Sensitization of amphetamine-induced stereotyped behaviors during the acute response: role of D1 and D2 dopamine receptors

During the response to an injection of amphetamine, rapid changes occur in the ability of the drug to induce stereotyped behaviors. This enhanced responsivity does not involve changes in the caudate–putamen or nucleus accumbens extracellular dopamine response, but appears to require activation of dopamine receptors. In the present studies we examined the role that D₁ and D₂ dopamine receptors might play in the development and expression of the enhanced stereotypy response. In one series of experiments we used the dopamine agonists, SKF 82958 and quinpirole as relatively selective probes at D₁ and D₂ dopamine receptors, respectively, to test for changes in dopamine receptor sensitivity following a pretreatment (‘priming') with 4.0 mg/kg amphetamine. Doses of both SKF 82958 and quinpirole which were sub-threshold to induce perseverative behaviors in control animals, promoted stereotyped behaviors in amphetamine-primed animals, suggesting an enhanced sensitivity of both D₁ and D₂ receptors. In a second series of experiments, we sought to determine whether priming with these relatively selective dopamine receptor agonists, as well as the mixed D₁/D₂ agonist, apomorphine, would result in an enhanced stereotypy response to the subsequent administration of non-stereotypy producing doses of amphetamine (0.5–1.5 mg/kg). Priming with the dopamine receptor agonists each resulted in an enhanced amphetamine-induced stereotypy response. These results indicate that both D₁ and D₂ dopamine receptors contribute to both the development and the expression of the altered stereotypy responsivity, though several dose- and time-related observations suggest that other mechanisms likely contribute as well. Because these changes are apparent during the amphetamine response, they may have important implications for the evolving behavioral alterations which result when stimulants are administered in a binge pattern of drug abuse.     

Neurochemical basis for the absence of overt "stereotyped" behaviors in rats with up-regulated striatal D2 dopamine receptors.

Because of substantial evidence for the hyperdopaminergic hypothesis of tardive dyskinesia (TD), animal models, especially rats, treated chronically with neuroleptics continue to be used to study this disorder. The rat model has been criticized because, unlike TD, in rats there is an apparent lack of spontaneous abnormal movements even when striatal D2 dopamine receptor (DAr) density is substantially increased. Our data suggest a mechanism by which rats suppress these abnormal movements normally associated with elevated DAr levels. We correlated neurochemical with behavioral changes using several animal models, including nonneuroleptic ones, which elicit varied levels of DAr upregulation. There was (as expected) a robust, significant, positive correlation between striatal DAr density and apomorphine-induced stereotypic behaviors. In contrast, there was a significant negative correlation between increased DAr density and synthesis capacity for striatal DA (Vmax for tyrosine hydroxylase). We conclude that this decrease in Vmax is a compensatory adjustment of the nigrostriatal DA tract for the increased DAr density induced in our animal models. Our data further suggest the generalization that an observed increase in receptor density doesn't necessarily predict a functional change (spontaneous behavior, neuropathology) because compensatory neural mechanisms exist. In TD these compensatory neural mechanisms may fail, leading to spontaneous behaviors.     

D1 and D2 dopamine receptor mechanisms in dopaminergic behaviors

SKF 38393, a selective D1 dopamine receptor agonist, was investigated when administered alone and in combination with dopaminergic agonists in animal models of extrapyramidal behavior. SKF 38393 did not induce stereotypy in normal rats but enhanced apomorphine-induced stereotypy in a dose-dependent manner. SKF 38393 also augmented and altered the stereotypic response of dopaminergic agonists (+)-4-propylhydronaphthoxazine quinpirole, and ciladopa. The addition of SKF 38393 with ciladopa changed the behavioral response of ciladopa from a partial to a full agonist. SKF 38393 did not alter locomotor behavior; however, it augmented the stimulatory but not the inhibitory response of apomorphine on locomotion. In unilateral 6-hydroxydopamine-lesioned animals, SKF 38393 caused contralateral rotation that were similar to those of other dopaminergic agonists. The addition of SKF 38393 to both mixed D1/D2 (levodopa, pergolide) and selective D2 (PHNO, quinpirole) dopamine agonists resulted in a synergistic rather than an additive effect. No changes in behavior were observed in rats challenged with apomorphine after being treated 21 days with SKF 38393, PHNO, SKF 38393 plus PHNO, or saline. D1 agonism is capable of augmenting and altering dopaminergic behavior of both mixed D1/D2 and D2 dopamine receptor agonists. A combination of D1 and D2 dopamine agonists may represent optimal drug treatment for Parkinson's disease.     

