Locomotor Stimulation In Rats Research Articles

Cigarette smoke exposure during adolescence but not adulthood induces anxiety-like behavior and locomotor stimulation in rats during withdrawal

Adolescence is a critical period for cigarette smoking. Studies have shown that adolescent smokers are more likely to become addicted, are less likely to quit, and are more prone to relapse. In the present study, we examined the affective symptoms experienced by adolescents during withdrawal from cigarette smoke exposure. Towards this goal, adolescent male rats were repeatedly exposed to cigarette smoke, through an automated smoking machine, for 14 days. Then, cigarette smoke exposure was discontinued to induce spontaneous withdrawal. During the withdrawal period, anxiety-like behavior (elevated plus-maze test), locomotor activity (open-field test), and learning and memory (passive-avoidance test) were evaluated. These behavioral evaluations were conducted during the first, third, seventh, and fourteenth day of withdrawal. For comparison, parallel experiments were performed in adult rats. We found that adolescent rats exposed to cigarette smoke experiences increased anxiety-like behavior and locomotor activity during withdrawal relative to control rats. Learning and memory processes were undisturbed. On the other hand, adult rats exposed to cigarette smoke did not show any statistically significant behavioral alteration during withdrawal. These results are consistent with the notion that adolescents are differentially sensitive to the withdrawal effects of cigarette smoking. This sensitivity might be a factor why adolescent smokers have difficulty quitting and are more prone to relapse.

Chemokines and cocaine: CXCR4 receptor antagonist AMD3100 attenuates cocaine place preference and locomotor stimulation in rats

Plasma levels of the chemokine CXCL12 are elevated in mice following acute cocaine exposure and decreased in human cocaine abusers during withdrawal. CXCL12 is also one of the few chemokines located in the brain and can modulate dopamine transmission through activation of its receptor CXCR4. To assess a role for the CXCL12/CXCR4 system in behavioral effects of cocaine, we tested the hypothesis that AMD 3100 (Plerixafor), a CXCR4 antagonist, would inhibit conditioned place preference (CPP) and locomotor activation produced by cocaine. Rats injected with cocaine (10mg/kg) displayed CPP relative to saline-injected controls following 4 conditioning sessions. AMD 3100 (1, 2.5, 5mg/kg) administered prior to cocaine conditioning reduced development of cocaine CPP. AMD 3100 (5mg/kg) also inhibited expression of cocaine-induced CPP in a paradigm in which it was injected once (following cocaine conditioning and just prior to CPP testing). In addition, AMD 3100 (5, 10mg/kg) pretreatment reduced locomotor activation produced by an acute cocaine injection (15mg/kg) but did not affect basal locomotor activity relative to saline-injected controls. Repeated cocaine exposure produced a significant increase (1.49-fold) in CXCL12 mRNA expression in the ventral tegmental area (VTA). Our results suggest that the CXCL12/CXCR4 system in the brain reward circuit is impacted by cocaine exposure and influences behavioral effects related to the abuse liability of cocaine.

Delta-opioid agonists: differential efficacy and potency of SNC80, its 3-OH (SNC86) and 3-desoxy (SNC162) derivatives in Sprague-Dawley rats.

The diarylpiperazine delta-opioid agonist SNC80 [(+)-4-[(alphaR)-alpha-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-methoxyphenyl)methyl]-N,N-diethylbenzamide] produces convulsions, antidepressant-like effects, and locomotor stimulation in rats. The present study compared the behavioral effects in Sprague-Dawley rats of SNC80 with its two derivatives, SNC86 [(+)-4-[alpha(R)-alpha-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide] and SNC162 [(+)-4-[(alphaR)-alpha-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-phenyl)methyl]-N,N-diethylbenzamide], which differ by one functional group located in the 3-position of the benzylic ring. In behavioral measures, these three compounds demonstrated a rank order of potency and efficacy; SNC86 was the most potent and efficacious followed by SNC80 and then SNC162. In vitro, these compounds stimulated guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) binding in the caudate putamen of coronal brain slices from drug-naive rats as measured by in vitro autoradiography. In [(35)S]GTPgammaS binding studies, SNC86 seemed to be a full agonist at the delta-opioid receptor; however, SNC162 demonstrated reduced stimulation compared with SNC86, consistent with partial agonist activity. Although SNC80 was not fully efficacious in [(35)S]GTPgammaS autoradiography studies, it produced behavioral effects similar to those observed with SNC86, suggesting that the behavioral effects of SNC80 may be produced by its 3-hydroxy metabolite.

