Amphetamine-induced Locomotor Stimulation Research Articles

The Anorexigenic Peptide Neuromedin U (NMU) Attenuates Amphetamine-Induced Locomotor Stimulation, Accumbal Dopamine Release and Expression of Conditioned Place Preference in Mice.

Amphetamine dependence, besides its substantial economical consequence, is a serious cause of mortality and morbidity. By investigations of the neurochemical correlates through which addictive drugs, such as amphetamine, activate the mesoaccumbal dopamine system unique targets for treatment of drug addiction can be identified. This reward link consists of a dopamine projection from the ventral tegmental area to the nucleus accumbens (NAc) suggesting that these brain areas are important for reward. The physiological function of gut-brain peptides has expanded beyond food intake modulation and involves regulation of drug reinforcement. A novel candidate for reward regulation is the anorexigenic peptide neuromedin U (NMU). We therefore investigated the effects of intracerebroventricular (icv) administration of NMU on amphetamine’s well-documented effects on the mesoaccumbal dopamine system, i.e. locomotor stimulation and accumbal dopamine release in mice. In addition, the effect of accumbal NMU administration on locomotor activity was examined. The effect of NMU, icv or intra-NAc, on the expression of conditioned place preference (CPP) was elucidated. Firstly, we showed that icv administration of NMU attenuate the amphetamine-induced locomotor stimulation, accumbal dopamine release and expression of CPP in mice. Secondly, we found that a lower dose of NMU (icv) reduce the amphetamine-induced locomotor stimulation in mice. Thirdly, we demonstrated that NMU administration into the NAc block the ability of amphetamine to cause a locomotor stimulation in mice. However, accumbal NMU administration did not attenuate the amphetamine-induced expression of CPP in mice. Our novel data suggest that central NMU signalling is involved in development of amphetamine dependence.

Sub-chronic Ghrelin Receptor Blockade Attenuates Alcohol- and Amphetamine-Induced Locomotor Stimulation in Mice.

Ghrelin initially emerged as a gut-brain hormone controlling food intake, meal initiation and appetite mainly via hypothalamic circuits in both rodents and humans. The findings that ghrelin receptors (GHS-R1A) are expressed in reward-related areas, including the nucleus accumbens (NAc) and ventral tegmental area (VTA), suggest that ghrelin is a novel reward regulator. Indeed, ghrelin signalling mediates the rewarding and motivational properties of addictive drugs. In addition, daily co-administration of a GHS-R1A antagonist and various addictive drugs prevents the drug-induced locomotor sensitization in rats. The present series of experiment were designed to evaluate the effect of repeated pharmacological GHS-R1A suppression on drug-induced locomotor stimulation in more detail. We showed that sub-chronic pre-treatment of the GHS-R1A antagonist, JMV2959, attenuated the ability of acute administration of alcohol as well as of amphetamine to stimulate locomotion. However, there was no effect of sub-chronic JMV2959 treatment on locomotor activity per se or on the expression of the GHS-R1A gene (Ghsr) in the VTA or the NAc compared with vehicle treatment. In addition, sub-chronic ghrelin treatment caused a locomotor sensitization. While previous research has pinpointed ghrelin as an appetite regulator the present study together with previous studies suggest that ghrelin signalling modulates various reward-mediated behaviours in rodents. Collectively, this suggests that the GHS-R1A could be a key target for novel treatment strategies for addiction.

Ghrelin receptor antagonism attenuates cocaine- and amphetamine-induced locomotor stimulation, accumbal dopamine release, and conditioned place preference

IntroductionRecently we demonstrated that genetic or pharmacological suppression of the central ghrelin signaling system, involving the growth hormone secretagogue receptor 1A (GHS-R1A), lead to a reduced reward profile from alcohol. As the target circuits for ghrelin in the brain include a mesolimbic reward pathway that is intimately associated with reward-seeking behaviour, we sought to determine whether the central ghrelin signaling system is required for reward from drugs of abuse other than alcohol, namely cocaine or amphetamine.ResultsWe found that amphetamine—as well as cocaine-induced locomotor stimulation and accumbal dopamine release were reduced in mice treated with a GHS-R1A antagonist. Moreover, the ability of these drugs to condition a place preference was also attenuated by the GHS-R1A antagonist.ConclusionsThus GHS-R1A appears to be required not only for alcohol-induced reward, but also for reward induced by psychostimulant drugs. Our data suggest that the central ghrelin signaling system constitutes a novel potential target for treatment of addictive behaviours such as drug dependence.

