Dopamine D2 Agonist Quinpirole Research Articles

Dopaminergic modulation of reward-guided decision making in alcohol-preferring AA rats

R**esults from animal gambling models have highlighted the importance of dopaminergic neurotransmission in modulating decision making when large sucrose rewards are combined with uncertainty. The majority of these models use food restriction as a tool to motivate animals to accomplish operant behavioral tasks, in which sucrose is used as a reward. As enhanced motivation to obtain sucrose due to hunger may impact its reward-seeking effect, we wanted to examine the decision-making behavior of rats in a situation where rats were fed ad libitum. For this purpose, we chose alcohol-preferring AA (alko alcohol) rats, as these rats have been shown to have high preference for sweet agents. In the present study, AA rats were trained to self-administer sucrose pellet rewards in a two-lever choice task (one pellet vs. three pellets). Once rational choice behavior had been established, the probability of gaining three pellets was decreased over time (50%, 33%, 25% then 20%). The effect of d-amphetamine on decision making was studied at every probability level, as well as the effect of the dopamine D1 receptor agonist SKF-81297 and D2 agonist quinpirole at probability levels of 100% and 25%. d-Amphetamine increased unprofitable choices in a dose-dependent manner at the two lowest probability levels. Quinpirole increased the frequency of unprofitable decisions at the 25% probability level, and SKF-82197 did not affect choice behavior. These results mirror the findings of probabilistic discounting studies using food-restricted rats. Based on this, the use of AA rats provides a new approach for studies on reward-guided decision making.

Memantine alters striatal plasticity inducing a shift of synaptic responses toward long-term depression

Memantine is an open channel blocker that antagonizes NMDA receptors reducing the inappropriate calcium (Ca2+) influx occurring in presence of moderately increased glutamate levels. At the same time, memantine has the ability to preserve the transient physiological activation of NMDA receptor, essential for learning and memory formation at synaptic level. In the present study we investigated the effects exerted by memantine on striatal synaptic plasticity in rat striatal spiny projection neurons (SPNs). In vitro application of memantine in striatal slices elicited a disruption of long-term potentiation (LTP) induction and maintenance, and revealed, in the majority of the recorded neurons, a long-term depression (LTD), whose amplitude was concentration-dependent (0.3–10 μM). Interestingly, preincubation with the dopamine (DA) D2 receptor antagonist sulpiride (10 μM) prevented memantine-induced LTD and restored LTP. Moreover, the DA D2 agonist quinpirole (10 μM), similarly to memantine, induced LTD in a subgroup of SPNs. In addition, memantine-induced LTD was also prevented by the CB1 endocannabinoid receptor antagonist AM 251 (1 μM). These results suggest that the actions exerted by memantine on striatal synaptic plasticity, and in particular the induction of LTD observed in SPNs, could be attributed to its ability to activate DA D2 receptors. By contrast, blockade of NMDA receptor is not involved in memantine-induced LTD since APV (30 μM) and MK801 (10 μM), two NMDA receptor antagonists, failed to induce this form of synaptic plasticity. Our data indicate that memantine could be used as treatment of neurological disorders in which DA D2 receptor represents a possible therapeutic target.

Dopamine Modulates the Voltage Response of Human Rod Photoreceptors by Inhibiting thehCurrent

The h current (I(h)) is a hyperpolarization-activated current that plays important roles in the physiological functions of different types of cells. In the retina of lower vertebrates, I(h) contributes to the rod responses to light stimuli by bringing the membrane potential back to the dark level in the presence of continuous light. The purpose of this study was to determine how dopamine modulates I(h) in human rods and regulates voltage responses. A patch-clamp recording technique was used on surgically excised human retinas to investigate the effects of dopamine on the I(h) of isolated rods. Dopamine was applied in the superfusate. Dopamine reversibly decreased the amplitude of the I(h) induced by hyperpolarizing voltage steps from a holding potential of -60 mV. At a voltage step of -100 mV, 20 μM dopamine decreased the amplitude of I(h). The D2 dopamine agonist quinpirole inhibited I(h), but the D1 agonist SKF-38393 had no effect. Dopamine-induced reduction of I(h) amplitude was blocked by the D2 dopamine antagonist sulpiride. Under current-clamp conditions, an injection of hyperpolarizing current steps to rods produced voltage responses that exhibited a gradual decay. Adding dopamine to the superfusate inhibited the decay in the voltage responses. Quinpirole also inhibited the voltage decay, whereas SKF-38393 was ineffective. Dopamine reduced I(h) through a D2 receptor and inhibited the gradual decay in the voltage response through a D2 receptor, indicating that dopamine slows the recovery phase of responses to light stimuli by inhibiting I(h) in human rods.

