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Comparative analysis of anxiety-like behavior in partition and plus-maze tests after agonistic interactions in mice.

The behavior of C57BL/6J male mice with experience of repeated victories (winners) or defeats (losers) in daily agonistic interactions, was examined in the plus-maze and partition tests. The latter procedure assesses the reactivity of mice to another conspecific in the neighboring compartment of a common cage, communicative behavior or level of sociability. The behavior of mice after 10 days (T10) and 20 days (T20) of agonistic confrontations, as well as in controls (5 days of individual housing) was analyzed. Significant differences were found between T10 and T20 losers and controls in both tests. In the partition test, a decrease in the number of approaches and total and average time spent near the partition was found in T10 and, more pronounced, in T20 losers. In the plus-maze, losers showed fewer open and total entries than controls. Moreover, rarely did they pass from one enclosed arm to another, and also showed a decreased number of 'peepings' from enclosed arms. Percentage of open time did not differ significantly in losers compared to controls. It is suggested that the level of losers' sociability, estimated as low by the partition test, can include anxiety as a component, which is confirmed, at least partly, by some parameters of the plus-maze test. There were no differences in the partition or plus-maze tests between T10 winners and controls. However, all parameters of partition behavior were significantly different between T20 winners and controls. In the plus-maze, similar to losers, T20 winners displayed fewer open arm entries, number of "peepings,' and passages than controls. It was concluded that parameters of the partition and plus-maze tests correlate in mice with the alternative experience of agonistic confrontations, positive or negative. A combination of these two tests may be used for estimation of developing anxiety in mice.

Agonistic Behavior↗

[The effect of the deprivation of paradoxical sleep on the rotational and stereotyped behavior induced by selective agonists of the dopamine receptors].

The ability of selective D1 and D2 agonists of dopamine (DA) receptors SKE-38393 and Ly-171555 to induce rotational and stereotypes behaviour were studied in rats with unilateral striatal kainic acid lesion before and after procedure of REM sleep deprivation (REMSD) lasting for 5 days. It was found that REMSD SKF-38393 given along induced the ipsilateral rotation. REMSD increased the circling and decreased an oral stereotype simultaneously when SKF-38393 and Ly-171555 were given together. The depletion of brain DA in part with alpha-methyl-p-tyrosine (AMPT) in nondeprived rats fails to influence the rotational behaviour and stereotype when SKF 38393 was injected 30 min following Ly-171555. After REMSD the AMPT pretreatment prevents the rotational behaviour caused by Ly-171555 which restores SKF-38393. The results suggest that prolonged REMSD may induce nonidentical changes in the sensitivity of the postsynaptic D1 and D2 receptors.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

YM796, a novel muscarinic agonist, improves the impairment of learning behavior in a rat model of chronic focal cerebral ischemia.

We studied effects of YM796, a novel muscarinic agonist, on behavioral, histological and regional cerebral blood flow changes in the chronic phase after focal cerebral ischemia in rats. YM796 (0.03, 0.1, 0.3 and 1 mg/kg) was administered orally once a day from the 7th to the 13th day after the permanent occlusion of left middle cerebral artery. On the 7th day, rats were trained in one-trial step-through passive avoidance task 45 min after drug administration. Test trials were carried out on the 8th and 14th days. Neurological deficits, including hemiplegia and abnormal posture, were observed on the 7th and 14th days. After the completion of behavioral studies, the rats were decapitated and cerebral infarction was measured. Regional cerebral blood flow was also measured by the hydrogen clearance technique 7 days after MCA occlusion. YM796 (0.1-1 mg/kg) significantly (P < 0.05) attenuated the impairment of learning behavior in a dose-dependent manner without affecting spontaneous locomotor activity. The ameliorating effect of YM796 (0.3 mg/kg) on the impaired learning behavior was significantly (P < 0.05) suppressed by intracerebroventricular injection of pirenzepine (10 micrograms/rat), an M1 antagonist. No significant difference in either neurological deficits or cerebral infarction was found between the vehicle- and YM796-treated groups. Further, YM796 (0.3 mg/kg) had little effect on the reduced blood flow in the ipsilateral frontal cortex 7 days after occlusion. These results suggest that YM796 improves the impaired learning behavior probably by activating central M1 receptors in a rat model of chronic focal cerebral ischemia.

Animals↗

Genetic variations in midbrain dopamine cell number: parallel with differences in responses to dopaminergic agonists and in naturalistic behaviors mediated by central dopaminergic systems.