PRECLINICAL STUDY: Long‐term haloperidol treatment (but not risperidone) enhances addiction‐related behaviors in mice: role of dopamine D2 receptors

The high prevalence of psychostimulant abuse observed in schizophrenic patients may be related to the development of mesolimbic dopaminergic supersensitivity (MDS) or nigrostriatal dopaminergic supersensitivity (NDS) in response to the chronic blockade of dopamine receptors produced by typical neuroleptic treatment. We compared the effects of withdrawal from long-term administration of the typical neuroleptic haloperidol (Hal) and/or the atypical agent risperidone (Ris) on MDS and NDS, behaviorally evaluated by amphetamine-induced locomotor stimulation (AILS) and apomorphine-induced stereotypy (AIS) in mice, respectively. We further evaluated the duration of MDS and investigated the specific role of dopamine D2 receptors in this phenomenon by administering the D2 agonist quinpirole (Quin) to mice withdrawn from long-term treatment with these neuroleptics. Withdrawal (48 hours) from long-term (20 days) Hal (0.5 mg/kg i.p.) (but not 0.5 mg/kg Ris i.p.) treatment potentiated both AILS and AIS. Ris co-administration abolished the potentiation of AILS and AIS observed in Hal-withdrawn mice. Ten days after withdrawal from long-term treatment with Hal (but not with Ris or Ris + Hal), a potentiation in AILS was still observed. Only Hal-withdrawn mice presented an attenuation of locomotor inhibition produced by Quin. Our data suggest that the atypical neuroleptic Ris has a pharmacological property that counteracts the compensatory MDS and NDS developed in response to the chronic blockade of dopamine receptors imposed by Ris itself or by typical neuroleptics such as Hal. They also indicate that MDS may be long lasting and suggest that an upregulation of dopamine D2 receptors in response to long-term treatment with the typical neuroleptic is involved in this phenomenon.

The antipsychotic aripiprazole antagonizes the ethanol- and amphetamine-induced locomotor stimulation in mice

Most drugs of abuse cause a locomotor stimulation, an effect, at least in part, mediated by increased accumbal dopamine (DA) overflow. Locomotor stimulation has been suggested to be a putative endophenotype for drug addiction. We therefore investigated the effects of aripiprazole, a partial DA D 2-receptor agonist, on ethanol as well as amphetamine-induced locomotor stimulation. In the present series of experiments, we found that aripiprazole (1.25 mg/kg, intraperitoneally [i.p.]) antagonized ethanol (1.75 g/kg, i.p.) as well as amphetamine (2 mg/kg, i.p.)induced locomotor stimulation in mice. We suggest that this effect might be related to aripiprazole's ability to alleviate drug-induced hyperdopaminergia without causing hypodopaminergia. Given that altered DA functions in drug dependence have been observed, it may be suggested that aripiprazole could be a new treatment strategy for treatment of drug dependence.

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.

Nitric oxide synthase inhibition blocks amphetamine-induced locomotor activity in mice

