Alkylation of striatal dopamine receptors abolishes stereotyped behavior but has no effect on dopamine stimulated adenylate cyclase activity

The role of dopamine stimulated adenylate cyclase (AC) activity in behaviours elicited by apomorphine stimulation of striatal dopamine receptors was investigated. Rats were treated with the irreversible dopamine receptor alkylating agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) alone or after pretreatment with either a D1 or D2 receptor antagonist and subsequently challenged with apomorphine. Animals that received no antagonist pretreatment showed significantly decreased striatal concentrations of D1 and D2 receptors and an abolition of apomorphine induced sniffing behaviour despite showing no change in striatal AC activity. In the groups which received antagonist pretreatment the reduction in the sniffing response paralleled the reduction in D2 receptor concentration whereas the incidence of vacuous oral movements was inversely related. In no case were the behavioural responses associated with changes in AC activity. We conclude that these behavioural effects observed in response to dopamine stimulation by apomorphine may be mediated through another second messenger system.     

Pressure reversed extracellular striatal dopamine decrease produced by D1 receptor agonist SKF 38393, and D2 receptor agonist LY 171555, but failed to change the effect of the activation of both D1 and D2 receptors.

When human divers or experimental animals are exposed to high pressure, they develop the high-pressure neurological syndrome which is characterized by electroencephalographic changes, and behavioral disturbances. Recently, neurochemical disorders such as a pressure-induced increase in dopamine release have been demonstrated. In the present study, pharmacological experiments, using dopamine receptor agonists such as D1 receptor agonist SKF 38393, D2 receptor agonist LY 171555, and D1/D2 receptor agonist apomorphine, were performed to investigate dopamine receptor function at the neurochemical level. Only apomorphine and mixed SKF 38393 + LY 171555 prevented the pressure-induced increase in dopamine release while SKF 38393 or LY 171555 administered alone failed to do so. The results suggest that the D1-D2 link would be reduced under high pressure because of an abnormal function of D1 receptors which would allow high-affinity D2 states for dopamine. If so, such a preponderance of high-affinity states in D2 postsynaptic receptors could be associated with hyperbaric hyperlocomotor activity. Elsewhere, results also suggested that the pressure-induced disorders in dopamine receptor function could be involved in the pressure-induced elevation in dopamine release.     

Repeated administration of a selective dopamine D2 receptor agonist to 6-OHDA — lesioned rats does not affect the survival and outgrowth of intrastriatal fetal mesencephalic grafts

The objective of the present study was to investigate the effects of chronic activation of dopamine D2 receptors on the development of grafted fetal rat mesencephalic dopaminergic neurons. Therefore, unilaterally 6-hydroxydopamine — lesioned rats received intrastriatal mesencephalic cell suspension grafts and were subsequently chronically treated with the selective dopamine D2 receptor agonist LY 171555 (Quinpirole). After treatment for 6 consecutive weeks, the rats were processed for tyrosine-hydroxylase immunocytochemistry to assess the survival and outgrowth from grafted dopaminergic neurons. Morphological analysis revealed that, like the volume and morphology of the graft, neither the number nor the cell area of grafted dopaminergic neurons was significantly different between vehicle- and LY 171555-treated animals. To obtain a quantitative estimate of the graft-derived dopaminergic reinnervation, a computerized image analysis system was used. Using this procedure, which was based on the densitometric measurement of tyrosine hydroxylase immunoreactivity in the area adjacent to the grafted tissue, it was found that the extent of graft-derived outgrowth also appeared to be un-affected upon chronic treatment with LY 171555. It is concluded that long-term concurrent administration of a dopamine D2 receptor agonist for 6 consecutive weeks does not impair the survival and outgrowth of grafted rat fetal mesencephalic dopaminergic neurons.     

Anticonvulsant effect of striatal dopamine D2 receptor stimulation: dependence on cortical circuits?

In the pilocarpine model of epilepsy, dopamine can either inhibit (via D2 receptors) or facilitate (via D1 receptors) the spread of limbic motor seizures. The anticonvulsant action of D2 receptor activation has been localized to the anterior striatum, but disappears if excessive damage is caused to the overlying cerebral cortex. This study examines the possibility that the corticostriatal projection is involved in the anticonvulsant response to striatal D2 receptor stimulation, by comparing the seizure-protecting efficacy of intrastriatal trans-(+)-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-2H-pyrazolo-(3,4-g)quinol ine hydrochloride (LY 171555) in control rats, and in rats bearing discrete bilateral kainic acid lesions of the cerebral cortex. The results show that neurotoxin injection induces a punctate lesion of the primary motor area of the cortex in each hemisphere, with no injury to the underlying caudate-putamen, or to more distant structures such as the hippocampus. The lesion, however, was sufficient to abolish the protective effect of intrastriatal LY 171555 against pilocarpine challenge. To explain these findings, an interplay between nigrostriatal dopaminergic and corticostriatal glutamatergic neurons is proposed, in which the anticonvulsant tendency of the excitatory amino acid is accentuated by dopamine, probably by acting on D2 receptors which facilitate the release of glutamate from axon terminals.     

