Triiodothyronine attenuates estradiol-induced increases in dopamine D-2 receptor number in rat anterior pituitary

Estrogens promote adenohypophyseal enlargement and tumor transformation, and thyroid hormones antagonize these effects. Hormone-induced pituitary enlargement may be mediated by alterations in pituitary dopaminergic function. The present study examined the effects of chronic (20 days) administration of estradiol benzoate (EB), triiodothyronine (T3), or EB and T3 (T3 + EB) on dopamine (D-2) receptors in rat anterior pituitary. D-2 receptor number increased after EB without altered receptor affinity. T3 alone did not affect D-2 receptor number in the anterior pituitary but significantly attenuated the effect of EB. T3 administration also inhibited EB-induced anterior pituitary hyperplasia. D-2 receptor upregulation by EB more likely could reflect a compensatory response to decreased receptor occupation. The present results suggest that D-2 receptors could play an important role in estrogen-induced adenohypophyseal tumor formation and hyperprolactinemia and that thyroid hormones may inhibit estrogen-induced pituitary tumor development via adenohypophyseal D-2 receptors.     

Increase of dopamine D2(High) receptors in the striatum of rats sensitized to caffeine motor effects

It has been previously demonstrated how rats can develop behavioral dopamine supersensitivity after long-term administration of caffeine. Since behavioral dopamine supersensitivity in rats is usually accompanied by an elevation in striatal dopamine D2(High) receptors, we examined whether alterations in D2(High) receptors occurred in the striatum of rats administered caffeine according to a regimen capable of eliciting behavioral dopamine supersensitivity (15 mg/kg i.p. every other day for 14 days). An increase of 126% in striatal D2(High) receptors was found in caffeine-sensitized rats. This marked elevation in D2(High) receptors may account for the caffeine-induced behavioral dopamine supersensitivity and may help elucidate the interactions between caffeine and dopamine neurotransmission.     

Can the supersensitivity of rodents to dopamine be regarded as a model of tardive dyskinesia?

1. The paper presents arguments derived from both, clinical work and animal experiments, for or against the traditional hypothesis suggesting that tardive dyskinesia (TD) is caused by supersensitivity to dopamine. The main aim of this study was to answer the question posed in the title - whether the supersensitivity to dopamine evoked in rodents by neuroleptics can be regarded as an adequate pharmacological model of TD. 2. The data presented here prove that chronic administration of neuroleptics to schizophrenic patients cannot be the only factor inducing TD; furthermore, symptoms similar or identical to those of TD are also observed in the course of other disorders, not connected with neuroleptics, e.g. aging or schizophrenia itself. 3. Clinical data offer no clear evidence for the existence of a direct cause-effect relationship between super-sensitivity to dopamine and occurrence of TD. 4. The role of brain degeneration, caused by different factors but in particular by the process of aging, in the pathogenesis of dyskinetic disorders, including TD, has been stressed. 5. Pharmacological and biochemical data show that chronic administration of classic neuroleptics to animals induces an increase in the density of dopamine D-2 receptors (Bmax). It seems that this receptor-mediated supersensitivity may concern both the postsynaptic and the presynaptic D-2 dopamine receptors. On the other hand, it is not clear enough whether a dopamine D-1 receptor-mediated supersensitivity might also be a causal factor of TD. 6. The analysis in animals, of biochemical and pharmacological effects of neuroleptics which do not induce TD showed that in some situations these drugs may also evoke the receptor-mediated supersensitivity concerning dopamine D-2 receptors. 7. The method of a prolonged (approx. 1 year) oral administration of neuroleptics seems to differentiate those which induce TD from those which do not, at least regarding the induction of an increase of Bmax for butyrophenone neuroleptics and an increase of apomorphine-induced stereotypy, however, some exceptions are noted. 8. The above analysis of clinical and experimental data suggests that the supersensitivity to dopamine in rats treated chronically with neuroleptics cannot be accepted as a model which reflects the etiopathogenesis of TD. Neither a positive nor a negative result obtained in this test is reliable enough, and either depends on the tested parameters (apomorphine stereotypy and [3H]spiperon binding seem to be the most reliable), route of neuroleptic administration, duration of treatment and, probably, a number of other, still unknown factors.(ABSTRACT TRUNCATED AT 400 WORDS)     

Comparative distribution of dopamine D-1 and D-2 receptors in the basal ganglia of turtles, pigeons, rats, cats, and monkeys