Mice of the inbred strain BALB/cJ have more midbrain dopaminergic cell bodies and greater activity of the catecholamine-synthesizing enzyme, tyrosine hydroxylase (TH), in the nigrostriatal and mesolimbic dopaminergic systems than mice of the CBA/J strain. This difference in cell number and TH activity in the midbrain dopaminergic systems are paralleled by differences in drug responses and behaviors which are dependent on the release of dopamine in midbrain dopaminergic system. BALB/cJ mice showed greater locomotion and stereotypy than CBA/J mice after D-amphetamine (2-20 mg/kg, i.p.). There was no difference in the amount of amphetamine accumulated in brain at the peak of drug response or in the duration of drug effect, suggesting that the differences in behavioral effect were not due to strain differences in pharmacokinetic distribution of the drug. In contrast to the greater stereotypy to D-amphetamine, BALB/cJ mice showed less stereotypy after apomorphine (2-10 mg/kg, i.p.) than CBA/J mice. BALB/cJ mice also showed more exploration than CBA/J mice, measured as locomotion and rearing in a novel open field and investigation of a novel object. Genetically determined differences in the number of midbrain dopaminergic cell bodies and in the relative density of innervation of DA terminals in target fields and in TH activity in the nigrostriatal and mesolimbic dopaminergic systems are paralleled by difference in behavioral responses mediated by release of dopamine. The number of cells of a particular neurochemical class may dictate the magnitude of behaviors, drug-induced or spontaneous, mediated by those neurons.

Animals↗

Interactions between the benzodiazepine receptor antagonist Ro 15-1788 (flumazepil) and the inverse agonist beta-CCE: behavioral studies with squirrel monkeys.

The effects of Ro 15-1788 and ethyl-beta-carboline-3-carboxylate (beta-CCE) were studied alone and in combination on the behavioral performances of squirrel monkeys. Under one procedure, performances maintained by food were suppressed by electric shock presentation (punishment or "conflict" procedure). Under a second procedure, responding was maintained either by food or electric shock delivery under a 5-min fixed-interval schedule. Doses of beta-CCE between 0.1 and 3.0 mg/kg, i.m., produced graded decreases in punished responding which were reversed by pretreatment with Ro 15-1788 (1.0 - 10.0 mg/kg, i.m.). Low doses of beta-CCE (0.03 - 0.3 mg/kg, i.m.) increased responding of monkeys maintained by shock presentation, but did not affect food-maintained responding; higher doses of beta-CCE decreased responding under both schedules. These effects of beta-CCE are opposite those produced by the benzodiazepines under this procedure. Ro 15-1788 (1.0 mg/kg i.m.) antagonized the effects of beta-CCE, producing a shift to the right in the dose-response curves. These findings provide further support for the view that beta-CCE and Ro 15-1788 produce effects mediated by the same benzodiazepine receptor recognition site.

Animals↗

Chronic flurazepam differentially regulates a behavioral effect of GABA agonists.

Subsensitivity to gamma-aminobutyric acid (GABA) agonists was sought in rats treated 1 or 4 weeks with flurazepam (FZP). Sensitivity to GABA and 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) was assessed by measuring contralateral rotation following unilateral microinjection of drug into the substantia nigra pars reticulata (SNpr). Immediately and 48 h after chronic treatment GABA, 200 micrograms or THIP, 60 ng was infused into SNpr. Immediately, but not 48 h after 1 week of FZP treatment, GABA subsensitivity was shown by a significantly reduced total number of contralateral turns and peak rotation rate. There was no change in the response to THIP after 1 week FZP treatment. Following 4 week FZP treatment, no subsensitivity to GABA or THIP was evident. Previous results showed subsensitivity to muscimol after 4, but not 1 week of FZP treatment. Since muscimol and THIP are not subject to uptake, there may be increased uptake of GABA after 1 week of FZP treatment, though it may not persist during continued treatment. Differential regulation of GABA agonist effects in SNpr may be related to their acting at differing GABAA receptor subpopulations, and variable responses of these subpopulations to chronic BZ treatment.

Animals↗

In vivo binding behavior of dopamine receptor agonist (+)-PD 128907 and implications for the "ceiling effect" in endogenous competition studies with [(11)C]raclopride-a positron emission tomography study in Macaca mulatta.