Opposing effects of dopamine D2 receptor stimulation on the spontaneous and the electrically evoked release of [3H]GABA on rat prefrontal cortex slices.

The spontaneous and the electrically evoked release of [3H]GABA were studied in vitro on slices of rat medial prefrontal cortex. The slices were preincubated with [3H]GABA and then superfused with a Krebs' solution. The superfusion with a Ca(2+)-free medium progressively increased the spontaneous [3H]GABA release and strongly decreased the electrically evoked release of [3H]GABA (-65%). The effects of three dopaminergic D2 receptor agonists (RU24926, lisuride and LY171555) were studied on both the spontaneous and the electrically evoked [3H]GABA release. The spontaneous release of [3H]GABA was increased by exposure to each of these three D2 agonists. RU24926 produced a dose-dependent increase from 10(-9) to 3 x 10(-8) M and the maximal effect was totally abolished by the dopaminergic D2 receptor antagonist sulpiride (10(-5) M). With lisuride a progressive increase of [3H]GABA release was observed and a plateau value was reached with concentrations between 10(-7) and 10(-6) M. These effects were totally reversed by 10(-5) M sulpiride. The dose-response relation for LY171555 was bell-shaped, with a maximal effect being obtained with 10(-9) M) LY171555. This effect decreased with a higher concentration (10(-8) M) and finally was no longer observed for 10(-7) M LY171555. The maximal increase induced by LY171555 was totally abolished by 10(-5) M sulpiride. In contrast, the electrically evoked release of [3H]GABA was inhibited by these three D2 agonists. The IC50 value of the inhibition was 4.1 x 10(-8) M for RU24926 and 2 x 10(-7) M for lisuride. Sulpiride (10(-5) M) totally abolished the effect of 10(-7) M RU24926. In the concentration range of lisuride examined, a 50% reduction of the lisuride inhibition was obtained in the presence of sulpiride (10(-5) M). The dose-response curve obtained with LY171555 had a U-shape, with a maximal inhibition reached with 10(-8) M, whereas no effect was observed with 10(-6) M. The inhibition induced by 10(-8) M LY171555 was completely antagonized by 10(-5) M sulpiride. The D2 agonist-induced inhibition of the electrically evoked release of [3H]GABA was mimicked by dopamine endogenously released by 10(-5) M amphetamine. This effect was reversed by 10(-5) M sulpiride. Our data provide further evidence for a dopaminergic control of GABA interneurons in the prefrontal cortex. This regulation implies the activation of D2 dopaminergic receptors. The possible mechanisms underlying the opposite effects of D2 agonists on the spontaneous and the electrically evoked release of [3H]GABA are discussed.     

Age-related changes in the regulation of behavior by D-1:D-2 dopamine receptor interactions.

Functional interactions between D-1 and D-2 dopamine receptor systems appear important in the regulation of psychomotor behavior, and may alter with aging. Male Sprague-Dawley rats of 5 and 20-24 months were challenged with the selective D-2 agonist LY 163502 alone or following pretreatment with the selective D-1 antagonist SCH 23390. Typical sniffing and locomotor responses to LY 163502 alone were significantly reduced in aged animals. Pretreatment with SCH 23390 blocked these typical responses in both young and aged animals, consistent with their regulation by cooperative D-1:D-2 interactions; however, SCH 23390 released a significant excess of atypical limb/body jerking to LY 163502 in aged animals, a response which appears to have its basis in oppositional D-1:D-2 interactions. These results suggest that the net effect of aging on dopaminergic transmission is to reduce tonic activity through D-1 receptors to a greater extent than that occurring through D-2 receptors. As the present aged animals showed a selective loss of striatal D-2 but not of D-1 receptors in radioligand binding studies, such a reduction of D-1-mediated transmission with aging would seem to involve loss of presynaptic function or of postsynaptic mechanisms beyond the D-1 recognition site.     