The distribution and density of dopamine D-1 and D-2 receptors were studied in the basal ganglia of adult turtles, pigeons, rats, cats, and monkeys. Dopamine receptors were measured in vitro by quantitative autoradiography in alternate sections processed for D-1 and D-2 receptor subtypes and compared to adjacent sections stained for acetylcholinesterase (AChE) activity. [3H]-SCH 23390 and [3H]-spiroperidol were used to label the D-1 and D-2 dopamine receptor subtypes, respectively. The anatomic distribution of both D-1 and D-2 receptors in the basal ganglia was remarkably similar across all species examined. Whereas the absolute number of D-1 and D-2 receptors in the basal ganglia varied between species, the percentage of D-1 and D-2 receptors in a region was quite similar among species. The pattern of binding to the D-1 and D-2 receptor varied among the different species. The adult turtles, pigeons, and rats demonstrated nonpatchy D-1 and D-2 receptor binding in the striatum and pallidum. The adult cat and monkey caudate nucleus and putamen demonstrated mildly heterogeneous receptor binding in a pattern that differed from that seen with AChE staining, but did occasionally demonstrate similar patterns of the D-1 and D-2 receptor subtypes. The immature cat striatum was characterized by heterogeneous D-1 receptor binding that corresponded to heterogeneous AChE rich patches, whereas D-2 receptor binding was homogeneous. Heterogeneous binding was seen in other basal ganglia structures including the nucleus accumbens, olfactory tubercle, and substantia nigra pars compacta and reticulata. Complementary D-1 and D-2 receptor binding patterns were seen in the pallidum and substantia nigra of the mammals. The results of this study indicate that both D-1 and D-2 dopamine receptors are present in the basal ganglia of five different vertebrates. A common feature of dopamine receptors in the basal ganglia is their heterogeneity in distribution and density. The heterogeneity of dopamine receptors has similarities to and differences from the distribution of presynaptic dopamine and other neurotransmitter markers of the basal ganglia.     

B-HT 920 is a full agonist at both pre- and postsynaptic D-2 dopamine receptors

Summary Stimulation of presynaptic D-2 dopamine receptors by B-HT 920 or by apomorphine inhibited the synthesis of dopamine in the corpus striatum of gammabutyrolactone-treated mice to about the same extent. Stimulation of postsynaptic D-2 dopamine receptors by B-HT 920 given in combination with the D-1 receptor agonist SKF38393 enhanced the motor activity of reserpinetreated mice at least as much as observed following the combined D-1/D-2 receptor agonist apomorphine. Since B-HT 920 is as effective as apomorphine in these models, B-HT 920 appears to be a full agonist at both pre- and postsynaptic D-2 dopamine receptors.     

Dopamine D-5 receptor modulates hippocampal acetylcholine release

Dopamine is intimately involved in cognitive processes in the brain. Of the several subtypes of dopamine receptors, the possible role of dopamine D1-like receptors in brain functions, especially in learning and memory, has recently generated much interest. However, molecularly the D1-like receptors are comprised of at least two subtypes, namely D-1 and D-5, and it has not been possible to ascertain which of these two receptor classes is responsible for these functions due to the lack of selective ligands. In the present study, utilizing a combined antisense-in vivo dialysis approach, we show that the D-5 subtype is the dopamine D1-like receptor involved in modulating hippocampal acetylcholine (ACh) release, a transmitter implicated in a variety of cognitive processes. This is one of the first evidence for a functional role for the D-5 receptor.     

Distribution of dopamine D-2 receptors in the rat striatal complex and its comparison with acetylcholinesterase

The distribution of D-2 dopamine receptors in the rat striatal complex was studied with autoradiography after specific in vivo labeling with the dopamine agonist [3H]N-n-propylnorapomorphine and subsequent irreversible fixation. This labeling technique allows the visualization of D-2 receptors at the cellular level by light microscopic emulsion autoradiography. During the preparation of emulsion autoradiograms, the recovery of the label was 75%, the specific and the aspecific label being equally affected. The distribution of label before and after the loss of radioactive label occurred, did not show differences. In rat neostriatum, dopamine D-2 receptors are not homogeneously distributed: in the caudate-putamen the density is laterally higher than medially. Moreover, there exists a mosaic-like pattern of receptor density. In the ventral striatum, comprising the fundus striati, nucleus accumbens septi and olfactory tubercle, the receptor density is lower than in the caudate-putamen, except for the core regions in the islands of Calleja and the rim of these islands, which contain high (as high as the lateral caudate-putamen) and a moderate density of receptors, respectively. In caudate-putamen and lateral nucleus accumbens it appeared that the intensity of acetylcholinesterase staining parallels more or less the distribution of dopamine D-2 receptors. In medial nucleus accumbens and in olfactory tubercle, the high intensity of acetylcholinesterase is not paralleled by a high D-2 receptor labeling density. This receptor labeling density does not seem to be matched by differences in densities of medium-sized neuronal cell bodies.     