In in vivo positron emission tomography (PET) studies, dopamine that is released secondary to amphetamine administration appears unable to achieve a receptor occupancy that is significantly higher than 50% ("ceiling effect"). Also with exogenous agonists no studies have reported a higher than 50% occupancy. To investigate the feasibility of exceeding 50% occupancy in vivo with a dopamine receptor agonist we administered D2/D3 agonist (+)-PD 128907 over an extensive dose range. Two anesthetised Macaca mulatta males were used in a bolus-infusion protocol for [(11)C]raclopride. (+)-PD 128907 was administered as an intravenous challenge during separate PET scans in a dose range of 10 to 10000 nmol/kg. Occupancy by (+)-PD 128907 was estimated by comparing the binding before and after challenge. In a striatal region of interest, receptor occupancy by (+)-PD 128907 increased in an orderly dose-dependent manner to a maximum of at least 85%. This is the first indication that virtually all dopamine D2/D3 receptors in the striatum are in principle accessible to agonist binding. In the case of dopamine a number of protective mechanisms may be responsible for the ceiling effect.

Animals↗

Impact of cannabinoid receptor ligands on behavioural sensitization to antiaggressive methamphetamine effects in the model of mouse agonistic behaviour.

OBJECTIVES: Psychostimulants and cannabinoids can elicit so called behavioural sensitization after repeated administration, a gradually increased behavioural response to a drug. This phenomenon if conditioned by previous pre-treatment with different drug is termed cross-sensitization. The present study was focused on a possible sensitisation to antiaggressive effect of methamphetamine and cross-sensitization to this effect after repeated pre-treatment with cannabinoid CB1 and CB2 receptor ligands with different intrinsic activity (CB1 agonist methanandamide, CB2 agonist JWH 015, and CB1 antagonist AM 251). METHODS: Behavioural interactions of singly-housed mice with non-aggressive group-housed partners were video-taped and behavioural elements of agonistic behaviour of isolates were recorded in four categories: sociable, timid, aggressive and locomotor. RESULTS: Repeated administration of methamphetamine elicited a significant sensitization to its antiaggressive effects. Methanandamide pre-treatment provoked cross-sensitization to this methamphetamine effect, whereas pre-treatment with JWH 015 did not. Combined pre-treatment with methamphetamine+AM 251 suppressed the sensitization to antiaggressive effects of methamphetamine. CONCLUSIONS: Our findings have shown that it is possible to provoke sensitization not only to the stimulatory effects as stated widespread in the literature but also to inhibitory antiaggressive effects of methamphetamine. Furthermore, we confirmed our working hypothesis that it is possible to elicit either cross-sensitization to inhibitory effects of methamphetamine conditioned by repeated pre-treatment with cannabinoid CB1 receptor agonist methanandamide, or suppression of methamphetamine sensitizing influence by co-administration of CB1 receptor antagonist.

Agonistic Behavior↗

The effect of (-) deprenyl (selegiline) on different behavioral changes induced by dopamine agonists in the rat.

The effect of (-) deprenyl was investigated both on the stereotyped behavior and on other types of activities induced by various dopamine (DA) agonists. (-) Deprenyl was given in a single dose, 1 h prior to the DA agonists. 1-2 mg/kg sc (-) deprenyl decreased the stereotypy induced by amphetamine (AMPH, 2.5 mg/kg sc), but 20 mg/kg was needed to reduce the stereotypy-inducing effect of apomorphine (APO, 0.3 mg/kg sc). The stereotypy-inducing effect of phenyl-ethyl-amine (PEA, 40 mg/kg sc) was significantly enhanced by 0.25 mg/kg sc (-) deprenyl pretreatment. The PEA or AMPH-induced increase in the horizontal activity (locomotion) and the vertical activity (rearing) remained unchanged after a single dose of (-) deprenyl, showing that this drug acts primarily on the nigro-striatal dopaminergic system.

Amphetamine↗

The novel benzodiazepine inverse agonist RO19-4603 antagonizes ethanol motivated behaviors: neuropharmacological studies.

