Enhanced response to the inhibitory action of LY171555, a dopamine D2-agonist, on in vivo striatal dopamine release in DOCA/NaCl-hypertensive rats

Our previous studies have demonstrated that LY171555 (quinpirole), a specific dopamine (DA) D₂-receptor agonist, has a pressor effect in the conscious rat which is accompanied by increased sympathetic outflow and arginine vasopressin release. To test the hypothesis that LY171555 inhibits in vivo release of DA and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), from central dopaminergic neurons of the conscious, freely moving rat by activation of presynaptic DA receptors in the central nervous system and that this mechanism may be altered in the desoxycorticosterone acetate (DOCA)/NaCl model of hypertension, we used the in vivo push-pull perfusion method to study the effect of LY171555 on central DA release in normotensive and DOCA/NaCl-hypertensive rats. Levels of the DOPAC and HVA were measured in striatal perfusates by HPLC before and after administration of LY171555 (1 mg/kg, i.v.) of conscious, unrestrained 4-week DOCA/NaCl hypertensive and uninephrectomized H₂O control rats. There were no significant differences in basal striatal HVA (80 ± 12 vs 89 ± 11 pg/min; DOCA/NaCl vs control) or DOPAC levels (37 ± 5 vs 17 pg/min; DOCA/NaCl vs control) during the entire 240-min collection period. LY171555 significantly reduced HVA and DOPAC levels in perfused striatum in both normotensive control and DOCA/NaCl-hypertensive rats. The LY 17555-induced suppression in HVA levels was significantly greater in DOCA/NaCl rats (Δ = 60.7 ± 3.6%) than in H₂O controls (Δ = 49.0 ± 3.5%, P < 0.05). Pretreatment with metoclopramide (10 mg/kg, i.v.), a specific central and peripheral DA D₂-receptor antagonist, completely blocked the suppressive effects of LY171555 on HVA and DOPAC levels. These observations provide direct evidence for the presence of functionally significant presynaptic inhibitory DA D₂-receptors which modulate dopaminergic neuro-transmission in the striatum of conscious, freely moving rats. This regulatory mechanism appears to be altered in the DOCA/NaCl model of hypertension. These results support the concept that DOCA/NaCl-hypertensive rats have altered central dopaminergic activity.     

The influence of cost manipulation on water contrafreeloading induced by repeated exposure to quinpirole in the rat

Rationale Quinpirole (QNP), a D2/D3 dopaminergic receptor agonist, was found to elicit an apparently antieconomical drinking behavior called contrafreeloading (CFL). The perseverative operant responding observed may represent a compulsive-like behavior prompted by sensitization to the effects of QNP. Objectives In the present study, we investigated the effect of different response costs on instrumental behavior and CFL in rats repeatedly treated with QNP (0.5 mg/kg i.p.). Moreover, we studied the consummatory components of ingestive behavior in no-choice paradigms and the role of learned operant conditioning in free drinking. Materials and methods In experiment 1, rats were trained to perform under three different fixed ratio schedules of reinforcement (FR1, FR3, and FR10) and were given a choice between operant and free access to water. In experiment 2, rats were divided into four groups, each one resembling experiment 1 in one or more features, with no choice available and water consumption measured at an interval of 0–60 min. Results (a) Increasing FR significantly reduced CFL % in saline—but not in QNP-injected groups; (b) under free-drinking conditions, QNP caused a progressive hypodipsic effect which was, however, contrasted by maintaining cues formerly contingent on operant access to water; and (c) under CFL conditions QNP-treated rats drank more than under free access conditions. Conclusions QNP confers rigidity in responding for water, impeding adaptation to different contingencies for access to the resource. In QNP-treated rats, CFL behavior appears adaptive as far as it allows animals to partially circumvent the hypodipsic effect of the drug.     

