the rat. Unilateral intrastriatal injections of clonidine (5-100 microng) caused no discernable behavioural effects in rats. 3. Injection of apomorphine (10 microng) bilaterally into the region of the nucleus accumbens of the rat resulted in a hyperactive response, while bilateral injection of clonidine (50 microng) into this region caused marked sedation, thus mimicking the effects of these drugs on motor activity when administered systemically. Combinations of systemic or nucleus accumbens apomorphine and clonidine resulted in potentiated stereotype and prolonged hyperactivity responses. 4. Clonidine (0.5 mg/kg) potentiated the cataleptic effect of the dopamine antagonist haloperidol (0.1-2 mg/kg) in rats. Clonidine therefore potentiated those behavioural responses exhibiting a locomotor component (viz. circling and hyperactivity), but was without effect on stereotypy. The potentiation of catalepsy induced by clonidine may be explained in non-specific sedatory terms. It is apparent that clonidine acts through a secondary neurone system which modifies the effects of dopamine receptor stimulation, although the exact site of this interaction is not clear. The tentative conclusion might be that clonidine inhibits 5-HT neuronal activity, and the possible relationships between 5-HT and NA and dopamine are discussed.     

Effects of chronic amphetamine in BALB/cBy mice, a strain that is not stimulated by acute administration of amphetamine

The effects of d-amphetamine and methylphenidate on locomotor activity of BALB/cByJ mice were evaluated. d-Amphetamine had no effect or inhibited locomotor activity at acute doses of up to 10 mg/kg while methylphenidate stimulated locomotor activity at acute doses between 10 and 32 mg/kg. The dose-response curves for methylphenidate and d-amphetamine appeared to be quantal in nature. During a 21-day chronic treatment with 10 mg/kg d-amphetamine no evidence of tolerance to the depressant effects of relatively high doses of d-amphetamine was observed. However, a 3.2 mg/kg dose of d-amphetamine, which acutely inhibited locomotor activity, was found to stimulate locomotor activity following chronic amphetamine treatment. Doses of methylphenidate which acutely stimulated activity were without effect in mice chronically receiving amphetamine. Although the mechanism underlying these behavioral effects has yet to be established, our results indicate that inherent alterations can differentially affect both acute and chronic susceptibility to the behavioral effects of amphetamine and methylphenidate. Use of such altered strains of mice can be especially revealing of subtle behavioral effects brought about by chronic drug treatment which are not readily demonstrated following acute administration of amphetamine.     

Mecamylamine attenuates ephedrine-induced hyperactivity in rats

Ephedrine is a central nervous system stimulant that has a pharmacological profile similar to amphetamines. Ephedrine induces hyperactivity after acute administration to rats and locomotor sensitization develops to ephedrine with repeated administration. Recent research suggests that nicotinic receptors (nAChRs) play a role in the development of locomotor sensitization to d-amphetamine and the goal of the present study was to determine if nAChRs similarly mediate the effects of ephedrine after acute and repeated drug injection. On 12 consecutive days, rats were pretreated with the nAChR antagonist mecamylamine (0.3-3.0 mg/kg) or saline followed by (-)-ephedrine (10-30 mg/kg) or saline injection and locomotor activity was measured. Ephedrine produced a dose-dependent increase in locomotor activity, and sensitization to ephedrine developed with repeated injection. Mecamylamine pretreatment attenuated the hyperactivity and sensitization produced by repeated, but not acute, ephedrine (10 mg/kg) injection. The inhibitory effect of mecamylamine was overcome at the higher ephedrine dose (30 mg/kg). The present results indicate that nAChRs play a mediating role in the development of locomotor sensitization to ephedrine.     

Hypolocomotor effects of acute and daily d-amphetamine in mice lacking the dopamine transporter

RATIONALE: Mice lacking the dopamine transporter (DAT(-/-)) exhibit high extracellular dopamine levels and marked hyperactivity. This hyperlocomotion is paradoxically decreased by acute administration of amphetamine-like psychostimulants, an effect that has been previously related to the activation of serotonergic neurotransmission. OBJECTIVES: The goal of the present study was to investigate the effects of acute and daily administration of d-amphetamine on the locomotor activity of DAT(-/-) mice and examine the development of behavioral sensitization. In addition, we tested the implication of the serotonin system in the observed effects. METHODS: DAT(+/+), DAT(+/-), and DAT(-/-) mice were injected with acute amphetamine (0, 0.3, 1, 3, or 10 mg/kg, SC), repeated amphetamine (1 mg/kg for 8 days, SC), or with the serotonin reuptake inhibitor fluoxetine (0, 5, 10, or 20 mg/kg, SC) and their locomotor activity was evaluated. Moreover, the expression of the serotonin transporter and 5-HT(1A) receptors in the brain of DAT(-/-) mice was studied using autoradiography. RESULTS: Acute and repeated d-amphetamine injection (1 mg/kg) induced an hypolocomotor response in DAT(-/-) and DAT(+/-) mice, but only DAT(+/-) mice developed locomotor sensitization to the drug. Acute treatment with fluoxetine decreased locomotion in DAT(-/-) mice in a dose-dependent manner. The common hypolocomotor effect induced by d-amphetamine and fluoxetine in DAT(-/-) mice suggests an action on the serotonin transporter. However, autoradiography of the serotonin transporter and 5-HT(1A) receptors showed normal density and distribution in the brain, suggesting no compensatory effects due to the deletion of the DAT. CONCLUSIONS: These findings indicate that partial or total DAT gene deletion result in decreased locomotion in response to d-amphetamine and modify behavioral sensitization depending on the proportion of DAT removed, suggesting that inhibition of the DAT is necessary for the development of sensitization to psychostimulant drugs.     