Muscarinic receptor activation attenuates D2 dopamine receptor mediated inhibition of acetylcholine release in rat striatum: indications for a common signal transduction pathway

In the present investigations, we used a superfusion system to study the effect of simultaneous activation of D2 dopamine receptors and so-called muscarinic "autoreceptors" on the K(+)-evoked in vitro release of [3H]acetylcholine from rat striatal tissue slices. Activation of D2 receptors with the selective agonist LY 171555 (0.01-1 microM) clearly decreased the evoked release of [3H]acetylcholine. This effect was markedly attenuated in the presence of either the selective muscarinic receptor agonist oxotremorine (3 microM) or the cholinesterase inhibitor physostigmine (1 microM). Conversely, D2 receptor activation with LY 171555 (1 microM) completely abolished the muscarinic receptor mediated inhibition of evoked [3H]acetylcholine release induced by oxotremorine (0.03-10 microM). These results show that the inhibitory effects of D2 dopamine receptor and muscarinic receptor activation on striatal acetylcholine release are non-additive and therefore are interdependent processes. In addition, we investigated some aspects of the signal transduction mechanism by which the muscarinic receptor mediates inhibition of K(+)-evoked in vitro release of [3H]acetylcholine from rat striatal tissue slices. It appeared that the effect of muscarinic receptor activation was not significantly influenced either by a lowering of the extracellular Ca2+ concentration from the usual 1.2-0.12 mM or by an increase of the intracellular cyclic adenosine-3',5'-monophosphate content. However, increasing extracellular K+ strongly decreased the inhibition of evoked [3H]acetylcholine release mediated by activation of muscarinic receptors. This set of results indicates that the muscarinic "autoreceptor" mediates the decrease of depolarization induced [3H]acetylcholine release from rat striatum to a large extent through stimulation of K+ efflux (opening of K+ channels) in a cyclic adenosine-3',5'-monophosphate independent manner.(ABSTRACT TRUNCATED AT 250 WORDS)     

The D1 dopamine agonist SKF 38393, but not the D2 agonist LY 171555, decreases the affinity of type II corticosteroid receptors in rat hippocampus and ventral striatum

Type I and type II brain corticosteroid receptors are regulated by adrenal hormones as well as being under neural control. Recent studies have indicated that neurotransmitters such as serotonin and noradrenaline are also involved in the regulation of corticosteroid receptors. In a previous study, we showed that dopamine also modulates activity of the corticosteroid receptor system. In the present study, we examined the roles of the dopamine D₁ and D₂ receptor subtypes in the regulation of corticosteroid receptors. Adrenalectomized rats whose corticosterone levels were maintained within normal limits by corticosterone replacement implants, were injected intraperitoneally with the D₁ agonist SKF 38393 or the D₂ agonist LY 171555. Corticosteroid receptors were assayed in the ventral striatum and hippocampus. We have shown that the D₁ agonist SKF 38393 decreased type II receptor affinity in both regions, whereas the D₂ agonist LY 171555 had no effects.

The results show that the influence of the dopaminergic system on corticosteroid receptors appears to be mediated by D₁ receptors.     

Effect of D1 receptor stimulation in normal and MPTP monkeys

The effect of a selective agonist of the dopamine D1 receptor (SKF 38393) and of the D2 receptor (LY-171555) was tested acutely in normal and in monkeys with a parkinsonian syndrome induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The D2 agonist induced a strong locomotor response and lingual dyskinesia in both normal and parkinsonian monkeys. The D1 agonist however had no locomotor effect by itself but induced tongue protrusions in normal monkeys only. It appeared to potentiate the dyskinetic effect of LY 171555 in MPTP monkeys but it antagonized the locomotor action of the D2 agonist in both normal and MPTP monkeys. The selective D1 and D2 antagonists SCH 23390 and sulpiride were also tested. Both compounds were able to suppress the dyskinetic action of the combined agonists in normal animals but only the D2 antagonist was effective in the same conditions in MPTP monkeys. These findings emphasize the importance of the D2 receptor in mediating the locomotor response as well as dyskinesia in monkeys.     

Decrease of behavioral and biochemical denervation supersensitivity of rat striatum by nigral transplants.