Acute MDMA Exposure Causes Reference Memory Impairments in the Radial Arm Maze with Rats

disruption to working memory function [1, 2]. This possibility was examined using a version of the 8-arm radial maze task with rats that is designed to separate working memory function from reference memory function [3]. In Experiment 1 the effects of MDMA were compared to the classic amnetic drug scopolamine (which has been shown to produce working memory deficits in the current radial arm maze task [4]). The effects of MDMA were also compared to the dopamine agonist GBR12909 and serotonin agonist citalopram (in Experiment 2) as well as the dopamine D2 agonist Quinpirole and the dopamine D1 agonist A68930 (in Experiment 3) in order to further examine the possible role of dopamine in an MDMA-induced performance deficit.

Behavioural effects of quinpirole following withdrawal of chronic treatment with the CB1 agonist, HU-210, in rats

The present study investigated spontaneous and quinpirole-induced motor responses of in rats, following withdrawal from chronic treatment with the potent cannabinoid agonist HU-210. Withdrawal from chronic HU-210 (20 microg/kg daily, 14 days) produced a decrease in spontaneous activity at 1 and 2 days and enhanced the hyperactivity induced by acute administration of the dopamine D2 agonist quinpirole (0.5 mg/kg) at 4 days after the end of HU-210 treatment. Administration of quinpirole on day 4 of withdrawal from chronic HU-210 enhanced stereotyped responses and induced jumping behaviour. These results suggest that withdrawal from chronic exposure to cannabinoid agonists could induce a time-dependent alteration in dopamine D2 psychomotor function, leading to a behavioural disorganization, comparable to acute psychotic episodes after continuous cannabinoids.

P.6.034 Role of dopamine D1 receptor on dopaminergic supersensitivity induced by sleep deprivation in mice

Stereotyped behavior and striatal c-fos levels induced by chronic treatment with the D1 dopamine antagonist SCH 23390 have been investigated in rats which received subsequent subacute dopamine agonist treatment. SCH 23390 treatment (0.5 mg/kg/day) for 21 days increased both apomorphine-induced orofacial stereotypies and striatal c-fos levels. Treatment with the D1 dopamine agonist SKF 38393 (10 mg/kg/day) and the combination of SKF 38393 with the D2 dopamine agonist quinpirole (1 mg/kg/day), for 5 consecutive days, attenuated apomorphine-induced stereotypies without changing c-fos levels in rats previously treated with SCH 23390. These findings suggest that SCH 23390-induced behavioral supersensitivity and the increased striatal c-fos levels are concomitant but unrelated phenomena.

Effects of dopamine agonists and antagonists on locomotor activity in male and female rats

Male and female Sprague–Dawley rats were treated with cocaine, the specific dopamine uptake inhibitor GBR 12909, the dopamine D1 agonist SKF 82958 or the dopamine D2 agonist quinpirole. After treatment, the rats were placed in an activity chamber for 30 min and locomotor activity was monitored. Cocaine, GBR 12909 and SKF 82958 all increased locomotor activity in both males and females, but greater increases were observed in females. In contrast, quinpirole produced decreases in activity, with males showing greater decreases than females. Separate groups of animals were given SCH 23390 or eticlopride prior to cocaine. The D1 antagonist SCH 23390 reduced the locomotor activating effects of cocaine in both males and females, with females showing greater sensitivity to SCH 23390. The D2 antagonist eticlopride also reduced the locomotor activating effects of cocaine, with no clear differences between males and females. These results suggest that the differences between males and females in their locomotor response to cocaine can be at least partially attributed to differences in the function of dopamine D1 and D2 receptors.

Electrophysiological and behavioural evidence for an antagonistic modulatory role of adenosine A2A receptors in dopamine D2 receptor regulation in the rat dopamine-denervated striatum.