Effect of the rat estrous cycle at ovariectomy on striatal D-1 dopamine receptors

We have investigated the effect of the surgical suppression of gonadal steroid hormones by ovariectomy on striatal D-1 dopamine (DA) receptors, in relation with the stage of the estrous cycle at the time of surgery. Plasma levels of 17 beta-estradiol and progesterone declined rapidly to a minimum one and two days after ovariectomy, respectively. Ovariectomy of female rats in proestrus led to an increased density of striatal D-1 DA from the first to the fourth day following surgery with a return to control values on the 7th day. Rats ovariectomized (OVX) in estrus showed an increased striatal D-1 DA receptor density from the second to the fourth day following surgery with a return to control values 7 days following ovariectomy. Striatal D-1 DA receptor density of rats OVX in diestrus remained constant up to 7 days after surgery. The affinity of striatal D-1 DA receptors remained unchanged in all cases. Therefore, this report illustrates that steroid hormonal fluctuations as occurring during the 4-day estrous cycle of the rat can modulate striatal D-1 DA receptors.     

Blockade of D-2 dopamine receptors strongly enhances the potency of enkephalins to inhibit dopamine-sensitive adenylate cyclase in rat neostriatum: involvement of delta- and mu-opioid receptors

The interactions between dopamine receptors and opioid receptors coupled to adenylate cyclase in rat neostriatum were investigated. cAMP efflux from neostriatal slices induced by simultaneous activation of (stimulatory) D-1 and (inhibitory) D-2 dopamine receptors with 30 microM dopamine was inhibited by the preferential delta-opioid receptor agonist [D-Ala2-D-Leu5] enkephalin (DADLE) and the mu-opioid receptor agonist morphine with an EC50 of 100 and 800 nM, respectively. On selective D-1 receptor activation (i.e., with D-2 receptors blocked by 10 microM (-)sulpiride), the EC50 of DADLE was strongly reduced to 3 nM, whereas that of morphine was unaffected. When D-1 and D-2 receptors were activated simultaneously, the inhibitory effects of DADLE (0.3 microM) and morphine (3 microM) on cAMP efflux were antagonized equally well by naloxone, a mu-opioid receptor antagonist. In contrast, on selective D-1 receptor activation, naloxone was about 20 times more potent in antagonizing the inhibitory effect of morphine than DADLE. Moreover, the delta-opioid receptor antagonist ICI 174864 (0.75 microM) did not affect the inhibitory effect of morphine but antagonized that of DADLE, provided that D-2 receptors were blocked. The highly selective delta-opioid receptor agonist [D-Pen2-D-Pen5] enkephalin (DPDPE) inhibited dopamine-stimulated cAMP efflux only when D-2 receptors were blocked. Similar results were obtained when the agonists SKF 38393 and LY 141865 were used to activate D-1 and D-2 receptors, respectively. These data indicate that blockade of D-2 receptors in the neostriatum elicits the coupling of delta-opioid receptors to dopamine-sensitive adenylate cyclase, thereby making it considerably more sensitive to inhibition by the enkephalins.     

Striatal c-fos levels do not correlate with haloperidol-induced behavioral supersensitivity

Striatal c-fos levels and stereotyped behavior have been evaluated in chronically haloperidol-treated rats which received subsequent subacute dopamine (DA) agonist treatment to investigate the possible relationship between striatal c-fos and behavioral supersensitivity. Haloperidol treatment (1 mg/kg/day for 21 days) increased apomorphine-induced stereotypies but did not modify striatal c-fos levels. The subacute administration of the DA D-1 agonist SKF38393 (10 mg/kg/day for 5 days) and the combination of the D-1 agonist with the D-2 agonist quinpirole (1 mg/kg/day for 5 days) attenuated apomorphine-induced stereotypies after haloperidol pretreatment. The administration of quinpirole alone, however, did not modify the response to haloperidol. All DA agonists significantly increased c-fos levels after apomorphine injection. The dissociation between haloperidol-induced behavioral supersensitivity and striatal c-fos levels observed in this study suggests that mechanisms different from striatal c-fos induction might be involved, and that striatal c-fos levels are not a good marker of behavioral supersensitivity expression. © 1996 Wiley-Liss, Inc.     