Enhanced self-stimulation responding from the substantia nigra after chronic amphetamine treatment: A role for conditioning factors

Rats treated with 2 mg/kg of d-amphetamine and tested for self-stimulation responding supported from the substantia nigra (pre-trial group), showed a progressive augmentation in rates of self-stimulation responding relative to control animals following repeated drug/test pairings for 10 days. A similar behavioral profile was not observed among animals that received behavioral testing followed by drug administration (post-trial group) during the chronic phase. On test day (Day 11), rats that received repeated drug/test pairings during the chronic phase exhibited a facilitated self-stimulation response to a low test dosage of d-amphetamine (0.5 mg/kg) which otherwise had no behavioral effect, whereas rats exposed to chronic test/drug pairings during the chronic phase did not show enhaced self-stimulation rates to the test dosage of d-amphetamine. Animals chronically treated with pre-trial injections of amphetamine also showed facilitated self-stimulation responding when tested with saline, relative to animals that were chronically treated with post-trial injections of amphetamine and tested with saline. These findings were not parallelled by drug-induced changes in locomotor activity. Response sensitization after chronic amphetamine treatment does not appear to involve the accumulation of the drug in adipose tissue. A role for conditioning factors in the development of the response sensitization is discussed.     

Effects of Catecholamine Receptor Blocking Agents on Toxicity and Thermal Responses Induced by Amphetamine Isomers in Adult and Developing Mice

Abstract The toxicity of d-amphetamine was greater than that of 1-amphetamine in adult mice with intraperitoneal dosage range of 10–50 mg/kg. In these doses neither isomer was toxic to developing mice aged 12–16 days. Both isomers of amphetamine induced a dose-dependent hyperthermia in adults, and the response was stronger after the d- than the 1-form. Ten mg/kg of d-amphetamine increased the temperature of developing mice, while 50 mg/kg of both isomers was markedly hypothermic; p-OH-amphetamine (10 and 50 mg/kg) was not lethal and lacked the thermal effect in adult and developing mice. Phenoxybenzamine (20 mg/kg) completely protected adult mice against the toxicity of 50 mg/kg of d-amphetamine. It also attenuated the d-amphetamine-induced hyperthermia in adult as well as hypothermia in developing mice. Propranolol (10 mg/kg) partially protected adult mice against d-amphetamine toxicity and clearly antagonized the hyperthermia. In combination with propranolol d-amphetamine was toxic to developing mice and potentiated the hypothermia. Metoclopramide (40 mg/kg) partially protected adult mice against d-amphetamine toxicity and diminished the hyperthermia. In developing mice, metoclopramide increased d-amphetamine toxicity, but decreased the hypothermia. It is suggested that amphetamine preferentially affects noradrenergic mechanisms in adult mice and dopaminergic mechanisms in developing mice. Central noradrenaline receptors seem to be mainly responsible for the mediation of amphetamine toxicity. Amphetamine-induced disturbances in thermoregulation play a minor role in amphetamine toxicity in both adult and developing mice.     

Modulation of the behavioral effects of amphetamine in rats by clonidine

Clonidine (0.01, 0.05, 0.5 mg/kg) dramatically reduced the locomotor response to amphetamine (2 mg/kg) in a dose related fashion. In contrast, the same doses of clonidine had no effect on locomotions produced by a higher dose of amphetamine (6 mg/kg). Clonidine also had no effect on stereotyped head movements or the duration of the behavioral response to amphetamine. The lower dose of clonidine reduced amphetamine induced licking/biting while the two higher doses potentiated amphetamine induced licking/biting. Thus the behavioral effects of clonidine vary depending upon the dose of amphetamine and the particular behavior selected for study. The known neurochemical effects of clonidine do not account for this phenomenon.     