It has been shown that striatal adenosine A2A receptors can antagonistically interact with dopamine D2 receptors at the membrane level leading to a decrease in the affinity and efficacy of D2 receptors. Extracellular recordings and rotational behaviour were employed to obtain a correlate to these findings in an animal model of Parkinson's disease (PD). The recordings were performed in rats with unilateral 6-hydroxydopamine (6-OHDA)-induced catecholamine depletion. While recording in the dopamine-depleted striatum, local applications of the dopamine D2 agonist quinpirole reduced neuronal activity. However, when the adenosine A2A antagonist MSX-3 was applied simultaneously with quinpirole, the inhibition of neuronal firing seen after quinpirole alone was significantly potentiated (P< 0.001, n = 11). In contrast, local application of CGS 21680 attenuated the effect of quinpirole. The doses of MSX-3 and CGS 21680 used to achieve the modulation of quinpirole action had no effect per se on striatal neuronal firing. Furthermore, rotational behaviour revealed that MSX-3 dose-dependently increased the number of turns when administrated together with a threshold dose of quinpirole while no enhancement was achieved when MSX-3 was combined with SKF 38393. MSX-3 alone did not induce rotational behaviour. In conclusion, this study shows that low ineffective doses of MSX-3 enhance the effect of quinpirole on striatal firing rate, while the A2A agonist exerts the opposite action. This mechanism gives a therapeutic potential to A2A antagonists in the treatment of PD by enhancing D2 receptor function.

Presynaptic Inhibition of Primary Olfactory Afferents Mediated by Different Mechanisms in Lobster and Turtle

Presynaptic regulation of transmission at the first olfactory synapse was investigated by selectively imaging axon terminals of receptor neurons in the lobster olfactory lobe and turtle olfactory bulb. In both species, action potential propagation into axon terminals after olfactory nerve stimulation was measured using voltage-sensitive dyes. In addition, in the turtle, calcium influx into terminals was measured by selectively labeling receptor neurons with dextran-conjugated calcium indicator dyes. In the lobster, application of the inhibitory transmitters GABA or histamine suppressed action potentials in the terminals. The suppression was blocked by picrotoxin and cimetidine, respective antagonists to lobster GABA and histamine receptors. These results suggest that previously characterized GABA and histaminergic interneurons regulate olfactory input by suppressing action potential propagation into axon terminals of olfactory afferents. In contrast, in the turtle olfactory bulb, neither GABA nor dopamine had any effect on receptor cell action potentials as measured with voltage-sensitive dyes. However, calcium influx into axon terminals was reduced by the GABA(B) agonist baclofen and the dopamine D(2) agonist quinpirole, and paired-pulse suppression of calcium influx was reduced by the GABA(B) antagonist saclofen. These results indicate that in the turtle, GABA and dopamine mediate presynaptic inhibition not by affecting action potentials directly, as in the lobster, but by reducing calcium influx via GABA(B) and dopamine D(2) receptors. Thus, although mediated by different cellular mechanisms, presynaptic regulation of olfactory input to the CNS, via dual synaptic pathways, is a feature common to vertebrates and invertebrates. This inhibition may be important in the processing of olfactory information.

The validity of the pretreated, unilaterally MPTP-treated monkeys as a model of Parkinson's disease: a detailed behavioural analysis of the therapeutic and undesired effects of the D2 agonist quinpirole and the D1 agonist SKF 81297.

The goal of this study was to evaluate the validity of the pretreated, unilaterally MPTP-treated monkey as an animal model of Parkinson's disease (PD). For that purpose, a detailed ethogram was developed and assessed in four male rhesus monkeys that had received MPTP (2.5 mg) in the carotid artery contralateral to the dominant limb. Subsequently, the behavioural effects of the dopamine D2 agonist quinpirole and the dopamine D1 agonist SKF 81297 were studied. The ethogram was found to allow a clear-cut and objective separation of drug-induced behaviours into therapeutic and undesired effects in the MPTP-treated monkeys. Saline-treated monkeys predominantly displayed ipsilateral goal-directed fore-limb movements, and distinct types of ipsilaterally directed rotations. Although quinpirole and SKF 81297 increased motor behaviours, such as body displacement, contralateral fore-limb movements and contralateral rotational behaviours, assessment of the new detailed ethogram revealed that this increase was completely due to the activation of abnormal, non-goal-directed behaviours, such as dyskinetic fore-limb movements, pivoting and shuffling. Moreover, the new ethogram made clear that the drug treatments induced not only dyskinesia and dystonia, but also epileptoid behaviour, which was confirmed by EEG analysis. In summary, the detailed behavioural analysis showed that this model does not adequately predict the clinical effects of the D2 agonist. It is concluded that the pretreated, unilaterally MPTP-treated monkey is not a valid model to predict the therapeutic and undesired effects of dopaminergic drugs in humans.