Differential effects of D1 and D2 dopamine agonists on stereotyped locomotion in rats.

The study examines the effect of selective D1 dopamine stimulation with SKF38393 (1.25-10 mg/kg), on stereotyped locomotion induced by the D2 agonist, quinpirole (0.5 mg/kg). Quinpirole induces repeated travel along a few routes in a limited portion of the environment. Co-administration of low doses of SKF38393 (1.25-2.5 mg/kg) produces the following results: the rate of route perseveration is not affected; the area explored expands to encompass the entire periphery of the open field; and, spatial distribution of locomotion is transformed from routes that cross the center under quinpirole to travel only along the edge. Under higher doses of SKF38393, locomotion ceases. These findings suggest that D1 and D2 stimulation may control the spatial organization of locomotion in oppositional rather than synergistic manner.     

Striatal dopamine D1 and D2 receptors: widespread influences on methamphetamine-induced dopamine and serotonin neurotoxicity

Methamphetamine (mAMPH) is an addictive psychostimulant drug that releases monoamines through nonexocytotic mechanisms. In animals, binge mAMPH dosing regimens deplete markers for monoamine nerve terminals, for example, dopamine and serotonin transporters (DAT and SERT), in striatum and cerebral cortex. Although the precise mechanism of mAMPH-induced damage to monoaminergic nerve terminals is uncertain, both dopamine D1 and D2 receptors are known to be important. Systemic administration of dopamine D1 or D2 receptor antagonists to rodents prevents mAMPH-induced damage to striatal dopamine nerve terminals. Because these studies employed systemic antagonist administration, the specific brain regions involved remain to be elucidated. The present study examined the contribution of dopamine D1 and D2 receptors in striatum to mAMPH-induced DAT and SERT neurotoxicities. In this experiment, either the dopamine D1 antagonist, SCH23390, or the dopamine D2 receptor antagonist, sulpiride, was intrastriatally infused during a binge mAMPH regimen. Striatal DAT and cortical, hippocampal, and amygdalar SERT were assessed as markers of mAMPH-induced neurotoxicity 1 week following binge mAMPH administration. Blockade of striatal dopamine D1 or D2 receptors during an otherwise neurotoxic binge mAMPH regimen produced widespread protection against mAMPH-induced striatal DAT loss and cortical, hippocampal, and amygdalar SERT loss. This study demonstrates that (1) dopamine D1 and D2 receptors in striatum, like nigral D1 receptors, are needed for mAMPH-induced striatal DAT reductions, (2) these same receptors are needed for mAMPH-induced SERT loss, and (3) these widespread influences of striatal dopamine receptor antagonists are likely attributable to circuits connecting basal ganglia to thalamus and cortex.     

Blockade of both D1- and D2-dopamine receptors inhibits amphetamine-induced ascorbate release in the neostriatum

In vivo recordings with electrochemically modified microvoltammetric electrodes revealed that several neuroleptic drugs, including haloperidol, clozapine, and thioridazine, blocked the rise in extracellular ascorbate produced by amphetamine in the neostriatum of urethane-anesthetized rats. This effect was also observed in animals that received a combined injection of Sch-23390 and sulpiride, but not when either of these drugs were administered alone or in combination with the 5-HT₂ blocker, ritanserin. These results indicate that a combined blockade of D₁- and D₂-dopamine receptors blocks amphetamine-induced ascorbate release.     

The role of extrastriatal dopamine D2 receptors in schizophrenia.