Pentazocine-like discriminative stimulus effects of morphine are blocked by the dopamine D-1 antagonist SCH23390, but not by the dopamine D-2 antagonist sulpiride.

The effects of selective dopamine antagonists on the pentazocine-like discriminative stimulus effects of morphine were investigated in the rat trained to discriminate 3.0 mg/kg of pentazocine from vehicle. Morphine (3.0 mg/kg), a mu-selective agonist, produced stimulus effects in common with pentazocine (3.0 mg/kg), indicating that the stimulus effects are mediated through mu opioid receptors. The pentazocine-like stimulus effects of morphine (3.0 mg/kg) were clearly inhibited by the dopamine D-1 antagonist SCH23390 (0.03-0.56 mg/kg) but not by the dopamine D-2 antagonist sulpiride (20.0-80.0 mg/kg). The results suggest that the pentazocine-like discriminative stimulus effects of morphine are mediated via dopamine D-1 receptors.     

Independent in vitro regulation by the D-2 dopamine receptor of dopamine-stimulated efflux of cyclic AMP and K-stimulated release of acetylcholine from rat neostriatum

Two types of dopamine receptors whose stimulation affect cAMP efflux (and by inference formation) could be identified in rat neostriatum. One type of receptor, called D-1 receptor, increased cAMP efflux whereas stimulation of a second type of dopamine receptor, called D-2 receptor, was followed by a reduction in cAMP efflux induced by stimulation with a D-1 receptor agonist. D-2 receptor agonists inhibited the effects of D-1 receptor agonists on cAMP efflux in a non-competitive way. These inhibiting effects of D-2 receptor agonists occured also in the absence of Ca²⁺-ions which could imply that some of the D-2 receptors are located on cells possessing D-1 receptors.

The dopamine receptor mediating inhibition of the release of radiolabeled acetylcholine (ACh) in the neostriatum appeared to have the same pharmacological characteristics as the D-2 dopamine receptor mediating the inhibition of the D-1 receptor agonist induced cAMP efflux. Selective D-2 receptor agonists like LY 141865 and RU 24926 stimulated this receptor while the D-1 receptor agonist SKF 38393 was inactive. Effects of the selective D-2 receptor agonists could be antagonized by (—)-sulpiride, a selective D-2 receptor antagonist. Although the pharmacological characteristics of the dopamine receptors mediating inhibition of both ACh release and (D-1 dopamine receptor agonist induced) cAMP efflux appeared to be similar, drugs stimulating cAMP efflux did not affect ACh release or LY 141865 induced inhibition of ACh release from rat neostriatum. Therefore it is still questionable whether the dopamine receptor mediating inhibition of both ACh release and cAMP efflux is one and the same functional entity.     

D-1 and D-2 receptor mediation of sensorimotor behavior in rats depleted of dopamine during development.

The effects of selective D-1 and D-2 antagonists on sensorimotor behavior were studied in rats treated with 6-OHDA or its vehicle solution on either postnatal day 3, 20, or 35. Blockade of either D-1 or D-2 receptors induced akinesia and somatosensory neglect in adults treated with vehicle at any of the three ages. The behavioral effects of antagonists on rats with 6-OHDA-induced dopamine depletions varied as a function of the age at the time of damage. Adults depleted of DA on Day 35 exhibited behavioral deficits after either D-1 or D-2 blockade and at doses that were ineffective in controls. Adults depleted of DA on Day 20 exhibited deficits after either D-1 or D-2 blockade but were not any more sensitive than were controls. In contrast, adults depleted of DA on Day 3 were insensitive to the behavioral effects of D-1 or D-2 blockers but were impaired after the dual administration of both antagonists. Moreover, simultaneous administration of subthreshold doses of D-1 and D-2 antagonists produced behavioral deficits in controls and rats depleted on Day 3. These data demonstrate that activity within residual DA neurons remains critical for the expression of sensorimotor behavior in rats depleted of DA during development. However, the specific contribution of D-1 and D-2 receptors to these behaviors depends upon the animals' age at the time of depletion.     

