Differential behavioral response to dopamine D? agonists by sexually naive, sexually active, and sexually inactive male rats.

This study was performed with male rats categorized as sexually active (SN), sexually active (SA). or sexually inactive (SI). In a first experiment the effects of the dopamine (DA) D? agonist SND 919 (0.05, 1, and 10 mg/kg) on the copulatory behavior of SN, SA. and SI rats were assessed. In a second experiment the DA D? agonist B-HT 920 (0.2 mg/kg) was used, and examination was limited to SN and SA rats. The effects exerted on stretching-yawning, penile erection, and sedation by the same compounds at the same doses in these three rat categories were also investigated. The main findings were that SND 919 and B-HT 920 facilitated ejaculation in SA rats, and that the rats that were different as regards level of sexual activity exhibited different behavioral responses to the two DA agonists. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Involvement of dopamine D2 receptors in the effect of cocaine on sexual behaviour and stretching-yawning of male rats

The effect of cocaine (7.5, 15 and 30 mg/kg) administered in acute or subchronic mode, on the mating behaviour of sexually active male rats varied in a dose- and mode-dependent manner. Regardless of mode of treatment, 30 mg/kg markedly impaired the rats copulatory ability and impairment continued for a week after suspension of subchronic treatment. An acute dose of 15 mg/kg reduced intromission frequency, while in subchronic mode it also reduced ejaculation latency. Mount frequency was increased by 7.5 and 15 mg/kg, but only on first injection. In the case of sexually-naive male rats, acute administration of cocaine (3-30 mg/kg) stimulated penile erections at 7.5 mg/kg and motor hyperactivity at all doses. (-) Eticlopride (0.025 and 0.05 mg/kg), a DA D2 antagonist, counteracted cocaine-induced motor hyperactivity but not penile erection, which it enhanced. (-) Eticlopride at the same doses also antagonized cocaine potentiation of lisuride (0.2 mg/kg)-induced behavioural effects. When male rats treated with subchronic cocaine (15 mg/kg) were injected with the DA D2 agonist SND 919 (0.1 mg/kg), they displayed a more marked stretching-yawning behaviour than control animals receiving SND 919 at the same dose. The involvement of DA D2 receptors in cocaine-induced effects is suggested.     

Striatal synaptophysin levels are not indicative of dopaminergic supersensitivity

Recent evidence suggests that behavioral supersensitivity to dopamine (DA) agonists observed in chronic neuroleptic-treated animals might be related to changes in synaptic morphology and density. The aim of this study was to test this hypothesis using Western blotting to determine the striatal synaptophysin levels in rats chronically treated with haloperidol followed by sub-acute administration of a DA agonist. Chronic haloperidol treatment (1 mg/kg/day for 21 days) produced an 88% increase in striatal synaptophysin levels and a 73% increase in apomorphine-induced stereotypes. Sub-acute administration of the DA D-1 receptor agonist SKF38393 (10 mg/kg/day for 5 days) or the DA D-2 receptor agonist quinpirole (1 mg/kg/day for 5 days) did not modify the haloperidol-induced increase in striatal synaptophysin levels. However, sub-acute administration of SKF38393 attenuated (62%) haloperidol-induced stereotypies. We conclude that there is no direct relationship between stereotyped behavior and synaptophysin levels indicating that striatal synaptophysin levels are not a good marker of dopaminergic supersensitivity.     

Alterations in dopamine release but not dopamine autoreceptor function in dopamine D3 receptor mutant mice

Dopamine (DA) autoreceptors expressed along the somatodendritic extent of midbrain DA neurons modulate impulse activity, whereas those expressed at DA nerve terminals regulate both DA synthesis and release. Considerable evidence has indicated that these DA autoreceptors are of the D2 subtype of DA receptors. However, many pharmacological studies have suggested an autoreceptor role for the DA D3 receptor. This possibility was tested with mice lacking the D3 receptor as a result of gene targeting. The basal firing rates of DA neurons within both the substantia nigra and ventral tegmental area were not different in D3 receptor mutant and wild-type mice. The putative D3 receptor-selective agonist R(+)-trans-3,4,4a, 10b-tetrahydro-4-propyl-2H,5H-(1)benzopyrano(4,3-b)-1,4-oxazin+ ++-9-ol (PD 128907) was equipotent at inhibiting the activity of both populations of midbrain DA neurons in the two groups of mice. In the gamma-butyrolactone (GBL) model of DA autoreceptor function, mutant and wild-type mice were identical with respect to striatal DA synthesis and its suppression by PD 128907. In vivo microdialysis studies of DA release in ventral striatum revealed higher basal levels of extracellular DA in mutant mice but similar inhibitory effects of PD 128907 in mutant and wild-type mice. These results suggest that the effects of PD 128907 on dopamine cell function reflect stimulation of D2 as opposed to D3 receptors. Although D3 receptors do not seem to be significantly involved in DA autoreceptor function, they may participate in postsynaptically activated short-loop feedback modulation of DA release.     