The novel imidazothienodiazepine inverse agonist RO19-4603 has been reported to attenuate EtOH intake in home cage drinking tests for at least 24 h post-drug administration after systemic administration. In the present study, selectively bred alcohol-preferring (P) rats were trained under a concurrent (FR4-FR4) operant schedule to press one lever for EtOH (10% v/v) and another lever for saccharin (0.05% or 0.75% g/v), then dose-response and timecourse effects of RO19-4603 were evaluated. Systemic RO19-4603 injections (0.0045-0.3 mg/kg; i.p.) profoundly reduced EtOH responding by as much as 97% of vehicle control on day 1. No effects were seen on saccharin responding except with the highest dose level (0.3 mg/kg). In a second experiment, microinjections of RO19-4603 (2-100 ng) directly into the nucleus accumbens (NA) suppressed EtOH responding on day 1 by as much as 53% of control: Control injections dorsal to the NA or ventral tegmental area did not significantly alter EtOH or saccharin responding. On day 2, rats in both experiments received no RO19-4603 treatments; however, all 7 of the i.p. doses, and all 3 of the intra-NA infusions continued to significantly suppress EtOH responding by 43-85% of vehicle control levels. In addition, i.p. injections of RO19-4603 produced a dose-dependent decrease in the slope of the cumulative record for EtOH responding, while concomitantly producing a dose-dependent increase in the slope for saccharin responding. RO19-4603's actions appear to be mediated via recognition sites at GABAA-BDZ receptors which regulate EtOH reinforcement, and not via mechanisms regulating ingestive behaviors. Based on recent in situ hybridization studies in our laboratory, we hypothesize that occupation of alpha4 containing GABAA diazepam insensitive (DI) receptors in the NA, may mediate in part, the RO19-4603 suppression of EtOH responding in EtOH-seeking P rats.

Alcohol Deterrents↗

Intrastriatal injection of opioid receptor agonists inhibits apomorphine-induced behavior in 6-hydroxydopamine-treated mice.

The effects of intrastriatal (i.st.) injections of mu-, delta-, and kappa-selective opioid receptor agonists on the augmentation of apomorphine-induced behaviors were determined in 6-hydroxydopamine-treated mice by using multidimensional behavioral analyses. 6-Hydroxydopamine (16 mu g/mu l, i.st.) was unilaterally injected into the striatum 30 min after pretreatment with desipramine (25 mg/kg, s.c). Mice were tested 14 days after injection of 6-hydroxydopamine. Apomorphine (0.5 mg/kg, s.c.) produced a marked increase in linear locomotion, contralateral circling and/or rearing behavior in 6-hydroxydopamine- but not vehicle-treated mice. Although the mu-selective opioid receptor agonist [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin (DAMGO) (0.1 and 0.3 ng, i.st.) or the kappa-selective opioid agonist dynorphin A-(1-13) (0.1 and 0.3 mu g, i.st.) did not produce any significant effects on behavior, these peptides had an inhibitory effect on the apomorphine (0.5 mg/kg, s.c.)-induced increase in behavioral responses such as linear locomotion, contralateral circling and/or rearing behavior in 6-hydroxydopamine-treated mice. The inhibitory effects of DAMGO (0.3 ng, i.st.) and dynorphin A-(1-13) (0.3 mu g, i.st.) were fully reversed by selective opioid receptor antagonists such as beta-funaltrexamine (5 mu g, i.c.v.) and (--)-(1R,5R,9R)-5,9-diethyl-2-(3-furyl-methyl)-2'-hydroxy-6,7-benzomorph an (Mr2266) (10 mg/kg, s.c.), respectively. In contrast, the delta-selective opioid receptor agonist [D-Pen2,L-Pen5]enkephalin (DPLPE) (0.03, 0.1 or 0.3 mu g, i.st.) had no marked effects on the apomorphine (0.5 mg/kg, s.c.)-induced behavior in 6-hydroxydopamine-treated mice. These results suggest that the stimulation of mu- and kappa- but not delta-opioid receptors plays an inhibitory role in the behavioral augmentation induced by the activation of postsynaptic dopamine receptors in the striatum sensitized with 6-hydroxydopamine.

Animals↗

Effects of dopamine agonists on appetitive and consummatory male sexual behavior in Japanese quail.

The effects of pharmacological manipulations of dopaminergic transmission on appetitive and consummatory aspects of male sexual behavior were investigated in castrated male Japanese quail treated with exogenous testosterone. Appetitive male sexual behavior was assessed by measuring a learned social proximity response and consummatory behavior was assessed by measuring copulatory behavior per se. The nonselective dopamine receptor agonist, apomorphine, inhibited in a dose-dependent manner both components of male sexual behavior. Two indirect dopamine agonists were also tested. Nomifensine, a dopamine re-uptake inhibitor, decreased appetitive sexual behavior but increased the frequency of mount attempts, a measure of consummatory sexual behavior. Amfonelic acid, a compound that enhances dopaminergic tone by a complex mechanism, increased aspects of both appetitive and consummatory behaviors. These data suggest that, in quail, as in rodents, increases in dopaminergic tone facilitate both appetitive and consummatory aspects of male sexual behavior. Apomorphine may be inhibitory in quail because it acts primarily on D2-like receptors, unlike in rats, where it stimulates sexual behavior and acts primarily on D1-like receptors at low doses but interacts with D2-like receptors at higher doses. This is supported by the observation that stereotyped pecking, a behavior stimulated selectively in quail by D2 agonists, was increased by apomorphine but not by the two indirect agonists. The observed partial dissociation between the effects of these dopaminergic agonists on appetitive and consummatory sexual behaviors suggests that these two components of male sexual behavior may be controlled by the action of dopamine through different neuronal systems.