Dopamine D2(High) receptors moderately elevated by bifeprunox and aripiprazole

Because long-term antipsychotics elicit behavioral dopamine supersensitivity, the present study examined whether 7-9 days administration of partial dopamine D2 agonists with antipsychotic activity, bifeprunox and aripiprazole, could induce biochemical changes that suggest dopamine supersensitivity. In rats, behavioral dopamine supersensitivity is associated with increased dopamine D2(High) receptors in homogenized striata. In control rat striata, bifeprunox and aripiprazole had similar K(i) values at D2 receptors. In human cloned D2Long receptors, however, aripiprazole had a K(i) of 9.6 nM and recognized 41% of the D2 receptors to be in the D2(High) state, while the values for bifeprunox were 1.3 nM and 69%, indicating that bifeprunox had higher potency and efficacy at D2. Nine days of subcutaneously injected bifeprunox (0.25 mg/kg/day) and 7 days of aripiprazole (1.5 mg/kg) increased D2(High) receptors by 102-129% and 108-188%, respectively, although the total population of D2 receptors revealed no significant changes. The increase in D2(high) receptors induced by dopamine D2 partial agonists appear to be of smaller magnitude than those seen previously with D2 antagonist antipsychotics. Future research needs to test directly whether long-term treatment with dopamine partial agonists leads to any behavioral dopamine supersensitivity.     

Antidepressants given repeatedly increase the behavioural effect of dopamine D-2 agonist

Summary The effects of single or repeated doses of antidepressant drugs (imipramine, amitriptyline, citalopram, mianserin) on rat locomotor hyperactivity induced by quinpirole, a dopamine D-2 receptor agonist, was investigated. Single doses of antidepressants do not change the effect of quinpirole, but enhance it when they are administered repeatedly. This enhancement is inhibited by (±)-sulpiride, a dopamine D-2 receptor antagonist. The results obtained indicate that the enhancement of dopaminergically-stimulated hyperactivity induced by repeated doses of antidepressants is mediated by dopamine D-2 receptors.     

Dopamine D2(High) receptors moderately elevated by sertindole

Because long-term administration of antipsychotics can cause behavioral dopamine supersensitivity, this study examined whether the antipsychotic sertindole could elicit biochemical changes indicative of dopamine supersensitivity. In rats, behavioral dopamine supersensitivity is consistently associated with an increased proportion of dopamine receptors that have high affinity for dopamine, namely D2(High), in homogenized striata. Nine days of subcutaneously injected sertindole (1.25 mg/kg/day) increased the proportion of D2(High) receptors between 186% and 215%, although the total population of D2 receptors did not change. Although the findings suggest that rats or patients treated with sertindole might exhibit behavioral dopamine supersensitivity, the drug-induced increase in D2(High) receptors was less than that previously found with haloperidol.     

Long-term changes of striatal D-2 receptors in rats chronically exposed to morphine under aversive life conditions.

Chronic morphine treatment has been shown to cause the development of hyperreactivity of the dopamine system detected as the increased behavioral and biochemical responses to the action of specific dopamine agonists. Furthermore, inverted changes in animal behavioral reactivity to the stimulation of presynaptic, proposed D-2 receptors by apomorphine in a low dose was found in our previous study when morphine was chronically used in animals under conditions of restraint. To estimate the nature and proposed receptor mechanisms of changes found in behavioral reactivity due to chronic morphine administration in aversive life conditions at the level of highly sensitive D-2 receptors, the density and affinity of [3H] spiroperidol binding sites was studied in these animals two weeks after the last opiate administration. Increased density and affinity of D-2 receptors probably indicating their hypersensitivity was found in animals chronically exposed to two-hour restraint stress, while a significant decrease in density accompanied by increase in affinity of these receptors was typical to rats chronically exposed to morphine under conditions of restraint. The data are discussed in aspects of quantitative and qualitative changes in D-2 receptors, and their proposed mechanisms and functional significance in the mediation of modified organism's functional state due to chronic opiate administration in different environmental conditions.     