Role of NMDA glutamate receptors in regulating D2 dopamine-dependent Fos induction in the rat striatopallidal pathway

Acute administration of reserpine induces Fos expression in striatopallidal neurons, an effect blocked by pretreatment with the D2 dopamine agonist quinpirole. Pretreatment with the NMDA antagonists (+)MK-801 or CPP attenuated reserpine-mediated striatal Fos induction whereas pretreatment with ketamine or the inactive isomer (−)MK-801 did not. These results support a role of NMDA glutamate receptors in regulating the activity of the striatopallidal pathway.

Effects of intrastriatal cannabinoids on rotational behavior in rats: interactions with the dopaminergic system.

The effect of unilateral intrastriatal cannabinoid receptor stimulation on rotational behavior in rats was explored. The potent cannabinoid agonist CP 55,940 (5 microg/0.5 microl) induced contralateral turning when microinjected unilaterally into the striatum. The D2 dopamine agonist quinpirole reversed this contralateral rotation but failed to affect motor behavior on its own. Finally, the D1 dopamine agonist SKF 82958 inhibited movement when administered into the striatum and this inhibition was reversed by co-administration of the cannabinoid agonist. Surprisingly, microinjections of the cannabinoid agonist into the striatum induced movement through activation of the striatonigral pathway and/or inhibition of the striatopallidal pathway, while the D1 dopamine agonist produced the opposite effect.

The dopamine D2 agonist quinpirole disrupts attention to temporal signals without selectively altering the speed of the internal clock

Three groups of rats were trained to discriminate between 2 sec and 8 sec of darkness by responding to either the left or the right lever. Following acquisition of this temporal discrimination, psychophysical functions were obtained by presenting unreinforced signals of intermediate duration. Two groups of rats were trained with saline and subsequently tested with the specific D2 dopamine agonist quinpirole (0.08 mg/kg). One of these groups was naive to the drug prior to testing (DN), whereas the other had exposure to the drug but not during training sessions (DE). A third group (DT) was trained under quinpirole and tested with saline. The temporal discrimination was acquired rapidly and equiv-alently in Groups DN and DE. However, rats in Group DT were severely impaired in acquiring the discrimination. During psychophysical testing, quinpirole disrupted the accuracy of temporal discrimination equivalently in Groups DN and DE. Both the Weber fraction (WF) and the difference limen (DL) increased significantly in Groups DN and DE; however, the point of subjective equality (PSE) was not affected. In Group DT, the shift to saline during psychophysical testing did not result in any changes to the PSE, DL, or WF. These findings are not consistent with the hypothesis that the speed of the internal clock is selectively affected by D2 dopaminergic manipulations. Prior exposure to the drug does not appear to be a critical variable in the failure to observe a selective adjustment of the internal clock. The D2 agonist quinpirole appears to affect the accuracy of temporal discriminations generally, without altering the speed of the internal clock.

Effects of intrapallidal cannabinoids on rotational behavior in rats: interactions with the dopaminergic system.

The effect of unilateral intrapallidal cannabinoid receptor stimulation on rotational behavior in rats was explored. The potent cannabinoid agonist CP55,940 (5 microg/0.5 microl) induced ipsilateral turning when microinjected unilaterally into the globus pallidus. The D2 dopamine agonist quinpirole reversed this ipsilateral rotation but failed to affect motor behavior on its own. Finally, the D1 dopamine agonist SKF 82958 inhibited movement when administered into the globus pallidus, and this effect was not additive with CP55,940.

Protein kinase A inhibitor attenuates levodopa-induced motor response alterations in the hemi-parkinsonian rat

Chronically administered levodopa, the standard treatment for Parkinson's disease, is ultimately associated with disabling alterations in motor response. To evaluate the possible contribution of striatal cAMP-dependent protein kinase A (PKA) signaling pathways to these response modifications, the acute effects of a PKA inhibitor, Rp-cAMPS, on motor response changes attending chronic, twice-daily administration of levodopa were measured in 6-hydroxydopamine lesioned hemi-parkinsonian rats. A single intrastriatal injection of Rp-cAMPS (2.5 or 25 μg) attenuated both the shortened duration and augmented intensity of levodopa-induced turning in a dose dependent manner. Rp-cAMPS completely normalized motor responses to a dopamine D1 agonist (SKF 38392), but had no effect on those to a dopamine D2 agonist (quinpirole). These results suggest that D1 receptor-mediated PKA activation may contribute to the development of the altered motor responses associated with chronic levodopa treatment.