Dopamine regulation of extracellular glutamate in the nucleus accumbens

The capacity of dopamine to alter extracellular glutamate in the nucleus accumbens was examined by passing 1, 10 and 100 μM of amphetamine, the D_2/3 agonist, quinpirole, or the D₁ agonist, SKF-82958 through a microdialysis probe. It was found that amphetamine and quinpirole produced a dose-dependent reduction in the basal levels of extracellular glutamate, while SKF-82958 was without significant effect. The capacity of the D₁ antagonist, SCH-23390 (1.0 mg/kg, i.p.) or the D₂ antagonist, sulpiride (10 mg/kg, i.p.) to block the reduction in extracellular glutamate by amphetamine (100 μM) was examined. Both SCH-23390 and sulpiride prevented the reduction in extracellular glutamate by amphetamine. The data indicate that, similar to the striatum, glutamate release in the nucleus accumbens is modulated by presynaptic dopamine receptors.     

Interactive effects of stimulation of D1 and D2 dopamine receptors on fos-like immunoreactivity in the normosensitive rat striatum

Systemic administration of the selective, full, D₁ dopamine agonist A-77636 [(1R,3S)3-(1′-adamantyl)-1-aminomethyl-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyranhydrochloride] (0.36–2.9 mg/kg) led to a dose-dependent induction of Fos-like immunoreactivity (FLI) in the striatum. Quantitative analysis of the sections indicated that immunoreactive cells were more numerous in the medial than the lateral striatum and, within these regions, appeared to be randomly distributed. The staining produced by A-77636 could be abolished by pretreatment with the selective D₁ antagonist SCH-23390. The selective D₂ dopamine agonist quinpirole (3 mg/kg) had no effect on striatal FLI when given by itself, but markedly potentiated the weak striatal staining produced by low doses of A-77636. When combined with the highest dose of A-77636, which produced substantial staining by itself, quinpirole produced an increase in the number of immunoreactive cells seen in the lateral striatum but actually decreased the number present in the medial striatum. Statistical analysis of the distribution of immunoreactive cells demonstrated that, in both regions, quinpirole converted the relatively homogeneous staining seen after A-77636 alone into a markedly patchy pattern. These findings indicate that stimulation of D₂ receptors produces both stimulatory and inhibitory effects on the D₁-mediated expression of Fos in the striatum and that the interaction between D₁ and D₂ receptor stimulation must, therefore, be more complex than the simple synergism suggested by previous studies.     

Enhanced quinpirole response in rats lesioned neonatally with 5,7-dihydroxytryptamine

The ontogenic destruction of dopamine (DA) neurons in rat brain is associated with supersensitization of DA D₁ receptors. This effect is attenuated when rats are cotreated in ontogeny with the serotonin (5-HT) neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT). In an attempt to determine whether 5-HT fibers might have a similar modulatory role on the sensitivity of the DA D₂ receptor complex, we pretreated rats with desipramine HCl (20 mg/kg IP, base), 1 h before the DA neurotoxin, 6-hydroxydopamine (6-OHDA; 134 μg ICV, base) and/or 5,7-DHT (75 μg ICV) and/or vehicle. At about 3 months after birth dose-effect curves for quinpirole-induced oral activity were constructed for each group of rats. We found that quinpirole, an agonist for the DA D₂ receptor complex, produced a dose-related increase in oral activity in all groups of rats. After a 200 μg/kg dose of quinpirole HCl, however, neonatal 5,7-DHT-lesioned rats had a peak oral response of 54.4 ± 5.1 (mean and SEM) vs. 22.6 ± 4.8 for control rats (p < 0.01). In neonatal 6-OHDA-lesioned rats this dose of quinpirole increased oral activity to 36.8 ± 5.8 oral movements (p < 0.05 vs. control). In rats lesioned with both 5,7-DHT and 6-OHDA, the oral response was not different from control. The enhanced oral response to quinpirole in 5,7-DHT-lesioned rats was attenuated by spiperone, an antagonist for the DA D₂ receptor complex. These findings are believed to be the first to demonstrate that receptors of the DA D₂ complex become sensitized after ontogenic injury to 5-HT fibers. This effect is opposite to the attenuated sensitivity of DA D₁ receptors in rats with a similar 5-HT lesion.     