The effect of fetal mesencephalic transplants on dopamine receptor supersensitivity has been studied behaviorally and biochemically in rats with a unilateral lesion of the nigrostriatal pathway. Female rats were lesioned with 6-hydroxydopamine in the left substantia nigra. At least one month later they were tested with apomorphine (0.25 mg/kg, s.c.), amphetamine (5 mg/kg, s.c.), LY 171555 (D2 agonist) (0.5 mg/kg, i.p.) and CY 208243 (D1 agonist) (0.5 mg/kg, s.c.). A suspension containing approximately 1.5 x 10(6) cells from the ventral mesencephalon of rat embryos was distributed in three sites in a triangular fashion in the center of the denervated striatum. Six months later, grafted dopamine neurons reinnervated the medial part of the dorsal striatum, increased the dopamine level and reversed the rotational asymmetry evoked by amphetamine. Apomorphine given four months post-transplant still elicited contraversive circling but the number of turns was reduced. Circling evoked six months post-transplant by CY 208243 or LY 171555 was significantly less in grafted rats than in lesioned non-grafted rats. The density of dopaminergic receptors in the striatum of grafted and lesioned rats was examined by autoradiography by means of in vitro binding with [3H]SCH 23390 for D1 receptors and [3H] spiperone for D2 receptors. The results show that intrastriatal nigral transplants decrease the supersensitivity of the D2 receptors and to a lesser extent of the D1 receptors. Normalization of D2 receptors may explain the decrease of behavioral supersensitivity following administration of apomorphine and D2 agonist in grafted rats. D1 receptors were less affected by the lesion and also less normalized than D2 receptors by the transplants.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dopamine D-2 receptor mediation of response suppression learning of young rats

In three experiments, the effects of augmenting or blocking dopamine (DA) D-2 receptor activity on the ontogeny of response suppression learning of preweanling rat pups were determined. In the initial experiment, rat pups were trained to traverse a straight alley for nipple attachment to an anesthetized dam. When footshock (0.2 mA, 0.5 sec) was made contingent on responding, younger (11- and 13-day-olds) rat pups were deficient to older (17- and 19-day-olds) pups at withholding punished responding. In the subsequent experiments, response suppression learning was assessed after injecting 11- and 17-day-old rat pups with the specific DA D-2 agonist, LY 171555 (0.005-, 0.01-, and 0.1-mg/kg, i.p.), or the specific DA D-2 antagonist, sulpiride (5.0-, 15.0-, and 50.0-mg/kg, i.p.). LY 171555 enhanced the punished responding of both the 11- and 17-day-old rat pups; whereas, sulpiride increased the punished responding of the 17-, but not the 11-day-olds. In four additional experiments, the effects of LY 171555 and sulpiride on the locomotor activity, nociception, and reinforcement processes of 17-day-old rat pups was assessed. Rat pups given LY 171555 (0.01 mg/kg, i.p.) exhibited enhanced locomotor activity and a trend towards hyperanalgesia using a hot plate task. Sulpiride (15.0 mg/kg, i.p.) completely antagonized LY 171555's activity enhancing effects and had hyperalgesic properties. In two experiments, sulpiride did not affect the nonpunished appetitive responding of the 17-day-olds; whereas, haloperidol-treated pups responded on fewer reinforced trials than did saline-treated pups. Therefore, these results indicate that the response suppression learning of 17-day-old rat pups is mediated, at least partially, by a DAD-2 receptor system, and that D-2 receptors are also involved in the locomotor activity and nociceptive responses of young rat pups.     

Intracellular studies on the dopamine-induced firing inhibition of neostriatal neurons in vitro: evidence for D1 receptor involvement

Intracellular recordings were obtained from rat neostriatal slices. Bath-applied dopamine (1–10 μM) produced a reversible inhibition of the action potentials evoked by direct stimulation and a decrease in the amplitude of the intrastriatally evoked depolarizing postsynaptic potentials. No change in membrane potential was detected during the application of 1–10 μM dopamine. Dopamine application also produced a decrease in anomalous rectification in the depolarizing direction. This subthreshold inward rectification was abolished by tetrodotoxin, but not by calcium-free and cadmium (0.1–1 mM)-containing solutions. The dopamine-induced decrease in excitatory postsynaptic potential amplitude was evident at resting membrane potential or at more positive levels, but was absent at hyperpolarized values of the membrane potential. Addition of bicuculline (50–500 μM) to the medium did not affect the inhibitory action of dopamine. The inhibitory action of dopamina also persisted in calcium-free and cadmium-containing solutions. The adenosine 3′,5′-cyclic monophosphate analogue, 8-bromo-adenosine 3′,5′-cyclic monophosphate (0.1–1 mM), mimicked the effects produced by D1 receptor activation. Bath application of 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine (SKF 38393) (1–10 μM), a selective D1 dopaminergic agonist, mimicked the effects of micromolar concentrations of dopamine. The D2 dopaminergic agonists,4,4a,5,6,7,8,8a,9-octahydro-5-n-propyl-2H-pyrazolo-3,4-g-quinoline (LY 171555) and bromocriptine (both at 10 nM-10 μM), had no effects on neostriatal cells. The inhibition induced by micromolar doses of dopamine or SKF 38393 was antagonized by bath applications of R-( + )-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol (SCH 23390; 0.1–10 μM), a D1-selective antagonist, but not by sulpiride (10nM–10μM), a D2 antagonist.