Long-term treatment with chlorpromazine and haloperidol but not with sulpiride and clozapine markedly elevates neuropeptide Y-like immunoreactivity in the rat hypothalamus.

Male Wistar rats were injected intraperitoneally with chlorpromazine (2 or 10 mg/kg), haloperidol (0.5 or 2 mg/kg), sulpiride (50 or 100 mg/kg) or clozapine (10 or 25 mg/kg) once, for 14 or 28 consecutive days. Hypothalamic neuropeptide Y-like (NPY-like) immunoreactivity (NPY-LI) was determined 24 h after the last dose of the neuroleptic and on the eighth day after drug withdrawal following a 1 month administration. A marked increase in the NPY-LI level was observed only after long-term treatment with typical neuroleptics. The dopamine D2 agonist quinpirole antagonized the effects of chlorpromazine and haloperidol, but it did not change NPY-LI concentration by itself. Co-administration of the alpha 1 adrenergic antagonist prazosin with quinpirole to chlorpromazine-pretreated rats attenuated the effect of quinpirole but enhanced an increase in NPY-LI content elicited by chlorpromazine. Neither the dopamine D1 antagonist SCH 23390 (1 mg/kg) nor the dopamine D2 antagonist sulpiride (100 mg/kg) administered i.p. for 14 days by itself altered the hypothalamic NPY-LI level, but in combination they increased it. Our results suggest that NPY in hypothalamus may be involved in the mechanism of action of typical non-selective neuroleptics and that the influence of studied drugs on NPY-LI is at least partly mediated by a simultaneous prolonged blockade of both D1 and D2 dopaminergic receptors.

D2 dopamine receptor-mediated inhibition of a hyperpolarization-activated current in rod photoreceptors.

1. Using the whole cell patch clamp method, we investigated the effect of dopamine on a hyperpolarization-activated current (Ih) in the inner segments of rod photoreceptors of the Xenopus retina. 2. Ih was elicited by hyperpolarizing voltage steps to -120 mV from a holding potential of -40 mV. Dopamine reversibly reduced Ih in a dose-dependent manner. Dopamine-mediated inhibition of Ih was blocked by the D2 dopamine antagonist sulpiride. 3. The D2 dopamine agonist quinpirole (0.1-20 microM) inhibited Ih whereas the D1 agonist SKF-38393 (100 microM) had no effect on Ih. Quinpirole-induced inhibition of Ih was blocked by sulpiride, but not by the D4 antagonist, clozapine. The D3 agonists (+/-)-7-hydroxy-2-dipropylaminotetralin hydrochloride and trans-7-hydroxy-2[N-propyl-N-(3'-iodo-2'-propenyl)amino]-tetralin maleate were, respectively, 5 and 100 times less effective than quinpirole in inhibiting Ih. 4. Quinpirole failed to reduce Ih when the internal solution contained GDP beta S (500 microM). Internal application GTP gamma S (300 microM) progressively and irreversibly reduced Ih and blocked a further reduction by quinpirole, indicating that the inhibition of Ih by quinpirole involves a G protein. 5. The inhibition of Ih by quinpirole was not affected by intracellularly applied adenosine 3',5'-cyclic monophosphate (cAMP) or by the protein kinase inhibitor H-7, indicating that a cAMP-mediated second messenger cascade does not participate in the dopamine-mediated inhibition. 6. Ih was not altered when the patch pipette contained a nominally Ca(2+)-free internal solution, but the inhibition of Ih by quinpirole was abolished, suggesting an involvement of Ca(2+) in the quinpirole-induced effect. 7. We conclude that a D2 dopamine receptor modulates Ih through the activation of a G protein and that intracellular Ca2+, but not cAMP, plays a key role in this process. 8. The reduction of Ih by dopamine may reduce the ability of rods to signal time-modulated light stimuli.

Adenosine antagonists potentiate D2 dopamine-dependent activation of Fos in the striatopallidal pathway.