Involvement of dopamine receptor subtypes in mouse thermoregulation

The effects of dopamine agonists on core body temperature (BT) were tested in mice. Apomorphine (APO) reduced BT of the mice dose dependently. The response was inhibited by the D-2 antagonist sulpiride, but not by the D-1 antagonist SCH 23390. The D-2 agonist quinpirole also decreased BT and this was prevented by sulpiride pretreatment. Administration of the D-1 agonist SKF 38393 increased BT. This hyperthermia was decreased by SCH 23390 pretreatment. In reserpinized animals, APO caused a dose-related increase in BT. The hyperthermic response of the drug was abolished in animals pretreated with a combination of sulpiride with SCH 23390, but not by single administration of sulpiride or SCH 23390. Quinpirole and SKF 38393 caused hyperthermia in reserpinized mice. The response was decreased in animals pretreated with sulpiride or SCH 23390, respectively. BT of the intact mice was decreased, while that of reserpinized animals was increased by SCH 23390 but not by sulpiride pretreatment. It is concluded that the presynaptic dopamine neurons are involved in hypothermia, while both post-synaptic D-1 and D-2 dopamine receptors may mediated the hyperthermia induced by dopaminergic agents.     

Altered responsiveness of regional brain dopamine and DOPAC levels to systemic administration of quinpirole, a dopamine D2 agonist, in DOCA/NaCl-hypertensive rats

Our previous studies have demonstrated that administration of quinpirole (LY171555), a potent and highly selective dopamine (DA) D2 receptor agonist, to conscious Sprague-Dawley rats produces increases in arterial pressure through the activation of sympathetic outflow and vasopressinergic activity. To test the hypotheses that quinpirole inhibits in vivo release of DA from central dopaminergic neurons by activation of DA receptors in the central nervous system (CNS) and that this mechanism may be altered in the desoxycorticosterone acetate (DOCA)/NaCl model of hypertension, we examined the effects of quinpirole on stores of DA and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in brain regions of 4-week DOCA/NaCl-hypertensive rats and their normotensive controls. Levels of DA and DOPAC were measured in brain regions by HPLC 15 min after the i.v. administration of quinpirole (1 mg/kg). Quinpirole resulted in a significant increase in DA stores and decrease in DOPAC stores in most brain regions examined in both DOCA/NaCl-hypertensive rats and normotensive controls, presumably by inhibiting DA release through a presynaptic mechanism. In the vehicle-treated groups, DA stores in the anterior hypothalamus and DOPAC stores in the nucleus accumbens were lower in DOCA/NaCl-hypertensive rats than in H2O controls. Following quinpirole administration, DA stores in the anterior hypothalamus increased significantly in DOCA/NaCl-treated rats but not in H2O controls and DOPAC stores in the nucleus accumbens decreased significantly in H2O control rats but not in DOCA/NaCl-treated rats. These observations provide further evidence for the presence of inhibitory DA D2 receptors which modulate the activity of dopaminergic neurons in the CNS.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dopaminergic and serotonergic modulation of persistent behaviour in the reinforced spatial alternation model of obsessive–compulsive disorder