Animals↗

Dissociation between spontaneously emitted and apomorphine-induced stereotypy in Peromyscus maniculatus bairdii.

Stereotyped behavior is repetitive, topographically invariant motor activity that lacks an obvious function. We have previously characterized the spontaneous and persistent stereotypies that occur in deer mice housed in standard laboratory cages. Providing these animals with enriched environments markedly reduces their vulnerability to develop stereotypic behavioral repertoires, thus enabling us to generate behaviorally distinct (stereotypic and nonstereotypic) mice of the same species. As stereotypic behaviors are readily induced by systemic administration of a dopamine (DA) agonist, the present study tested whether apomorphine would induce stereotypies in environmentally enriched (nonstereotypic) deer mice that were topographically similar to the stereotypies that are spontaneously emitted by standard-caged (stereotypic) deer mice. The effects of apomorphine were also evaluated in the standard-caged (stereotypic) deer mice. DA agonist-induced behaviors in nonstereotypic mice included stereotypies that were largely topographically distinct from spontaneously emitted stereotypies; apomorphine failed to produce statistically significant elevations in two of the three stereotypic behaviors typical of standard-caged deer mice. Furthermore, there was no evidence of increased DA receptor sensitivity in stereotypic mice. Thus, environmentally related stereotypy is distinct from systemically administered DA agonist-induced stereotypy, and is not exacerbated by such drug treatment. The results obtained do provide support, however, for a limited involvement of the DA system in the mediation of these behaviors.

Animals↗

Effects of alpha-2 adrenoceptor agonists and antagonists on circling behavior in rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway.

The present study examined the influence of alpha-2 adrenoceptor ligands on circling behavior in rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway. The alpha-2 adrenoceptor agonists, clonidine and UK 14304, inhibited both the ipsilateral rotation induced by the indirect dopaminergic agonist, methylphenidate, and the contralateral circling induced by the direct dopaminergic agonist, apomorphine. In contrast, the alpha-2 adrenoceptor antagonists, idazoxan and (+/-)-efaroxan, enhanced the circling induced by either methylphenidate or apomorphine. The facilitating activity of efaroxan was stereoselective because the (+)-enantiomer mimicked the effect of (+/-)-efaroxan, whereas the (-)-enantiomer was essentially inactive, thus indicating a mediation by alpha-2 adrenoceptors. Upon administration alone, the above-mentioned compounds did not modify spontaneous circling behavior, except for UK 14304, which decreased, and (+)-efaroxan, which slightly increased, the ipsilateral rotation. We conclude that activation and antagonism of alpha-2 adrenoceptors inhibit and enhance, respectively, the circling behavior evoked by both direct and indirect dopaminergic agonists. Although a modulation of dopamine release may be involved in some of these drug effects, the effects on apomorphine-induced circling indicate an influence of alpha-2 adrenoceptor compounds on nigrostriatal neurotransmission at sites downstream from the dopaminergic neurons themselves. These findings support the notion of a potential benefit of alpha-2 adrenoceptor antagonists in the treatment of Parkinson's disease.

Adrenergic alpha-Agonists↗

Influence of hypophysectomy on dopamine receptors and dopaminergic behaviors.

Hypophysectomy (Hypox) has been proposed to alter the behavioral and biochemical indices of striatal dopamine (DA) function. Since the regulation of striatal DA receptors by hormones may involve the pituitary, it was relevant to reevaluate the effects of Hypox in male and female rats. Behaviorally, dopaminergic agonists exerted enhanced activity in Hypox male and female rats. It has been suggested that these changes are due to altered metabolism since no increase in the DA receptor populations was observed. Dopaminergic antagonists showed equivalent behavioral actions in male and female rats, whether intact or Hypox. Biochemically, neither the density nor the affinity of the striatal DA receptors is altered by Hypox in female rats for 1-2 weeks or male rats for 5-6 weeks. However, in female rats at 5-6 weeks after Hypox there is a significant decrease in receptor number. This decrease in density is not reflected in behavioral changes to either DA receptor agonists or antagonists. Therefore, all dopaminergic behavioral changes do not result from alterations in DA receptors and changes in DA receptors do not necessarily dictate altered behavioral responses to dopaminergic agents.

Animals↗