Adenosine antagonists potentiate dopamine-mediated behaviours. A2a adenosine and D2 dopamine receptors are abundantly co-expressed within the striatopallidal subset of striatal neurons, suggesting that this is the site of interaction between A2a and D2 receptors. We show that the D2-dependent induction of the immediate early gene c-Fos occurs in striatopallidal neurons 3 h following injection of reserpine (10 mg/kg). We used this paradigm to test whether adenosine antagonists modulate D2-dependent activation of striatopallidal neurons. The non-selective A1-A2 adenosine antagonists theophylline (25 mg/kg) or 3,7-dimethyl-1-propargylxanthine (25 mg/kg) potentiated the effect of a submaximal dose of the D2 dopamine agonist quinpirole (0.05 mg/kg) to prevent the induction of striatal c-Fos following reserpine. Co-administration of the A2a receptor antagonist 8-(3-chlorostyryl) caffeine (5 mg/kg) with quinpirole (0.05 mg/kg) also attenuated striatal c-Fos induction following reserpine to a greater extent than 0.05 mg/kg quinpirole alone. When administered prior to reserpine, theophylline (25 mg/kg) or 3,7-dimethyl-1-propargylxanthine (25 mg/kg) partially attenuate the induction of striatal c-fos. These results demonstrate that systemic administration of adenosine antagonists enhance D2 dopamine receptor-dependent regulation of c-Fos in the striatopallidal pathway. These results support a functional interaction between A2a adenosine and D2 dopamine receptors in striatopallidal neurons.

Phencyclidine- and dizocilpine-induced hyperlocomotion are differentially mediated.

The dopamine (DA) D2 agonist quinpirole and the D2 receptor antagonists, haloperidol, raclopride, and remoxipride, were examined for their ability to block the locomotion induced by the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists phencyclidine (PCP) and dizocilpine, both given in equipotent doses. Quinpirole, given in a "DA D2 autoreceptor selective" dose (0.01 mg/kg), failed to influence the motor stimulation by PCP. On the other hand, the locomotor response induced by dizocilpine was significantly reduced by quinpirole. The three DA receptor antagonists blocked dose dependently the motor stimulation produced by both the low (2 mg/kg) and the high dose (3 mg/kg) of PCP. Haloperidol and remoxipride also blocked dose dependently and fully the stimulation produced by the low dose (0.1 mg/kg) of dizocilpine, whereas raclopride partially reduced the effect. The motor stimulation produced by the high doses of dizocilpine (0.2 mg/kg) and PCP (3 mg/kg) was reduced by haloperidol and raclopride only in cataleptogenic doses. Remoxipride, in contrast, fully blocked the effects of both PCP (3 mg/kg) and dizocilpine (0.2 mg/kg) in noncataleptogenic doses. These data suggest that different mechanisms of action may account for the motor stimulatory effects of PCP and dizocilpine. At the presynaptic level, PCP and dizocilpine may differ in the way they act on "regulatory" NMDA receptors controlling neuronal activity in midbrain neurons, and at the postsynaptic level they may interact with subtypes of NMDA receptors differentially coupled to subpopulations of D2 receptors.

An autoradiographic study of the differential effects of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) on striatal and extrastriatal D-1 and D-2 dopamine receptors in the rat

The effect of in vivo administration of the alkylating agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) on striatal and extrastriatal D-1 and D-2 dopamine (DA) receptors was investigated in the rat. N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline treatment reduced specific [ 3H]SCH 23390 (7-chloro-8-hydroxy-2,3,4,5-tetrahydro-3-methyl-1-phenyl-1H-3-benzazepine) binding to D-1 DA receptors in the striatum (42–46% of saline-treated controls), entopeduncular nucleus (20%) and substantia nigra pars reticulata (23%). Similarly, specific [ 3H]spiperone binding to D-2 DA receptors was decreased in the striatum (28–37% of saline-treated controls). However, [ 3H]spiperone binding in the substantia nigra pars compacta (67%) was much less affected. In vivo pretreatment with the D-1 DA antagonist SCH 23390 selectively and dose dependently protected [ 3H]SCH 23390 binding against the effects of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline in the striatal/extrastriatal regions. Pretreatment with the D-2 DA antagonist raclopride or the D-2 DA agonist quinpirole selectively protected [ 3H]spiperone binding. In contrast, pretreatment with the D-1 DA agonist SKF 38393 (7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) not only protected [ 3H]-SCH 23390 binding but at very high doses protected striatal [ 3H]spiperone binding. The differential alkylating effects of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline on striatal vs extrastriatal D-1 and D-2 DA receptors may be related to their post- (striatal DA receptors) and pre-synaptic (extrastriatal DA receptors) localizations, respectively. The present results further demonstrate that in vivo, SCH 23390 and raclopride/quinpirole retain their D-1 and D-2 DA receptor selectivity.