Effects of the dopamine antagonist PD 152255 on juvenile rats' responses to dorsal stimulation, the transport response and related behaviors.

The authors gave 23- and 40-day-old rats doses of the dopamine D? antagonist PD 152255 and tested them on transport response intensity, vertical cling catalepsy duration, and dorsal immobility duration. Administration of PD 152255 resulted in dose-dependent increases in transport response intensity in 40-day-old rats but was without effect in 23-day-old rats. Administration of PD 152255 caused increases in dorsal immobility durations in both 23- and 40-day-old subjects. The drug was without effect on vertical cling catalepsy. Results are discussed with respect to the role of D? receptors in the transport response and the nature of D?-D? receptor interactions. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Differential effects of clozapine and haloperidol on dopamine receptor mRNA expression in rat striatum and cortex

The regulation of the dopamine (DA) receptors is of considerable interest, in part because treatment with antipsychotic drugs is known to upregulate striatal D2-like receptors. While previous studies have focused on the regulation of striatal DA receptors, less is known about the pharmacological regulation of cortical DA receptors. The purpose of this study was to examine the regulation of DA mRNA receptor expression in the cortex compared to the striatum following treatment with antipsychotic agents. Adult male Sprague-Dawley rats were injected daily with haloperidol (2 mg/kg/day), clozapine (20 mg/kg/day) or a control vehicle for a period of 14 days. Following treatment, brains were subjected to in situ hybridization for the mRNAs encoding the five dopamine receptors; only D1, D2, and D3 receptor mRNAs were detected in these regions. Haloperidol tended to either modestly upregulate or have no effect on dopamine receptor mRNAs detected in striatal structures, while clozapine generally downregulated these mRNAs. On the other hand, in the cortex, both drugs had striking effects on D1 and D2 mRNA levels. Cortical D1 mRNA was upregulated by haloperidol, but this effect was primarily restricted to cingulate cortex; clozapine also upregulated D1 mRNA, but primarily in parietal regions. Haloperidol downregulated D2 mRNA in the majority of cortical regions, but most dramatically in frontal and cingulate regions; clozapine typically upregulated this mRNA, but primarily in regions other than frontal and cingulate cortex. These results indicate that clozapine and haloperidol each have regionally-specific effects, and differentially regulate dopamine receptor mRNA expression in striatal and cortical regions of the rat brain.     

Clinical picture of community-acquired Chlamydia pneumoniae pneumonia requiring hospital treatment: a comparison between chlamydial and pneumococcal pneumonia

AIM: To assess potencies of tetrahydroprotoberberines (THPB) and hydrobenzyltetrahydroisoquinolines (HBTI) on DA receptors. METHODS: The receptor binding assay with calf striatum to D1 and D2 receptors, and the animal behavior tests were used. RESULTS: (+/-) 12-Chloroscoulerine (CSL) was the most potent one among the THPB and HBTI. The affinities of CSL to D1 and D2 receptors were 13 and 51 nmol.L-1, respectively. In rats, CSL showed an antagonistic effect on the stereotypy and induced catalepsy. In the 6-OHDA lesioned rats, however, CSL exerted the agonistic effect to DA receptors. CONCLUSION: CSL had dual actions to DA receptors and its effects were similar to that of (-)stepholidine.     

Substituted 3-phenylpiperidines: new centrally acting dopamine autoreceptor antagonists

The (+)-and (-)-enantiomer of compounds 4 and 5 were synthesized and tested for central dopamine (DA) receptor stimulating activity, using biochemical and behavioral tests in rats. Based on the available data the (-)-enantiomers of 4 and 5 are characterized as centrally acting DA autoreceptor antagonists with oral activity. They display a similar pharmacological profile as the prototype DA autoreceptor antagonists (+)-1 and (+)-2 and show a certain preference for the D3 DA receptor antagonist binding site.     

Rats given dopamine-depleting brain lesions as neonates are subsensitive to dopaminergic antagonists as adults.