Kappa-opioid receptor modulation of nicotine-induced behaviour

The ability of κ-opioid receptor ligands to modulate dependence-related behavioural effects of drugs like morphine and cocaine is well documented. The present study examined the effects of κ-opioid agonists on nicotine-induced locomotor stimulation in rats chronically pre-exposed to nicotine (0.4 mg/kg/day). U50,488 [0.5–3 mg/kg subcutaneously (s.c.)], U69,593 [0.08–0.32 mg/kg intraperitoneally (i.p.)] and CI-977 (0.005–0.02 mg/kg s.c.) administered 30 min prior to nicotine (0.06, 0.2 and 0.4 mg/kg s.c.) dose-dependently antagonised its acute locomotor-activating effect, which was completely prevented by the highest tested dose of each agonist. Baseline activity was unaffected by the largest doses of U50,488 and U69,593, but it was reduced by 0.01 and 0.02 mg/kg of CI-977. The selective κ-opioid receptor antagonist nor-BNI [30 μg intracerebroventricularly (i.c.v.)] blocked the effects of U69,593 on nicotine-induced behaviour, thus supporting the involvement of κ-opioid receptors in this effect. In conclusion, the activation of κ-opioid receptors clearly prevented nicotine-induced locomotor stimulation. The effects of at least two of the κ-opioid agonists were not due to a general motor suppression. It is suggested that the mechanism entails a depression of nicotine-induced increases in accumbal dopamine by these compounds. The results should encourage further research on the role of the κ-opioid system in the behavioural and neurochemical effects of nicotine, including those related to nicotine dependence.

Effects of the selective 5-HT2A receptor antagonist MDL 100,907 on MDMA-induced locomotor stimulation in rats

(+/-)3,4-Methylenedioxymethamphetamine (MDMA) releases dopamine and serotonin in vivo and stimulates locomotor activity. Previous work demonstrated that MDMA-stimulated dopamine release could be reduced by the selective 5-HT2A receptor antagonist [R-(+)-a- (2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinem ethanol] (MDL 100,907). In the present study MDL 100,907 significantly reduced MDMA-stimulated locomotion without affecting basal levels of locomotion. Other agents with 5-HT2A antagonist activity (ritanserin, clozapine, MDL 28,133A, or methiothepin), as well as agents that block 5-HT1A-(propranolol), D2-(haloperidol), or D1 receptors (SCH 23390) also reduced MDMA-stimulated locomotion. Intraventricularly administered 5,7-dihydroxytryptamine decreased regional 5-HT levels and attenuated MDMA-stimulated locomotion. These data support the conclusion that serotonin released onto 5-HT2A receptors contributes to MDMA-stimulated locomotion and suggest that MDMA-stimulated locomotion may be useful as an in vivo behavioral measure of 5-HT2A antagonism. The data also support previous reports of contributions of 5-HT1A, D1 and D2 receptors to MDMA-stimulated locomotion. A preliminary time-course analysis indicating time-dependent contributions of different receptors to MDMA-stimulated locomotion suggests the potential utility of this model for characterizing potential atypical antipsychotic compounds.

Quinpirole-induced locomotor stimulation in rats develops rapid sensitization when combined with brief footshocks

In rats exploring a symmetrical Y-maze, an acute injection of quinpirole or intermittent brief footshocks did not change the level of locomotion. The combined treatment of quinpirole and footshocks elicited an immediate locomotor stimulation. When the experimental session was repeated daily, there was a further increase of hyperlocomotion (i.e. sensitization). In parallel groups of rats treated with quinpirole and placed in the Y-maze daily without shock, or subjected only to daily footshock, locomotor activity did not increase. Footshock, therefore, has a synergistic effect in the development of sensitization to quinpirole. When the dose-response relationships of quinpirole were compared between naive and sensitized animals, the magnitude of stimulation differed, but the threshold stimulant dose did not change. Pretreatment with sulpiride completely antagonized the hyperlocomotion in both drug-naive and quinpirole-sensitized rats. The results support a view that quinpirole facilitates the emergence of patterned motor behaviors. Non-contingent, brief footshock elicits running as the prepotent behavior in the Y-maze, and hastens the development of behavioral sensitization to quinpirole.

Effects of Organogermanium Compound 2-Carboxyethyl Germanium Sesquioxide on Cardiovascular Function and Motor Activity in Rats

In rats anesthetized with urethane, intraperitoneal administration of a water-soluble organogermanium compound 2-carboxyethyl germanium sesquioxide (Ge-132) produced a dose-related reduction in either the mean arterial pressure or the heart rate. Both hypotension and bradycardia responses induced by Ge-132 injection were significantly inhibited by pretreatment of the animals with either spinal transection or bilateral vagotomy. The data indicate that Ge-132 induces both hypotension and bradycardia by promoting an activation of the parasympathetic efferent mechanisms and an inhibition of the sympathetic efferent mechanisms. On the other hand, following intraperitoneal injection of Ge-132, increased grooming and head swaying (as shown by an enhancement in fine movements monitored by an electronic activity counter) were provoked. Furthermore, the amphet-amine-induced enhancement in fine movements was potentiated by pretreatment of the animals with Ge-132. Thus, it appears that Ge-132 acts through the catecholaminergic mechanisms in the brain to induce locomotor stimulation in rats.