Effects of N G-nitroarginine methyl ester ( l-NAME), a nonspecific inhibitor of nitric oxide (NO) synthase, on amphetamine-induced locomotor activity were investigated in Swiss–Webster mice. Locomotor activity was measured for 30 min immediately following amphetamine (1, 2 and 4 mg/kg, i.p.) or saline treatments. l-NAME (15 and 30 mg/kg) and a combination of l-arginine (1000 mg/kg) and l-NAME (30 mg/kg) were injected 30 min before amphetamine (2 mg/kg) to other groups of the mice. l-Arginine was injected 30 min before l-NAME treatment when they were combined. l-NAME (30 mg/kg) and l-arginine (1000 mg/kg) were also tested for ability to depress or stimulate locomotor activity in the absence of amphetamine. Amphetamine caused a dose-dependent increase in locomotor activity of the mice. l-NAME blocked the amphetamine-induced locomotor stimulation dose dependently. l-Arginine pretreatment prevented the inhibitory effects of l-NAME on amphetamine-induced locomotor stimulation. l-NAME and l-arginine did not cause any significant change in locomotor activity in mice not treated with amphetamine. These results suggest that amphetamine-induced locomotor stimulation in mice is modulated by NO.

Parallel strain-dependent effect of amphetamine on locomotor activity and dopamine release in the nucleus accumbens: an in vivo study in mice

Vulnerability to develop drug abuse could be related to differential sensitivity to some central effects of such drugs. Several results point to mesoaccumbens dopamine release elicited by psychostimulants as the rate-limiting factor of their reinforcing, hence addictive, effects and to locomotor stimulation as an indirect index of such a response. In this paper, we report parallel differences in sensitivity to amphetamine-induced locomotor stimulation and mesoaccumbens dopamine release in two inbred strains of mice characterized by differential susceptibility to develop drug self-administration. Thus, mice of the C57BL/6 strain responded with a simultaneous increase of locomotor activity and mesoaccumbens dopamine release measured by intracerebral microdialysis to amphetamine challenge. On the contrary, mice of the DBA/2 strain did not present either response. No strain differences in mesoaccumbens dopamine outflow or 3,4-dihydroxyphenylacetic acid concentration were found in basal conditions or following saline challenges. However, mice of the C57BL/6 strain were characterized by higher levels of accumbal homovanillic acid in basal conditions, in line with the results obtained in rats rendered more sensitive to the locomotor effects of psychostimulants by repeated administration. Finally, in both strains amphetamine decreased accumbal levels of the two metabolites. These results suggest that genotype modulates the locomotor effects of amphetamine through sensitivity of the mesoaccumbens system to amphetamine-stimulated dopamine release. Moreover, they provide a basis to test the hypothesis of mesoaccumbens dopamine involvement in individual susceptibility to the addictive effects of drugs by quantitative trait loci analysis in recombinant inbred strains.

Ibogaine reduces amphetamine-induced locomotor stimulation in C57BL/6By mice, but stimulates locomotor activity in rats

The effect of ibogaine hydrochloride on locomotor stimulation induced by d-amphetamine sulfate was tested in male C57BL/6By mice and in female Sprague-Dawley rats. In mice, locomotor stimulation induced by d-amphetamine at 1 or 5 mg/kg s.c. was reduced by prior administration of one or two injections of ibogaine (40 mg/kg), given 2 or 18 hours earlier. This reduction in locomotor activity persisted for two days. Locomotor stimulation induced by a higher dose (10 mg/kg) of d-amphetamine was not reduced by such prior administration of ibogaine. A lower dose of ibogaine (20 mg/kg) did not reduce the subsequent locomotor activity induced by d-amphetamine. Ibogaine decreased striatal dopamine levels, while d-amphetamine increased them. Ibogaine treatment (2 × 40 mg/kg, 18 hours apart) induced a decrease by 30% in the level of striatal dopamine and its metabolites measured in tissue extracts 3 hours after the second ibogaine injection. One hour after d-amphetamine (5 mg/kg) administration, the level of striatal dopamine increased by 26%. Although the level of striatal dopamine was initially lower in the ibogaine-pretreated mice, d-amphetamine (5 mg/kg) administration induced an increase in striatal dopamine and its metabolites. The effect of ibogaine seems to be species specific, since in rats pretreated with ibogaine 18 hours before d-amphetamine, locomotor stimulation induced by d-amphetamine was further increased. In addition, the in vitro electrical-evoked release of [ 3H]dopamine from striatal tissue was either unchanged or inhibited in the presence of d-amphetamine, and after ibogaine pretreatment in vivo, the release of tritium in the presence of d-amphetamine was inhibited or stimulated in mice and rats, respectively.