Notes that extensive damage to central dopamine (DA)-containing neurons produces akinesia and sensory neglect when the lesions are made in adult rats. Similar behavioral impairments occur when dopaminergic function is disrupted temporarily by DA receptor blocking agents, and brain-damaged rats are particularly sensitive to the effects of those drugs. The present 2 experiments, with 67 male Sprague-Dawley rat pups, are thought to offer a contrast to these accepted findings that central DA-containing neurons are critical to the initiation of voluntary movement. After near-total destruction of the dopaminergic neurons in 3-day-old rats, there were no conspicuous behavioral dysfunctions at any time during the subsequent 5–8 mo, even when Ss received large intraperitoneal doses of the DA receptor blocking agents haloperidol (.2–2.0 mg/kg) and fluphenazine HCl (1 mg/kg). Findings suggest that some other neuronal system had replaced the absent dopaminergic neurons in the central control of movement. (18 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Hypochord, an enigmatic embryonic structure: study of the axolotl embryo

Age-dependent alterations in behavioral and neuronal functioning were assessed in young (2-3 month), middle-aged (12 month), and aged (24 month) Fischer 344 rats treated with the indirect dopamine agonist amphetamine (2.25 or 5 mg/kg), the D1 agonist SKF 38393 (7.5, 15, 30 mg/kg), or the D2 agonist quinpirole (0.3, 1.0, 3.0 mg/kg). Drug-induced changes in activity and stereotypy were measured during a 90-min testing session, with Fos immunohistochemistry being used to assess the neuronal response to dopamine agonist treatment. As expected, aged rats given amphetamine (5 mg/kg) had fewer activity counts and higher stereotypy scores than young rats. Middle-aged rats also had fewer activity counts but were similar in stereotypy scores to young rats. Amphetamine also induced different patterns of Fos immunoreactivity in the neostriatum and nucleus accumbens of young and aged rats, as Fos expression in aged rats exhibited a distinctive dorsal to ventral pattern of decline. In general, SKF 38393 had few age-related actions, although aged rats did show a slight relative increase in stereotypy. In contrast, the D2 agonist quinpirole substantially enhanced the motor activity and Fos expression of young rats, while only modestly affecting aged rats. Hence, these results suggest that the D2 receptor is more vulnerable to the effects of aging than the D1 receptor.     

Sensitization of amphetamine-induced stereotyped behaviors during the acute response

The quantitative and qualitative features of the behavioral response to amphetamine-like stimulants in rats can be dissociated from the dopamine response. This dissociation is particularly evident in the temporal profiles of the extracellular dopamine and stereotypy responses to higher doses of amphetamine. One possible mechanism contributing to this temporal dissociation is that during the acute response to amphetamine, dopamine receptor mechanisms are enhanced such that stereotyped behaviors can be supported by synaptic concentrations of dopamine which are not sufficient to initiate these behaviors. To further explore the dynamics of stimulant sensitivity during the acute response, we examined the behavioral and extracellular dopamine responses to a low, nonstereotypy-producing dose of amphetamine (0.5 mg/kg) at various times after an acute, priming injection of 4.0 mg/kg when stereotypies had subsided and extracellular dopamine was approaching predrug baseline levels. The low-dose challenge produced intense stereotypies although the regional dopamine responses were not significantly different from control animals. Blockade of the expression of stereotypies during the priming response by the D2 antagonist haloperidol or the D1 antagonist SCH 23390 prevented the expression of an enhanced stereotypy response to the challenge injection. Our results suggest that an exposure to amphetamine results in a rapid sensitization of the stereotypy response which does not involve changes in the extracellular dopamine response but requires activation of dopamine receptors. Such a mechanism may be significantly implicated during binge patterns of stimulant abuse and may also play a role in the sensitization associated with repeated amphetamine administration.     

Effect of long-term haloperidol treatment on striatal neuropeptides: relation to stereotyped behavior

Behavioral and biochemical responses to D1 and D2 dopamine (DA) agonists were used to evaluate the participation of striatal peptidergic mechanisms in the motor function alterations that attend chronic neuroleptic treatment. Rats, given haloperidol (1 mg/kg, i.c.) for 21 consecutive days, were randomly allocated to one of the following treatments: the D1 agonist SKF 38393, the D2 agonist quinpirole, their combination or saline. Stereotyped behavior and neuropeptide levels were evaluated after 5 days treatment and 4 days washout. Haloperidol increased most oral behaviors including licking, chewing and biting as well as striatal enkephalin and somatostatin levels. Subsequent treatment with SKF 38393 diminished the haloperidol-induced increase in licking and chewing; quinpirole reduced chewing behavior. The administration of both agonists together decreased chewing and biting. Neither DA agonist alone, nor their combination, reduced the haloperidol-induced increase in enkephalin levels. Both SKF 38393 and quinpirole, when given alone, tended to decrease the haloperidol-induced increase in somatostatin levels; when both D1 and D2 agonists were administered together, somatostatin levels declined significantly. These results suggest that somatostatin- but not enkephalin-containing striatal neurons contribute to the expression of haloperidol-induced stereotypies.     