We conclude that the inhibitory effect of dopamine on rat striatal neurons is postsynaptically mediated by the activation of D1 dopaminergic receptors via the reduction of a voltage-dependent tetrodotoxin sensitive inward conductance.     

Regulation of human D1 dopamine receptor function and gene expression in SK-N-MC neuroblastoma cells.

SK-N-MC human neuroblastoma cells express functional D1, but not D5, dopaminergic receptors. Stimulating cells with dopamine or the D1-selective agonist, SKF R-38393, rapidly (t(1/2) = 1 h) resulted in > 95% attenuation of dopamine-mediated accumulation of cyclic AMP, without any change in D1 dopamine receptor levels. Prolonged (> 4 h) exposure of cells to dopamine attenuated D1 receptor levels to 45-50% of control (t(1/2) = 8 h) and was accompanied by a loss of high-affinity binding sites. At the molecular level, the expression of D1 receptor messenger RNA was bimodal: an initial increase (by approximately 60%) of receptor messenger RNA within 2 h of treatment of cells with dopamine was followed by a decline to 50% below control messenger RNA levels. Low concentrations (1-10 nM) of dopamine also potentiated D1 messenger RNA levels (up to 48%), resulting in a twofold increase in receptor levels. Transfection studies with the cloned human D1 promoter construct, pGL-D1P, indicated that the up-regulation of D1 messenger RNA was due to activation of promoter by dopamine. The dopamine-mediated up-regulation of both D1 receptor messenger RNA and promoter was prevented by the D1-selective antagonist, SCH 23390. The results suggest that dopamine regulates D1 receptor gene and protein expression in a bimodal manner, partly through activation of the receptor promoter. Moreover, the effects of dopamine are independent of the second messenger, cyclic AMP.     

Localization of striatal dopamine receptor function by central injection of an irreversible receptor antagonist

The stereotypic head-down sniffing response to systemically administered apomorphine (0.65 mumol/kg) was assessed in rats 48 h after the bilateral injection of 0.2-0.5 microliters of the irreversible receptor antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (60 micrograms/microliters) into the caudate-putamen and nucleus accumbens. This response was significantly attenuated in animals that had received injections of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline into the anterior/ventral part of the caudate-putamen but not in those that received injections into regions more dorsal/posterior. Animals were killed after apomorphine challenge and the region of dopamine D1 or D2 receptor reduction due to N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline mapped and quantified. This analysis revealed that the dopamine receptors involved in the apomorphine-induced stereotyped head-down sniffing response were located in a discrete region of the ventrolateral caudate-putamen and the dorsolateral nucleus accumbens. Animals that were pretreated with the selective dopamine D2 receptor antagonist raclopride (0 20 mumol/kg, i.p.) 20 min prior to central injection of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline into this area showed a dose-dependent protection of the stereotyped sniffing response to systemic apomorphine 48 h later. This combination of techniques constitutes a novel way to investigate striatal function and the results obtained support the concept of a functional subdivision of both the caudate-putamen and the nucleus accumbens.     

Synergism between D1 and D2 dopamine receptors in the inhibition of the evoked release of [3H]GABA in the rat prefrontal cortex.

In order to examine a possible interaction between D1 and D2 receptors in the dopaminergic control of the electrically-evoked release of [3H]GABA in the rat prefrontal cortex, the effects of D1 and D2 dopamine agonists were studied in vitro on cortical slices. The D1 agonist SKF38393 (10(-5) M) inhibited the electrically-evoked release of [3H]GABA. This effect was totally reversed by both the D1 antagonist SCH23390 (10(-7) M) and the D2 antagonist sulpiride (10(-5) M). We previously observed that maximal D2-mediated inhibition of the electrically-evoked release of [3H]GABA was obtained with 10(-7) M RU24926 and 10(-8) M LY171555. Here we showed that the inhibition produced by these two D2 agonists is also abolished by 10(-7) M SCH23390. In dopamine-depleted slices from reserpine-treated animals, it was not possible to detect an effect of either RU24926 (10(-7) M) or SKF38393 (10(-5) M), suggesting a permissive role of endogenous dopamine in the effect of either D2 or D1 agonist. Finally, SKF38393 used at a subliminar concentration (10(-6) M) was able to potentiate the effect of a liminar concentration of RU24926 (1.5 x 10(-8) M). Taken together these results strongly suggest that in the rat prefrontal cortex a D1-D2 receptor synergism is involved in the dopaminergic control of the electrically-evoked release of [3H]GABA.     