Inbred rat strain comparisons indicate different sites of action for cocaine and amphetamine locomotor stimulant effects

Cocaine and amphetamine produce several behavioral effects, most notably locomotor stimulation. Biochemically, evidence suggests specific involvement of dopaminergic systems, although not necessarily identical sites, in mediating cocaine- and amphetamine-induced locomotor stimulation. This study examined the effects of cocaine or amphetamine on locomotor activity in rats from the ACI, F344, LEW and NBR inbred strains. Dose-dependent increases in locomotor activity were found for both drugs in all strains. However, large potency and efficacy differences were found. Further, significant strain by drug interactions were found, in that the strain rank order for stimulant response to the two drugs was not identical. Since striatal dopaminergic neurons influence locomotor activity, we also assessed ligand affinity and receptor density of dopamine transporters and dopaminergic D1 and D2 receptors in striatal tissue from these same strains of rats. No differences in these receptor binding parameters were found. These findings support the conclusion that these two drugs produce their locomotor stimulant effects through different sites of action, and that genetic differences in response to these drugs at the behavioral level do not appear to be mediated significantly by differences in structure or number of striatal dopaminergic sites. The further use of genetic methods, however, may aid in determining the specific sites of action of these widely used stimulant drugs.

Effects of antihistaminics on locomotor activity in mice. Comparison with opiate and amphetamine-induced hyperactivity

1. 1. Three histamine H1-receptor antagonists (tripelennamine, diphenhydramine and cyclizine) and two H2-receptor antagonists (ranitidine and cimetidine)—1 and 10 mg/kg—were tested alone or in combination with the opioid partial agonist buprenorphine (1 mg/kg), the opioid antagonist naloxone (1 mg/kg) or dextroamphetamine (3 mg/kg) on locomotor activity in mice. 2. 2. All three H1-antihistaminics tested and the H2-antihistaminic, cimetidine, enhance locomotor activity in a dose-dependent manner. 3. 3. Furthermore, tripelennamine, diphenhydramine, cyclizine, ranitidine and cimetidine potentiate the buprenorphine-induced hyperactivity. 4. 4. Previous administration of naloxone blocks the tripelennamine- and diphenhydramine-induced hyperactivity. 5. 5. On the other hand, none of antihistaminics tested modifies the amphetamine-induced locomotor stimulation. 6. 6. These results suggest that H1- and H2-receptor antagonists effects on locomotor behavior in mice may be related with opioid mechanisms, but not with amphetamine mechanisms.

The reserpine-sensitive dopamine pool mediates (+)-amphetamine-conditioned reward in the place preference paradigm

The neural basis of amphetamine-conditioned reward was investigated in the conditioned place preference paradigm. When bilaterally injected into the nucleus accumbens before the test session, a dopamine receptor blocker, α-flupenthixol, blocked the expression of the amphetamine-conditioned place preference. α-Flupenthixol had no significant effect on spontaneous locomotor activity. Bilateral microinjections of a tyrosine hydroxylase inhibitor, α-methyl-p-tyrosine (α-MPT), decreased (+)-amphetamine locomotor stimulation in a dose-dependent fashion. Two doses of α-MPT that completely blocked (+)-amphetamine locomotor stimulation had no effect on the expression of the conditioned place preference when injected into the nucleus accumbens before testing. Reserpine administered subcutaneously before testing blocked the expression of the conditioned place preference. A dose of reserpine (4.0 mg/kg), which completely blocked the conditioned place preference, did not attenuate (+)-amphetamine-induced locomotor stimulation. This dose of reserpine depleted dopamine in the nucleus accumbens to 4% of its normal value. These data show that (+)-amphetamine-conditioned reward, expressed as a conditioned place preference, is mediated by dopamine release in the nucleus accumbens. Moreover, the dopamine is released from the reserpine sensitive pool, and probably not from the newly synthesized α-MPT-sensitive pool.