Despite numerous studies on extrastriatal regions involved in schizophrenia, studies on the functional implications of dopamine (DA) D2 receptors in the extrastriatal regions, including the cortex and thalamus, are limited. We review postmortem and in vivo human imaging studies as well as animal studies, focusing on the function of extrastriatal DA D2 receptors and their role in the pathophysiology of schizophrenia. Based on recent findings, cortical DA D2 receptors may interact with the gamma-aminobutyric acid system to modulate DA transmission, and thalamic DA D2 receptors are likely to participate in sensory gating function into the prefrontal cortex. We have found decreased DA D2 receptors in the anterior cingulate cortex and thalamic subregions of patients with schizophrenia. These observations may suggest that alterations of extrastriatal DA D2 receptors are involved in dysregulation of DA transmission and sensory signals from the thalamus to the cortex. Excessive excitatory signals from the thalamus might flow into the cortical neurotransmission system, aggravating dysregulation of DA transmission in both the striatal and extrastriatal regions in schizophrenia. These notions suggest the need for future investigations of extrastriatal DA D2 receptor function to gain important clues regarding the pathogenesis and of possible treatments for schizophrenia.     

Quinpirole-induced 50 kHz ultrasonic vocalization in the rat: role of D2 and D3 dopamine receptors

The goal of the present investigation was to study a full dose-response of quinpirole in production of species-specific 50 kHz ultrasonic vocalizations in rats, and to study involvement of D2 and D3 dopamine receptors in this response. Quinpirole, a D2/D3 dopamine agonist with high selectivity for D2 dopamine receptors, was injected into the shell of the nucleus accumbens. Quinpirole induced species-specific 50 kHz ultrasonic vocalizations at a wide range of doses as compared to saline. The dose-response study showed a triphasic effect of quinpirole and reached two comparable peak responses in the number of emitted vocalizations at 0.25 μg and 6 μg, respectively (a 24-fold dose difference). These two peaks were separated by a decreased phase. A medium dose range (0.5-1.0 μg) of quinpirole consistently depressed production of calls to the control level. Application of antagonists of D2 dopamine receptors (raclopride) and D3 dopamine receptors (U-99194A) before quinpirole revealed that quinpirole activates differentially the D2 and D3 dopamine receptors at different doses. The vocalization response induced by the low dose of quinpirole (0.25 μg) was antagonized by local pretreatment with the D3 receptor antagonist but not by the D2 receptor antagonist. On the other hand, the response induced by the high dose of quinpirole (6 μg) was antagonized by a similar local pretreatment with the D2 receptor antagonist but not by the D3 receptor antagonist. In conclusion, the results indicated that quinpirole can induce 50 kHz vocalizations after its direct intra-accumbens application in rats, and both D2 and D3 dopamine receptors are involved in the response. They play, however, different functional roles, as revealed by the triphasic effect of increasing doses of quinpirole.     

Dopamine displays an identical apparent affinity towards functional dopamine D1 and D2 receptors in rat striatal slices: Possible implications for the regulatory role of D2 receptors

In this study we examined the selectivity of dopamine (DA) for rat striatal DA D₁ and D₂ receptors. In a Krebs-HEPES buffer, the K_i values of DA for D₁ binding sites (labelled with [³H]SCH23390) and D₂ binding sites (labelled with [³H]spiroperidol) in striatal membranes amounted to about 30 and.0.3 μM, respectively. However, the EC50s of DA (3 μM) and the DA releasing drug amphetamine (1 μM) were identical considering D₁ receptor-stimulated and D₂ receptor-inhibited adenylate cyclase activity in superfused striatal slices. Moreover, these EC₅₀ values were also obtained studying DA- and amphetamine-induced D₂ receptor activation, resulting in inhibition of the electrically evoked release of [¹⁴C]acetylcholine from the slices. Therefore, with regard to the apparent affinity of exogenous and endogenous DA for D₁ and D₂ receptors in rat striatal slices, the ligand-receptor binding data appeared to be misleading. Thus, our data show that in rat striatal slices DA has an identical apparent affinity towards functional D₁ and D₂ receptors, which is particularly intriguing in view of the very high receptor selectivity of synthetic D₁ and D₂ receptor agonists for these functional receptors in superfused brain slices as predicted on the basis of binding assays. This may have important implications for our understanding of central DA neurotransmission. For instance, since the inhibitory effect of opioid and muscarinic receptor activation on adenylate cyclase activity has been shown to be inversely related to the degree of DA D₂ receptor activation, the degree of activation of D₁ and D₂ receptors by released DA is suggested to act as a functional gate allowing distinct neurotransmitters to play a role in striatal neurotransmission. © 1994 Wiley-Liss, Inc.     