RATIONALE: We have proposed rewarded T-maze alternation as a model of obsessive-compulsive disorder (OCD): the serotonin agonist m-chlorophenylpiperazine (mCPP) increments persistence therein, while chronic pretreatment with selective serotonin reuptake inhibitor (SSRI fluoxetine) but not benzodiazepine or desipramine abolishes mCPP effects. However, we noted that acute SSRI administration also causes transient persistence increase, counteracted by mCPP pretreatment. OBJECTIVES: This study (a) further explores the cross-tolerance between fluoxetine and mCPP and (b) extends the model by investigating its sensitivity to dopaminergic manipulations (D2, 3 agonism--quinpirole). MATERIALS AND METHODS: In both experiments, baseline and drug testing were carried out under daily T-maze alternation training. Exp. 1: Matched group (n = 8) pairs of rats received one of the following 20-day pretreatments (daily intraperitoneal administration): (1) saline, (2) low-dose fluoxetine (2.5 mg/kg), (3) low-dose mCPP (0.5 mg/kg) or (4) combined fluoxetine + mCPP. One group per pretreatment then received a 4-day challenge with high-dose fluoxetine (10 mg/kg), the other with high-dose mCPP (2.5 mg/kg). Exp. 2: One group (n = 12) of rats received 20-day treatment with saline, another with quinpirole (0.5 mg/kg). RESULTS: Exp. 1: Saline and low-dose mCPP- or fluoxetine-pretreated animals showed significant persistence increases under both challenges, while combined low-dose fluoxetine + mCPP pretreatment afforded full protection from either challenge. Exp. 2: Quinpirole significantly increased directional persistence after 13 administration days. CONCLUSIONS: These results establish the sensitivity of the rewarded alternation OCD model to D2, 3 receptor activation, thereby extending its profile of pharmacological isomorphism with OCD. Furthermore, they suggest a common mechanism of action of an SSRI and a serotonin agonist in the control of directional persistence.     

Compartmentally specific effects of quinpirole on the striatal Fos expression induced by stimulation of D1-dopamine receptors in intact rats

Injections of the full D₁-agonist A-77636 (1.45 mg/kg) were found to induce clear Fos-like immunoreactivity (FLI) in the striatum of neurologically intact rats. Pretreatment with the D₂-like agonist quinpirole (3 mg/kg) potentiated staining in the lateral striatum, but actually decreased the number of immunoreactive cells observed in the medial portion of the rostral striatum. Comparison with adjacent sections processed for the calcium binding protein calbindin, indicated that quinpirole pretreatment specifically suppressed staining in the matrix compartment of the striatum while tending to potentiate it in the striosomes, resulting in an extremely patchy pattern of labeling. These results suggest that exogenous stimulation of D₂-receptors, although not essential for the induction of FLI, may play an important role in the compartmental patterning of neuronal activity within the striatum.     

Microiontophoretic studies of the effects of D-1 and D-2 receptor agonists on type I caudate nucleus neurons: lack of synergistic interaction.

Several lines of evidence have suggested there may be a physiologically relevant form of synergistic interaction between D-1 and D-2 dopamine (DA) receptors located on postsynaptic neurons in the forebrain that receive a dopaminergic innervation. Because of the theoretical importance of such an interaction with respect to understanding the normal physiology of dopaminergic systems, we evaluated effects of D-1 and D-2 selective agonists, applied microiontophoretically, on the spontaneous electrical activity of a single, identifiable subpopulation of neurons within the caudate nucleus, the type I striatal neuron, in locally anesthetized, gallamine-paralyzed rats. It was observed that the D-2 receptor agonist quinpirole (QUIN) produced biphasic effects on cell firing rate. Low ejection currents significantly increased firing rate, while higher currents produced an inhibition. Similar effects were observed for the D-1 agonists SKF 38393; however, the overall excitations observed at low ejection currents were far less than those observed for QUIN. When these two agonists were applied concurrently, a simple additive effect (but not synergism) was always observed. The acute reduction of striatal levels of DA, by as much as 84% (with pretreatment with alpha-methyl-p-tyrosine, AMPT), did not alter the responsiveness of type I striatal neurons to the DA receptor agonists applied alone or in combination. These observed effects were not altered either by chloral hydrate anesthesia (in which glutamate-driven activity was studied) or by a more severe depletion of striatal DA levels (98% depletion produced by combined pretreatment with AMPT and reserpine).