Characteristics of “reverse tolerance” to amphetamine-induced locomotor stimulation in mice

The characteristics of chronically administered amphetamine on the locomotor and anticonvulsant effects were studied in adult CF-1 mice. The influence of dose of the drug and interdose interval on the development of “reverse tolerance” to the locomotor stimulation was investigated, in addition to the selectivity of the response and the persistence of the change in pharmacodynamics. Once-daily treatment with 6 mg/kg amphetamine for 4 weeks resulted in a 2–3 fold increase in locomotor activity. The increase in responsiveness, however, was limited to the first period of 2 weeks and there was no subsequent change in pharmacodynamics during the last 2 weeks of treatment. After 36 days of withdrawal, the response had not returned to that of control, illustrating the persistence of the effect. The results of varying the interdose interval indicated that “reverse tolerance” occurred even when the interval was as long as 14 days. These results represent additional evidence of the persistence of the phenomenon. Selectivity of the changes in the CNS was illustrated by the cross-reactivity with a motor-stimulant dose of cocaine but not with that of morphine. Selectivity was also demonstrated by the failure of “reverse tolerance” to develop to the anticonvulsant effects of amphetamine, which also appear to be mediated dopaminergically.

Interaction between clozapine and a lipophilic α1-adrenergic agonist

Acute intraperitoneal injection of clozapine produced marked hypothermia and ataxia in Swiss-Webster mice. These two effects were almost completely blocked by the lipophilic α 1-adrenergic agonist, St 587, but not by the peripherally-acting α 1 agonist methoxamine. It was inferred that these effects of clozapine are central in origin and probably resulted from α 1 adrenergic blockade. However, since prazosin, a selective α 1-adrenergic antagonist did not elicit either hypothermia or ataxia in mice it became clear that the α 1 adrenergic blocking effect of clozapine is not entirely responsible for these effects, but has a major contributory role in their production. Both clozapine and prazosin inhibited the d -amphetamine-induced locomotor stimulation in mice. St 587 did not significantly reduce this amphetamine-blocking effect of clozapine. It was inferred that this response to d -amphetamine involving the release of mesolimibic dopamine is distinct from the other two St 587-sensitive responses. The hypothermic and ataxic effects of clozapine developed complete tolerance after just four days of treatment, but ten days of such treatment was required for the development of tolerance to the amphetamine-blocking effect of clozapine. The possible relationships between St 587-sensitive and insensitive effects of clozapine and its antipsychotic property are discussed.

Nifedipine and flunarizine block amphetamine-induced behavioral stimulation in mice

Sixteen calcium channel inhibitors (CCl's) were tested in a model utilizing amphetamine-induced behavioral stimulation in mice. Nifedipine, flunarizine and possibly PY 108-068 were effective in blocking amphetamine-induced locomotor stimulation. Verapamil, diltiazem and many other CCl's were ineffective in this experimental paradigm.

Effects of chronic lithium treatment on brain monoamine metabolism and amphetamine-induced locomotor stimulation in rats.

The aim of the present study was to investigate how chronic lithium treatment affects brain monoamine metabolism and amphetamine-induced locomotor stimulation in rats. Chronic lithium treatment was found to increase the synthesis of brain 5-hydroxytryptamine, an effect which may be mediated via increased brain levels of tryptophan. The synthesis and release of dopamine were, on the other hand, found to be decreased. Finally, chronic lithium treatment was found to suppress amphetamine-induced locomotor stimulation, probably due to counteraction by lithium on amphetamine-induced release of catecholamines.

Hypothalamic involvement in the locomotor stimulant or satiety action of thyrotropin-releasing hormone and amphetamine.