Further evidence for the mediation of both subtypes of dopamine D1/D2 receptors and cerebral neuropeptide Y (NPY) in amphetamine-induced appetite suppression

Amphetamine (AMPH) is known as an anorectic agent. Repeated treatments of AMPH for several days induced a marked anorexia on day 1 followed by a gradual return of food intake to normal level. Previously, using daily food intake (DFI) as an indicator, we found that both dopamine (DA) D1 and D2 receptors were involved in AMPH anorexia. In the present study, using DFI and body weight change (BWC) as indicators, we took a further step to examine whether repeated co-administrations of D1 and D2 agonists might produce an AMPH-like action. Results revealed that repeated co-administrations of D1 and D2 agonists, but not D1 or D2 agonist alone, produced an AMPH-like action (i.e., tolerant DFI and BWC), confirming the previous study. In addition, we examined whether cerebral neuropeptide Y (NPY), an orexigenic neurotransmitter reported to mediate AMPH anorexia, was involved in the anorectic action of D1/D2 co-administration. Our result revealed that injection of NPY antisense into brain could modify the anorectic action of repeated D1/D2 agonists, indicating the involvement of NPY. Taken together, the present results confirmed that both subtypes of D1 and D2 receptors and cerebral NPY were involved in the anorectic action of AMPH.     

Chronic treatment with dopamine receptor antagonists: behavioral and pharmacologic effects on D1 and D2 dopamine receptors

Rats were treated for 21 d with the selective D1 dopamine receptor antagonist SCH23390, the selective D2 dopamine receptor antagonist spiperone, the nonselective dopamine receptor antagonist cis-flupentixol, or a combination of SCH23390 and spiperone. In addition, a group of rats received L-prolyl-L-leucyl-glycinamide (PLG) for 5 d after the 21 d chronic spiperone treatment. Chronic treatment with SCH23390 resulted in a significant increase in D1 dopamine receptor density with no change in the D2 dopamine receptor density. Conversely, spiperone treatment resulted in a significant increase in D2 dopamine receptors and no change in D1 dopamine receptor density. PLG treatment had no effect. SCH23390 plus spiperone treatment resulted in a significant increase in both D1 and D2 dopamine receptor densities. However, although in vitro cis-flupentixol has an equal affinity for D1 and D2 dopamine receptors, only the D2 dopamine receptor density increased after chronic treatment with cis-flupentixol. In vivo treatment with the protein-modifying reagent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), which irreversibly inactivates D1 and D2 dopamine receptors, was used to investigate the paradoxical, selective D2 dopamine receptor up-regulation induced by cis-flupentixol treatment. In vivo treatment with cis-flupentixol before EEDQ administration prevented the D1 and D2 dopamine receptor reductions induced by EEDQ. However, cis-flupentixol protected, in a dose-dependent manner, a greater percentage of D2 dopamine receptors than of D1 dopamine receptors from EEDQ-induced modification. These data indicate that, in vivo, cis-flupentixol preferentially interacts with D2 dopamine receptors and could explain why only D2 dopamine receptors were up-regulated following chronic treatment with cis-flupentixol. Rats were tested for their cataleptic response to the administered drug over the course of the chronic drug treatment. Catalepsy scores of rats receiving spiperone decreased over the course of treatment, with a significant reduction in catalepsy occurring by treatment day 5. The profound catalepsy observed in rats receiving SCH23390 did not change over the 21 d of treatment. Rats receiving cis-flupentixol demonstrated tolerance to its cataleptogenic effects, with a significant reduction in catalepsy observed by treatment day 7. During the 3 week treatment, the time between drug injection and a full cataleptic response to cis-flupentixol increased from 20 to 60 min, suggesting a tolerance to the D2, but not D1, dopamine receptor antagonism by cis-flupentixol.(ABSTRACT TRUNCATED AT 400 WORDS)     

Bidirectional regulation of dopamine D2 and neurotensin NTS1 receptors in dopamine neurons