Tumor necrosis factor-alpha mediates endotoxin induced suppression of gonadotropin-releasing hormone pulse generator activity in the rat

Little is known regarding the developmental regulation of the cardiac angiotensin type 1 (AT1) and type 2 (AT2) receptor genes or their role in normal cardiac growth. Regulation of AT1 and AT2 receptor genes were examined using total and poly A + RNA isolated from whole Sprague-Dawley rat hearts. AT1 mRNA levels were 3.5-fold higher in the 19-day-old fetal heart compared to the 90-day-old adult as detected with 2 or 5 microg of poly A + RNA. AT2 mRNA was only detectable with 20 microg of poly A + RNA. AT2 mRNA levels were highest in the 19-day-old fetal heart with no detectable message in the 90-day-old adult heart. Qualitative PCR for AT2 mRNA also could not detect AT2 mRNA in the adult heart. Treatment with the AT1 receptor antagonist losartan for 3 weeks in the 21-day-old rat or for 4 days in the 38-day-old rat resulted in a significant decrease in heart/body weight in both groups and body weight in the 3-week treatment group. AT2 blockade for 4 days with PD123319 or beta-receptor blockade with propranolol for 3 weeks did not alter heart/body weights. Losartan treatment also resulted in a three-fold increase in cardiac AT1 mRNA levels in both the 4-day and 3-week treatment groups compared to controls. We conclude that Ang II, acting primarily, if not exclusively via the AT1 receptor plays a significant role in the regulation of normal cardiac growth in the young rat.     

Pharmacological characterization of PD 152255, a novel dimeric benzimidazole dopamine D3 antagonist

152255 (E-1,1'-(2-butene-1,4-diyl)bis[2-[4-[3-(1-piperidinyl)propoxy]-phe nyl]-1H-benzimidazole]) exhibited high affinity (Ki = 12.7 nM) for human dopamine (DA) D3 receptors expressed in CHO K1 cells but not for DA D2L receptors (Ki = 565 nM), DA D42 or DA D1 receptors (Ki > 3 microM) and a number of other neurotransmitter receptors. Affinity for human muscarinic receptors was seen in vitro but no functional muscarinic agonist and/or antagonist action was observed in vivo. Antagonist activity at DA D3 receptors was demonstrated by blockade of quinpirole-stimulated [3H]-thymidine uptake in D3 transfected cells, an effect that was 28-fold more potent than in D2-transfected cells. Unlike classical DA D2 antagonists, PD 152255 did not increase rat brain DA synthesis and it increased locomotion in habituated rats. However, like antipsychotics, PD 152255 reduced locomotor activity in mice and reduced spontaneous and amphetamine-stimulated locomotion in nonhabituated rats. These results demonstrate that PD 152255 is a DA D3 antagonist that may have antipsychotic activity.     

Anxiolytic effects of dopamine receptor ligands: I. Involvement of dopamine autoreceptors

The anxiolytic-like properties of dopamine agonists and antagonists with different receptor profiles were investigated in the ultrasonic vocalization test in rats after subcutaneous administration. Only dopamine D2 receptor agonists inhibited ultrasonic vocalization with the following ED50 values: apomorphine (0.07 mg/kg), quinelorane (0.01 mg/kg), quinpirole (0.04 mg/kg), pramipexole (0.09 mg/kg), roxindole (0.04 mg/kg), talipexole (0.04 mg/kg), (+/-)-7-OH-DPAT (0.05 mg/kg), (+/-)-PPHT (0.03 mg/kg), (-)-TNPA (0.06 mg/kg), PD128907 (0.13 mg/kg). The D2 antagonists haloperidol, mazapertine, raclopride, remoxipride, L745870, U99194A, U101958 and S(-)-DS121, the partial agonists PD143188 and preclamol, the selective D1 agonist R(+)-SKF38393 and the D1 antagonist SCH23390, and the uptake inhibitors GBR12909, GBR12935 and indatraline lacked significant inhibitory effects on ultrasonic vocalization. Because at least some of the D2 receptor agonists investigated have selectivity for dopamine autoreceptors, it is speculated that the dopamine autoreceptor may be a target for the development of new antianxiety drugs.     