The effect of chronic lithium administration and withdrawal on locomotor activity and apomorphine-induced locomotor stimulation in rats.

The effect of chronic lithium administration and withdrawal on locomotor activity and apomorphine-induced locomotor stimulation in rats was studied. Chronic lithium administration caused a decrease in locomotor activity, which might be due to a lithium-induced decrease of exploratory behaviour. Chronic lithium administration had no effect on apomorphine-induced locomotor stimulation. However, apomorphine-induced locomotor stimulation was increased two days after the withdrawal of lithium while no difference was found after four days, suggesting a transient increase in postsynaptic dopamine (DA) receptor sensitivity following lithium withdrawal.

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.

Clonidine-induced locomotor hyperactivity in rats. The role of central postsynaptic alpha-adrenoceptors.

The alpha-adrenergic agonist, clonidine, causes sedation in normal rats. The present study demonstrates that clonidine evokes strong locomotor stimulation in rats pretreated with 6-hydroxydopamine plus reserpine. Similar, but less intensive hyperactivity is observed in rats given clonidine after combined pretreatment with 6-hydroxydopamine plus p-chlorophenylalanine plus alpha-methyl-p-tyrosine, or with reserpine plus low doses of yohimbine. The aplha-adrenolytic drugs, phenoxybenzamine, phentolamine and aceperone, as well as high doses of yohimbine, antagonise the clonidine-induced locomotor stimulation; in contrast, the dopamine receptor blocking agents, pimozide and spiroperiodol, exert no antagonistic effect. The results indicate that in the brain of normal animals, clonidine predominantly activates presynaptic alpha-adrenoceptors on noradrenergic neurones and thereby induces sedation. After destruction of the noradrenergic fibres by 6-hydroxydopamine plus reserpine, activation of postsynaptic alpha-adrenoceptors prevails so that hyperactivity results.

Selective 60HDA-induced destruction of mesolimbic dopamine neurons: Abolition of psychostimulant-induced locomotor activity in rats

Selective large scale destruction of mesolimbic dopamine-containing terminals is produced by bilateral injection of 8 μg of 6-hydroxydopamine (60HDA) into the nucleus accumbens septi (NAS) of rats pretreated with pargyline and desipramine (DMI). The DMI prevents the destruction of the noradrenergic innervation of the forebrain normally produced by the NAS 60HDA lesion, without affecting the destruction of dopamine-containing neurons. The locomotor stimulation produced by the psychostimulants d-amphetamine (1.5 mg'kg) and cocaine (20 mg/kg) is blocked in rats with selective destruction of the mesolimbic dopamine system. In contrast the locomotor stimulation produced by the directly acting dopamine agonist apomorphine (1.0 mg/kg) is enhanced, which may indicate supersensitivity of the denervated dopamine receptors. These results lend further support to the view that psychostimulant-induced locomotor stimulation in rats results from effects on mesolimbic dopamine neurons. In addition, the protection by DMI of noradrenergic neurons from the toxic effects of 60HDA is evidence that 60HDA, as used here, destroys catecholamine neurons mainly by an uptake-dependent specific mechanism.

On the role of serotonin in apomorphine-induced locomotor stimulation in rats

The locomotor activity of rats injected with apomorphine (1.0 or 5.0 mg/kg) was measured. The increase of locomotion caused by apomorphine was stronger in rats pretreated with BOL or methysergide and in some case with p-chloroamphetamine. LSD did not change the stimulation evoked by apomorphine or decreased it. The results are discussed according to the previously expressed suggestion about the possible inhibitory role of serotonin in apomorphine-induced locomotor stimulation in rats.

Antagonism of amphetamine locomotor stimulation in rats by single doses of marijuana extract administered orally

The influence of marijuana extract distillate on (+)-amphetamine stimulation of locomotor activity was examined in rats. Marijuana was administered orally and amphetamine was injected intraperitoneally. In rats acclimated to the activity cages, doses of the extract of 5, 10, and 20 mg/kg Δ 9-THC administered one hour before amphetamine resulted in a significant antagonism of the locomotor stimulation induced by 1 mg/kg (+)-amphetamine; doses of 0·625, 1·25 and 2·5 mg/kg Δ 9-THC had no effect on the amphetamine response. A dose of 10 mg/kg Δ 9-THC (as the extract) antagonized the stimulation produced by 0·5,1 and 2 mg/kg (+)-amphetamine in acclimated animals without depressing baseline activity; however, the same dose of marijuana failed to alter significantly the stimulant effect of 1 mg/kg (+)-amphetamine in nonacclimated rats. Although pretreatment with marijuana extract 1 hr before injection of amphetamine resulted in a marked depression of the amphetamine response, when both drugs were administered at the same time only a small and non-significant decrement in the amphetamine response was observed. In conclusion, this study clearly demonstrates that orally administered marijuana antagonizes amphetamine-induced locomotor stimulation in the rat. Mo evidence of enhancement of the amphetamine effect was observed.