Several lines of evidence suggest a close association between dopamine (DA) and neurotensin (NT) systems in the CNS. Indeed, in the rodent brain, abundant NT-containing fibres are found in DA-rich areas such as the ventral tegmental area and substantia nigra. Moreover, it has been shown in vivo that NT, acting through its high-affinity receptor (NTS1), reduces the physiological and behavioural effects of DA D2 receptor (D2R) activation, a critical autoreceptor feedback system regulating DA neurotransmission. However, the mechanism of this interaction is still elusive. The aim of our study was thus to reproduce in vitro the interaction between D2R and NTS1, and then to characterize the mechanisms implicated. We used a primary culture model of DA neurons prepared from transgenic mice expressing green fluorescent protein under the control of the tyrosine hydroxylase promoter. In these cultures, DA neurons endogenously express both D2R and NTS1. Using electrophysiological recordings, we show that activation of D2R directly inhibits the firing rate of DA neurons. In addition, we find that NT, acting through a NTS1-like receptor, is able to reduce D2R autoreceptor function independently of its ability to enhance DA neuron firing, and that this interaction occurs through a protein kinase C- and Ca(2+)-dependent mechanism. Furthermore, prior activation of D2R reduces the ability of NTS1 to induce intracellular Ca(2+) mobilization. Our findings provide evidence for bidirectional interaction between D2R and NTS1 in DA neurons, a regulatory mechanism that could play a key role in the control of the activity of these neurons.     

A role for dopamine in control of the hypoxic ventilatory response via D2 receptors in the zebrafish gill

Dopamine is a neurotransmitter involved in oxygen sensing and control of reflex hyperventilation. In aquatic vertebrates, oxygen sensing occurs in the gills via chemoreceptive neuroepithelial cells (NECs), but a mechanism for dopamine in autonomic control of ventilation has not been defined. We used immunohistochemistry and confocal microscopy to map the distribution of tyrosine hydroxylase (TH), an enzyme necessary for dopamine synthesis, in the gills of zebrafish. TH was found in nerve fibers of the gill filaments and respiratory lamellae. We further identified dopamine active transporter (dat) and vesicular monoamine transporter (vmat2) expression in neurons of the gill filaments using transgenic lines. Moreover, TH- and dat-positive nerve fibers innervated NECs. In chemical screening assays, domperidone, a D₂ receptor antagonist, increased ventilation frequency in zebrafish larvae in a dose-dependent manner. When larvae were confronted with acute hypoxia, the D₂ agonist, quinpirole, abolished the hyperventilatory response. Quantitative polymerase chain reaction confirmed expression of drd2a and drd2b (genes encoding D₂ receptors) in the gills, and their relative abundance decreased following acclimation to hypoxia for 48 h. We localized D₂ receptor immunoreactivity to NECs in the efferent gill filament epithelium, and a novel cell type in the afferent filament epithelium. We provide evidence for the synthesis and storage of dopamine by sensory nerve terminals that innervate NECs. We further suggest that D₂ receptors on presynaptic NECs provide a feedback mechanism that attenuates the chemoreceptor response to hypoxia. Our studies suggest that a fundamental, modulatory role for dopamine in oxygen sensing arose early in vertebrate evolution.     

Oligomers of D2 dopamine receptors

There is increasing evidence that G protein-coupled receptors form oligomers and that this might be important for their function. We have studied this phenomenon for the D2 dopamine receptor and have shown using a variety of biochemical and biophysical techniques that this receptor forms dimers or higher-order oligomers. Using ligand-binding studies, we have also found evidence that this oligomer formation has functional relevance. Thus, for the receptor expressed in either CHO cells or Sf 9 insect cells, the binding properties of several radioligands (in saturation, competition, and dissociation assays) do not conform to those expected for a monomeric receptor with a single binding site. We propose that the receptors exist in oligomers with homotropic and heterotropic negatively cooperative interactions between ligands.     