To determine whether the locomotor stimulant and the anorexic actions of thyrotropin-releasing hormone (TRH) and amphetamine were mediated through the hypothalamic nuclei, rats were infused with either TRH or amphetamine through previously implanted hypothalamic cannulae. Administration of TRH or amphetamine into the ventromedial hypothalamus, but not the lateral hypothalamus and the anterior hypothalamus, caused locomotor stimulation in rats. On the other hand, administration of TRH or amphetamine into the lateral hypothalamus, but not the ventromedial hypothalamus or the anterior hypothalamus, caused a reduction in food consumption without affecting relative water intake (or water-to-food ratio) in the rat. The data indicate that the ventromedial hypothalamus is the most sensitive site of the TRH- or amphetamine-induced locomotor stimulation and the action of TRH or amphetamine on the lateral hypothalamus is also a possible mechanism mediating anorexia.

Role of dopaminergic neurotransmission in locomotor stimulation by dexamphetamine and ethanol.

Locomotor activity and brain tyrosine hydroxylation rate in vivo, assessed as dopa formation following dopa-decarboxylase inhibition by NSD 1015, was studied in mice. Dexamphetamine 91 mg/kg IP) induced increases in locomotor activity even from the high control baseline activity during the first 5 min in a motility meter. Inhibition of catecholamine synthesis by α-methyl-p-tyrosine (250 mg/kg) alone, given 30 min before test, reduced this high baseline locomotor activity, but such pretreatment did not affect the amphetamine-induced locomotor increase. The inhibition of synthesis itself was slightly attenuated by amphetamine. Low doses of apomorphine (0.1 and 0.2 mg/kg) markedly antagonized the initial locomotor increase by amphetamine but only incompletely antagonized the amphetamine-induced stimulation 15–30 min after the start of the recording. After reserpine pretreatment, apomorphine did not antagonize the amphetamine-induced locomotor stimulation. The data suggest that the release of transmitter causing behavioural stimulation by amphetamine is brought about via two independent mechanisms: facilitation of release from intact granular stores which is not critically dependent on continued catecholamine synthesis but is sensitive to receptor-mediated regulation, and facilitation of the release of newly synthesized transmitter, insensitive to such regulation. Results with ethanol suggest greater dependence on intact dopamine (DA) neurotransmission for the stimulatory effect of this drug. Dexamphetamine (4 mg/kg) caused a greater increase in striatal than in mesolimbic dopa formation, and apomorphine (0.2 mg/kg) only incompletely antagonized the effect in the former region. It is suggested that this difference reflects a relatively greater component of extrinsic feedback regulation of nigrostriatal neurones, the operation of which may contribute to a more pronounced increase in tyrosine hydroxylation, less sensitive to inhibition by apomorphine than that occurring in the mesolimbic nerve endings.

Influence of benzodiazepine tranquilizers on amphetamine-induced locomotor stimulation in mice.

Four benzodiazepine tranquilizers have been tested, alone or in combination with amphetamine, on spontaneous locomotor activity of C57BL/6 mice. Amphetamine-induced locomotor stimulation was enhanced by chlordiazepoxide, diazepam, and medazepam, but not by bromazepam. The results indicate that benzodiazepine derivatives may be somewhat differentiated on the basis of their interactions with amphetamine.

The effect of lithium on amphetamine-induced locomotor stimulation.

A behavioural study was performed to investigate how lithium interacts with monoamine mechanisms. Acute lithium pretreatment partially antagonized amphetamine-induced locomotor stimulation in mice. A rather small dose of L-dopa, which had no stimulant effect on locomotor activity of its own, caused a dose-dependent antagonism of the lithium-induced suppression of the amphetamine-induced locomotor stimulation. Additionally, acute lithium pretreatment had no effect on the apomorphine-clonidine-induced locomotor stimulation after elimination of presynaptic activity by means of pretreatment with reserpine and alpha-MT. Our interpretation of these results is that the inhibitory effect on amphetamine-induced locomotor stimulation is likely to be mediated via presynaptic mechanisms (i.e., decreased release of catecholamines or inhibition of catecholamine synthesis or a combination of both mechanisms) and, further, lithium seems to have no effect at or beyond the catecholamine receptors. However, the possibility that lithium may increase the activity in neuronal systems antagonizing the catecholamine neurons cannot be excluded.