Differential gene expression of dopamine D-2 receptor subtypes in rat chromaffin cells and sympathetic neurons in culture

Chromaffin cells and sympathetic neurons arise from a common bipotential progenitor which, if exposed to nerve growth factor (NGF), matures into a sympathetic neuron, but if exposed to glucocorticoids (GCs), differentiates into a mature chromaffin cell. Pharmacological evidence indicates that, in adrenal medulla and sympathetic neurons, dopamine (DA) receptors belonging to the D-2 family inhibit catecholamine secretion. The molecular characterization of these receptors, however, is not been yet described. Our data suggest that bipotential cells obtained from newborn rat adrenal medulla express both isoforms of the D-2 receptor, while D-3 receptor and D-4 receptor messenger RNAs (mRNAs) are not present. GC-mediated maturation induces the expression of D-4 receptors, without modification of D-2 isoforms. Sympathetic neurons differentiated in vitro selectively express the D-2short mRNA. Taken together, present results suggest that NGF and GCs play a role in regulating D-2 family receptor expression in neural crest-derived cells.     

Nigrostriatal lesion alters neurophysiological responses to selective and nonselective D-1 and D-2 dopamine agonists in rat globus pallidus

The effects of the selective D-1 dopamine agonist SKF 38393, the selective D-2 agonist quinpirole, and the nonselective D-1/D-2 agonist apomorphine on spontaneous activity of globus pallidus neurons were compared in normal control rats and rats with unilateral 6-hydroxydopamine induced lesions of the nigrostriatal pathway. In control, unlesioned rats, SKF 38393 (0.4 and 10 mg/kg, i.v.) caused no significant net change in the activity of globus pallidus neurons, although some individual cells showed significant increases or decreases in discharge rates following 10 mg/kg SKF 38393 administration. In animals with unilateral 6-hydroxydopamine induced lesions, SKF 38393 caused greater increases and decreases in the discharge rates of a larger percentage of pallidal cells recorded on the ipsilateral side than in control, unlesioned animals. These rate changes were effectively reversed by the D-1 antagonist SCH 23390, but not by the D-2 antagonist YM-09151-2. Quinpirole (0.3 mg/kg, i.v.) produced modest rate increases in control, unlesioned animals and significantly larger rate increases in nigrostriatal lesioned animals. YM-09151-2, but not SCH 23390, effectively reversed quinpirole's effects in the lesioned animals. As previously reported, the nonselective D-1/D-2 agonist apomorphine (0.3 mg/kg, i.v.) produced large increases in discharge rates of pallidal cells in control, unlesioned rats. In contrast, in nigrostriatal lesioned rats, the discharge rates of some ipsilateral pallidal neurons were markedly increased, others were decreased, and some were unaffected following apomorphine administration. The dopamine antagonist spiroperidol partially to fully reversed these rate changes. In summary, apomorphine's neurophysiological profile appears to be an exaggeration of the D-1 agonist profile in the globus pallidus of these lesioned animals. The degree of change observed after apomorphine administration is consistent with results from other studies that have indicated that a synergistic interaction between effects triggered by stimulation of the two receptor subtypes can occur in these animals, as in control, unlesioned animals. However, these results further show that in rats with unilateral nigrostriatal lesions, the denervated dopamine receptors or the processes they mediate are altered so that they no longer have the requirement seen in controls for concurrent stimulation of the complementary dopamine receptor subtype for expression of the selective agonist effects.     

On the roles of dopamine D-1 vs. D-2 receptors for the hyperactivity response elicited by MK-801

Summary The present study was aimed at clarifying to what extent the hypermotility induced by the uncompetitive N-methyl-D-aspartate (NMDA) antagonist MK-801 depends on dopamine (DA) D-1 compared to D-2 receptor tone. The D-1 receptor antagonist SCH 23390 was found to reduce locomotion to a greater extent in MK-801-treated than in vehicle-treated mice, whereas the reverse appeared to be the case for the DA D-2 receptor antagonist raclopride. In other words, MK-801-induced hyperactivity was more readily antagonized by SCH 23390 than by raclopride and, thus, DA D-1 receptors seem to be more important than D-2 receptors for MK-801-induced hyperactivity. These results are in line with our previous observation that MK-801 generally interacts synergistically with a DA D-1 but not with a D-2 receptor agonist in monoamine-depleted mice. In view of the possible role of deficient glutamatergic neurotransmission in schizophrenia, our findings underline the importance of investigating the efficacy of selective DA D-1 antagonists in this disorder.