The involvement of dopamine in nociception: the role of D(1) and D(2) receptors in the dorsolateral striatum

Determination of the neuroanatomical and neurochemical factors that contribute to nociception is an essential element in the study and treatment of pain. Several lines of evidence have implicated nuclei and neurotransmitters within the basal ganglia in nociception. For example, previous studies have shown that dopamine receptors in the striatum are involved in acute nociception, however, it remains to be determined if dopamine receptors in the dorsolateral striatum are involved in persistent nociception. The purpose of the present study was therefore to determine whether activation or antagonism of dopamine receptors in the dorsolateral striatum influences the nociceptive responses of rats in the formalin test, a model of persistent pain. It was found that micro-injection of the non-selective dopamine antagonist haloperidol into the dorsolateral striatum increases formalin-induced nociception whereas injection of the non-selective dopamine agonist apomorphine reduces formalin-induced nociception. Injection of the D(1) antagonist SCH23390 or the D(1) agonist SKF38393 does not affect formalin-induced nociception. In contrast, injection of the D(2) antagonist eticlopride enhances formalin-induced nociception, whereas injection of the D(2) agonist quinpirole reduces formalin-induced nociception. These results provide additional evidence that dopamine receptors in the striatum are involved in nociception. Furthermore, this study strongly suggests that D(2), but not D(1), dopamine receptors in the dorsolateral striatum are involved in modulation of persistent nociception.     

The computational role of dopamine D1 receptors in working memory.

The prefrontal cortex (PFC) is essential for working memory, which is the ability to transiently hold and manipulate information necessary for generating forthcoming action. PFC neurons actively encode working memory information via sustained firing patterns. Dopamine via D1 receptors potently modulates sustained activity of PFC neurons and performance in working memory tasks. In vitro patch-clamp data have revealed many different cellular actions of dopamine on PFC neurons and synapses. These effects were simulated using realistic networks of recurrently connected assemblies of PFC neurons. Simulated D1-mediated modulation led to a deepening and widening of the basins of attraction of high (working memory) activity states of the network, while at the same time background activity was depressed. As a result, self-sustained activity was more robust to distracting stimuli and noise. In this manner, D1 receptor stimulation might regulate the extent to which PFC network activity is focused on a particular goal state versus being open to new goals or information unrelated to the current goal.     

Evidence for thermoregulation by dopamine D1 and D2 receptors in the anteroventral preoptic region during normoxia and hypoxia

Hypoxia causes a regulated decrease in body temperature (Tb), a response that has been called anapyrexia. Stimulation of dopamine receptors in the central nervous system (CNS) reduces Tb in rats, and dopamine D1 and D2 receptors seem to be involved in this response. Thus, we predicted that injection of SCH 23390 and haloperidol, D1 and partly D2 receptor antagonists, respectively, into the anteroventral preoptic region (AVPO, the thermointegrative region of the CNS) would lessen the hypoxia-induced anapyrexia. We measured Tb of conscious Wistar rats before and after injection of SCH 23390 (50 and 100 ng/100 nl) or haloperidol (50 e 500 ng/100 nl) or their respective vehicles (saline and DMSO 5%) into the AVPO followed by 30 min of hypoxia (7% O2). Vehicles and the lower doses of SCH 23390 and haloperidol had no effect on Tb during normoxia or hypoxia. The higher doses of SCH 23390 and haloperidol attenuated (P<0.05) the drop in Tb elicited by hypoxia. However, this higher haloperidol dose also increased Tb during normoxia. The present data is consistent with the notion that dopamine is an important thermoregulatory neurotransmitter in a way that D2 receptors are mainly involved with maintenance of Tb in euthermia, while D1 receptors are activated to induce hypoxic anapyrexia in the AVPO.     

Nigral D1 and striatal D2 receptors mediate the behavioral effects of dopamine agonists