The effect of amantadine and (+)-amphetamine on motility in rats after inhibition of monoamine synthesis and storage

The effect of amantadine and (+)-amphetamine on motility was investigated by subcutaneous administration to rats. Amantadine 50 and 100 mg/kg induced a moderate increase of motility. (+)-amphetamine 1, 2.5 and 5 mg/kg showed a more potent locomotor stimulant effect. A stereotyped licking was found during the hypermotility induced by (+)-amphetamine 5 mg/kg.Pretreatment with the catecholamine synthesis inhibitor -methyl-p-tyrosine inhibited the effect of (+)-amphetamine but not that of amantadine. Reserpine potentiated the effects of both amantadine and (+)-amphetamine. Tetrabenazine antagonized the hyperactivity produced by (+)-amphetamine but potentiated amantadine induced hyperactivity. The locomotor stimulant effect of amantadine seems to differ in certain respects from that of amphetamine.     

Effects of neuroleptic drugs,clonidine and lithium on the expression of conditioned behavioral excitation in rats

Rats with a history of daily (21 days) amphetamine (2.5 mg/kg) treatment showed enhanced activity when under placebo in their amphetamine-associated environment. We found that this conditioned effect was reduced by haloperidol (0.06; 0.125; 0.25 mg/kg), pimozide (0.25; 0.5 mg/kg) and sulpiride (8; 16; 32 mg/kg) but only at doses similar to or, in the case of pimozide, higher than those required to antagonize the unconditioned stimulant effects of amphetamine (2.5 mg/kg). Conversely, we observed that clonidine (7; 15; 30; 60 g/kg) or lithium regimen (between days 15 and 21) leading to lithium plasma levels of 1.3±0.1 mEq/1, abolished amphetamine-conditioned hyperactivity but did not affect the unconditioned stimulation of amphetamine or locomotor activity in control rats. Moreover, we found that hyperactivity induced by the daily anticipation of food delivery shared identical pharmacological sensitivity with the behavioural excitation produced by a conditioning history with amphetamine. In light of the antimanic properties of lithium and clonidine and the ability of this latter drug to reduce noradrenergic transmission, our findings raise the posibility that incentive activity may model noradrenergic-dependent aspects of mania.     

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.     

Drug interactions on spontaneous locomotor activity in rats. Neuroleptics and amphetamine-induced hyperactivity

The locomotor activity of female rats was recorded during 10-min sessions in a circular open-field apparatus after the administration of vehicle or drug. Dose-response curves were obtained for seven neuroleptic drugs both alone (spontaneous activity) and in combination with 1.0 mg/kg of d-amphetamine. Haloperidol, pimozide, loxapine, thiothixene, molindone and chlorpromazine all produced graded decreases in spontaneous locomotor activity. Haloperidol, pimozide, loxapine, thiothixene and molindone also produced graded reversals of the hyperactivity produced by d-amphetamine, while chlorpromazine did not. Clozapine neither altered spontaneous activity nor reversed the hyperactivity produced by d-amphetamine. The data indicate that measures of locomotor activity provide important additional information about the actions of neuroleptics and do not necessarily mirror the actions of these drugs on other measures of performance such as lever-pressing for brain stimulation.     

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.     

Rapid decline of stereotyped behavior in rats during constant one week administration of amphetamine via implanted ALZET√ Osmotic Minipumps

Groups of rats were subcutaneously implanted with ALZET√ 2001 type osmotic minipumps containing d-amphetamine. Three doses of amphetamine (calculated as 0.47, 0.94 and 1.41 mg/kg/hour; measured values were approximately 50% lower), continuously released for 7 days, initially produced locomotor stimulation and stereotyped behavior slightly increasing over the first few days. During the later days, however, locomotor stimulation and stereotyped behavior markedly declined indicating tolerance development. These results contrast the often reported development of sensitization to the behavioral effect of amphetamine observed with repeated injections.     

Amphetamine-induced anxiety-related behavior in animal models

The purpose of this study was to examine the anxiety-related effects of acute and repeated amphetamine administration using the elevated plus maze (EPM) and light/dark box tests in mice. D-amphetamine (2 mg/kg ip, 30 min after injection) had a significant anxiogenic effect only in the EPM test, as shown by specific decreases in the percentage of time spent in the open arms as well as in the percentage of open arm entries. Tolerance to this anxiogenic action developed after 8 days of daily d-amphetamine administration (2 mg/kg, ip). An anxiolytic effect was observed after the ninth injection, i.e. there were specific increases in the percentage of time spent in the open arms and in the percentage of open arm entries. L-type voltage-dependent calcium channel antagonists: nimodipine (5, 10 and 20 mg/kg, ip), flunarizine (5, 10 and 20 mg/kg, ip), verapamil (5, 10 and 20 mg/kg, ip), and diltiazem (5, 10 and 20 mg/kg, ip) were also injected prior to an acute low dose of d-amphetamine or to each injection of subchronic d-amphetamine. Our results revealed that calcium channel blockers dose-dependently attenuated both an anxiogenic effect of d-amphetamine and the development of tolerance to this effect. Our results suggest that neural calcium-dependent mechanisms are involved in the anxiety-related responses to acute and subchronic amphetamine injection that may lead to addiction relapse in human users.     