Haloperidol induces changes in the electrocorticogram of rats with genetic petit mal epilepsy

The WAG/Rij rats, a genetic animal model of human absence epilepsy, were injected with D2 autoreceptor antagonist haloperidol. Increase in the amount of spike-wave discharges and the prevalence of short spike-wave discharges was observed. The pattern of spike-wave discharge sequence changed in a characteristic way. The findings may testify to participation of dopaminergic system both in the processes of generation and cessation of the spike-wave complex absence epilepsy.     

Effects of diet on sensitization to cocaine-induced stereotypy in female rats

The progressive increase in cocaine-induced stereotyped behavior that accompanies repeated cocaine injections (sensitization) was examined in rats consuming different diets. Adult female Sprague-Dawley rats were fed one of three diets: low protein (6% casein), adequate protein (25% casein), or a standard chow diet. Following 1 week of adaptation to the diets, the rats were injected every 3-4 days with either cocaine (30 mg/kg, IP) or saline, and the total amount of stereotypy was measured over a 90-min interval following each of four injections. Cocaine-induced stereotypy peaked at 40-50 min following each injection, after which it declined for all diet groups. With repeated injections, the total amount of stereotypy increased in all diet groups. By the fourth injection, the low protein diet group (6% casein) exhibited a slower onset and a possibly prolonged duration of cocaine-induced stereotypy when compared with the two adequate protein diet groups (25% casein and chow). Interestingly, the rats in the two purified diet groups (6% casein and 25% casein) exhibited significantly more stereotypy across injections than those in the chow diet group. Weight differences did not explain the differences in stereotypy present among the diet groups. This study concludes that diet significantly alters the pattern of cocaine-induced stereotypy in female rats, especially after repeated exposure.     

Roxindole, a potential antidepressant. I. Effect on the dopamine system

Roxindole (EMD 49980, 5-hydroxy-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl(1))-butyl(1)]-indole mesylate), a selective dopamine autoreceptor agonist and a potential antipsychotic drug, shows a clinical antidepressant efficacy. The present paper examined the neuropharmacological profile of roxindole in rats (male Wistar) and mice (male Albino Swiss) in respect of its influence on dopamine system. Used in low doses, roxindole decreased the locomotor activity, but in higher ones it did not induce a locomotor hyperactivity or stereotypy. It antagonized the amphetamine-induced hyperlocomotion, the amphetamine- or apomorphine-induced stereotypy, apomorphine climbing behaviour and reserpine-induced akinesia. The quinpirole-induced hyperlocomotion was inhibited by roxindole. When given alone, the drug in question, did not induce the catalepsy, but antagonized the catalepsy induced by haloperidol, spiperone and fluphenazine. The immobility time in the forced swimming test was reduced. Like typical antidepressants, roxindole given repeatedly (twice daily, 14 days) increased the hyperlocomotion induced by D-amphetamine. The results described above indicate that roxindole may have an antidepressant and antiparkinsonian activity and should be devoid of extrapyramidal side-effects.     

Effects of the dopamine D3 antagonist PD 58491 and its interaction with the dopamine D3 agonist PD 128907 on brain dopamine synthesis in rat

The dopamine (DA) D3 receptor antagonist PD 58491 [3-[4-[1-[4-[2-[4-(3-diethylaminopropoxy)phenyl]benzoimidazol++ +-1-yl-butyl]-1H-benzoimidazol-2-yl]phenoxy]propyl]diethylamine] bound with high affinity and selectivity to recombinant human DA D3 versus D2L and D4.2 receptors transfected into Chinese hamster ovary cells: Ki values of 19.5 nM versus 2,362 and >3,000 nM, respectively. In contrast, the putative DA D3 receptor antagonist (+)-AJ76 displayed low affinity and selectivity for D3 versus D2L and D4.2 receptors (91 nM vs. 253 and 193 nM, respectively). In vitro, PD 58491 (1 nM-1 microM) exhibited D3 receptor antagonist activity, reversing the quinpirole (10 nM)-induced stimulation of [3H]thymidine uptake in D3 CHOpro-5 cells, but did not have any significant intrinsic activity by itself in this assay. PD 58491 did not decrease the gamma-butyrolactone-induced increase in DA synthesis (L-3,4-dihydroxyphenylalanine accumulation) in rat striatum, indicating that the compound possessed no in vivo DA D2/D3 receptor agonist action at DA autoreceptors. PD 58491 (3-30 mg/kg, i.p.) generally did not alter DA or serotonin synthesis in either the striatum or mesolimbic region of rat brain. The D3-preferring agonist PD 128907 decreased DA synthesis in striatum and mesolimbic regions, and this effect was attenuated by pretreatment with PD 58491. These findings support the hypothesis that DA D3 autoreceptors may in part modulate the synthesis and release of DA in striatum and mesolimbic regions.