The mediation of behavior by nigral and striatal dopamine (DA) D1 and D2 receptors was investigated in rats that had sustained extensive unilateral 6-hydroxydopamine-induced injury to ascending DA neurons. Selective D1 and D2 agonists and antagonists were injected directly into the DA-denervated substantia nigra pars reticula or the caudate-putamen via a chronically indwelling cannula. Contralateral rotation resulting from unilateral stimulation of supersensitive DA receptors was quantified over 46 min. Intrastriatal apomorphine (5 micrograms) or the selective D2 agonist quinpirole (5 micrograms), but not the selective D1 agonist (+/-)-SKF 38393 (15 micrograms), induced vigorous rotation. The rotation induced by intrastriatal quinpirole was greatly diminished by systemic administration of the selective D2 antagonist eticlopride (0.5 mg/kg, i.p.) and could not be enhanced by additional injection of intrastriatal (+/-)-SKF 38393. Intranigral administration of apomorphine or (+/-)-SKF 38393, but not quinpirole (same doses as above), elicited vigorous rotation. However, the rotation induced by intranigral (+/-)-SKF 38393 could not be blocked by systemic administration of the selective D1 antagonist SCH 23390 (0.5 mg/kg, s.c.), and was mimicked by intranigral (-)-SKF 38393 (15 micrograms), which exhibits 100-fold less activity than the dextrorotatory enantiomer at the D1 receptor. In order to circumvent the problem of this drug's apparent non-D1-mediated action when injected intranigrally, rotation was induced by systemic (+/-)-SKF 38393 (2.0 mg/kg, i.p.) 10 min after intranigral administration of selective antagonists. Intranigral SCH 23390 (10 micrograms), but not eticlopride (10 micrograms), powerfully antagonized the rotation induced by systemic (+/-)-SKF 38393. Conversely, rotation induced by systemic quinpirole (0.5 mg/kg, i.p.) was potently blocked by intrastriatal eticlopride but not SCH 23390. Rotation induced by systemic apomorphine (0.25 mg/kg, i.p.) was not attenuated by either antagonist alone, regardless of intracerebral injection site. The results indicate that both nigral D1 and striatal D2 receptors mediate the behavioral effects of DA agonists. These data may be useful in elucidating the mechanism(s) underlying the D1/D2 synergism observed in neurologically intact animals, as well as in understanding the action of drugs used in the treatment of Parkinson's disease.     

Effect of D1 and D2 agonists in primates withdrawn from long-term treatment with haloperidol: the potential role of dopamine D1 receptors in dyskinesia.

The effects of dopamine (DA) D1 and D2 receptor agonists were evaluated in eight Cebus apella monkeys. The monkeys had previously received haloperidol for 2 years, and five of the monkeys had developed mild oral dyskinesia. SKF 81297 (a full D1 agonist) induced marked oral hyperkinesia, consisting of tongue protrusions and licking or chewing movements, most pronounced in the monkeys with pre-existing oral dyskinesia. SKF 38393 and SKF 75670 (partial D1 agonists) also induced some oral dyskinesia, but to a lesser extent than SKF 81297, and with few licking movements. The partial D1 agonists, but not the full agonist, induced sedation. All of the D1 agonists induced grooming behavior, the full D1 agonist to the greatest extent. In the case of SKF 81297, the grooming was closely associated with the licking behavior. Quinpirole (a selective D2 agonist) and apomorphine (a mixed D1/D2 agonist) induced a hyperactive syndrome (nonoral stereotypy with rapid repetitive movements and increased arousal and locomotor activity). Quinpirole induced no grooming behavior and reduced pre-existing oral movements. The data indicate behavioral differences between D1 and D2 receptors and suggest that D1 receptors may be involved in the pathophysiology of some forms of dyskinesia syndromes.     

Stimulant-conditioned locomotion is not affected by blockade of D1 and/or D2 dopamine receptors during conditioning

A series of experiments were conducted to investigate the role of dopamine (DA) D1 and D2 receptor subtypes in stimulant-conditioned locomotion in rats. Expt. 1 demonstrated that locomotion could be induced by a testing situation when that situation was previously paired with (+)-amphetamine (1.5 mg/kg, s.c.) or a D2 receptor selective agonist (PHNO, 15 or 30 micrograms/kg, s.c.), but not when the drug treatments were given 3 h after exposure to the situation. The selective D2 receptor antagonist, haloperidol (50 micrograms/kg, i.p.), and the D1 receptor antagonist, SCH 23390 (20 micrograms/kg, s.c.), blocked amphetamine-induced locomotion during the pairing process, but failed to block amphetamine-conditioned locomotion as assessed during a drug-free test in Expt. 2. This was true when the antagonists were given separately or together. The results of Expts. 3 and 4 showed that doses of the D1 (20 micrograms/kg, s.c.) and D2 antagonist (250 micrograms/kg, i.p.) that blocked the unconditioned locomotor effects of PHNO failed to block its conditioned locomotion. It is concluded that neither D1 nor D2 DA receptors are essential for the development of stimulant-conditioned locomotion.