Repeated pre-exposure to tobacco smoke potentiates subsequent locomotor responses to nicotine and tobacco smoke but not amphetamine in adult rats

These studies investigated if pre-exposure to tobacco smoke affects the locomotor response to tobacco smoke, nicotine, and amphetamine in adult rats. The rats were habituated to an open field for 3-4 days and then exposed to tobacco smoke for 2 h/day for 13-14 days. The effect of exposure to tobacco smoke on locomotor activity was investigated after 1, 7, and 14 days of smoke exposure and after one 2-hour exposure session that followed a 3-week off period. The effects of tobacco smoke on the locomotor responses to nicotine (0.04 and 0.4 mg/kg, base) and amphetamine (0.1 and 0.5 mg/kg) were investigated on day 14, one day after the last smoke exposure session. The locomotor response to tobacco smoke was increased after 7 and 14 days of smoke exposure and after one exposure session after the 3-week off-period. The acute administration of the high dose of nicotine (0.4 mg/kg) led to a brief period of hypoactivity that was followed by a period of hyperactivity. Pre-exposure to tobacco smoke attenuated the nicotine-induced hypoactivity and potentiated the nicotine-induced hyperactivity. The low dose of nicotine (0.04 mg/kg) did not affect locomotor activity in the control rats but increased the total distance traveled in the tobacco smoke exposed rats. Exposure to tobacco smoke did not affect the locomotor response to amphetamine. These findings indicate that exposure to tobacco smoke leads to tolerance to the depressant effects of nicotine and potentiates the stimulant effects of nicotine and tobacco smoke.     

Central noradrenaline depletion antagonizes aspects ofd-amphetamine-induced hyperactivity in the rat

The effects of noradrenaline (NA) depletion upon amphetamine-induced hyperactivity were examined in five experiments. Central NA depletion via either systemic DSP4 or neonatal 6-OHDA antagonised the amphetamine-induced (2 mg/kg SC) increase in rearing behaviour, whereas lesions of the dorsal noradrenergic bundle using 6-hydroxydopamine antagonised the increase in locomotor activity. Peripheral NA depletion following systemic 6-hydroxydopamine to adult rats did not cause any changes in motor activity after acute amphetamine administration. Desipramine, the selective NA uptake inhibitor, blocked the effects of DSP4 upon amphetamine-induced rearing. NA depletion antagonised hyperactivity produced by the 2 mg/kg dose of amphetamine, but not the hyperactivity (rearing or locomotion) effects of amphetamine at 1, 4 or 8 mg/kg.     

Evidence for involvement of 5-hydroxytryptamine in the actions of amphetamine

1 Pargyline treatment, 1 h before (+)-amphetamine (1 mg/kg), reduced amphetamine-stimulated motor activity. This inhibition was reversed in animals pretreated with p-chlorophenylalanine (PCPA).2 Following treatment with PCPA or 5,6-dihydroxytryptamine (5,6-DHT), amphetamine-induced locomotor activity was significantly potentiated. The increased response to amphetamine in PCPA-treated rats was reversed in animals pretreated with 5-hydroxytryptophan.3 The inhibition of amphetamine-stimulated locomotor activity by treatment with 6-hydroxydopamine was not reversed by PCPA treatment.4 Stereotypies produced by amphetamine were not found to be altered by depletion of 5-hydroxytryptamine.5 Induction of adrenal tyrosine hydroxylase activity produced by chronic amphetamine administration was significantly potentiated by PCPA, emphasizing the involvement of a 5-hydroxytryptamine inhibitory system in more than one action of amphetamine.     

The influence of oxaprotiline enantiomers given repeatedly on the behavioural effects of d-amphetamine and dopamine injected into the nucleus accumbens

The effects of (+)- and (-)-oxaprotiline, given repeatedly (10 mg/kg p.o., twice daily, 14 days), on the behavioural action of d-amphetamine and dopamine injected bilaterally into the nucleus accumbens were studied in rats. Repeated but not acute treatment with (+)- or (-)-oxaprotiline enhanced the d-amphetamine-induced locomotor hyperactivity. Both enantiomers, given repeatedly but not acutely, attenuated the inhibition of exploration activity induced by dopamine and potentiated the stimulating effect of dopamine as assessed in the open field test. The results indicate that, like other antidepressants studied previously, both oxaprotilines increase the responsiveness of the dopamine mesolimbic system (nucleus accumbens) of the rat.