Hippocampal signal transmission to the pedunculopontine nucleus and its regulation by dopamine D2 receptors in the nucleus accumbens: an electrophysiological and behavioural study

The integrative role of the nucleus accumbens and subpallidal area in relaying hippocampal signals to the mesencephalic locomotor region in the brainstem was investigated electrophysiologically in urethan-anaesthetized rats. A behavioural study of the functional connections was also performed in freely moving rats. In the electrophysiological experiments, subpallidal output neurons to the pedunculopontine nucleus and the adjacent ventral gray were first identified by their antidromic responses to electrical stimulation of the pedunculopontine nucleus. Hippocampal stimulation was then shown to inhibit orthodromically some of these subpallidal neurons. The inhibitory response was attenuated following microinjection of a dopamine D2 agonist (LY 171555), but not a D1 agonist (SKF 38393), into the accumbens. This suggests that signal transmission from the hippocampus to the subpallidal output neurons to the pedunculopontine nucleus is modulated by a D2 receptor-mediated mechanism in the nucleus accumbens. Injections of N-methyl-D-aspartate into the ventral subiculum of the hippocampus resulted in a threefold increase in locomotor responses. Injection of a D2 agonist into the accumbens reduced the hyperkinetic response dose-dependently and suggests that D2 receptors regulate locomotor responses initiated by the hippocampal-accumbens pathway. Injection of nipecotic acid, a GABA uptake inhibitor, into the subpallidal area or of procaine, a neural transmission blocker, into the region of the pedunculopontine nucleus, also reduced significantly the hippocampal-induced hyperkinetic response. These results provide evidence of limbic (e.g. hippocampus) influences on locomotor activity by way of nucleus accumbens-subpallidal-pedunculopontine nucleus connections which may contribute to adaptive behaviour. Signal transmission from the hippocampus may be regulated by a dopamine D2 receptor mechanism in the accumbens, presumably mediated by the converging mesolimbic dopaminergic input from the ventral tegmental area.     

Dopamine reduces odor- and elevated-K(+)-induced calcium responses in mouse olfactory receptor neurons in situ

Although D2 dopamine receptors have been localized to olfactory receptor neurons (ORNs) and dopamine has been shown to modulate voltage-gated ion channels in ORNs, dopaminergic modulation of either odor responses or excitability in mammalian ORNs has not previously been demonstrated. We found that <50 microM dopamine reversibly suppresses odor-induced Ca2+ transients in ORNs. Confocal laser imaging of 300-microm-thick slices of neonatal mouse olfactory epithelium loaded with the Ca(2+)-indicator dye fluo-4 AM revealed that dopaminergic suppression of odor responses could be blocked by the D2 dopamine receptor antagonist sulpiride (<500 microM). The dopamine-induced suppression of odor responses was completely reversed by 100 microM nifedipine, suggesting that D2 receptor activation leads to an inhibition of L-type Ca2+ channels in ORNs. In addition, dopamine reversibly reduced ORN excitability as evidenced by reduced amplitude and frequency of Ca2+ transients in response to elevated K(+), which activates voltage-gated Ca2+ channels in ORNs. As with the suppression of odor responses, the effects of dopamine on ORN excitability were blocked by the D2 dopamine receptor antagonist sulpiride (<500 microM). The observation of dopaminergic modulation of odor-induced Ca2+ transients in ORNs adds to the growing body of work showing that olfactory receptor neurons can be modulated at the periphery. Dopamine concentrations in nasal mucus increase in response to noxious stimuli, and thus D2 receptor-mediated suppression of voltage-gated Ca2+ channels may be a novel neuroprotective mechanism for ORNs.     

Effect of the dopamine D1-like receptor antagonist SCH 23390 on the microstructure of ingestive behaviour in water-deprived rats licking for water and NaCl solutions

The analysis of licking microstructure provides measures, size and number of licking bouts, which might reveal, respectively, reward evaluation and behavioural activation. Based on the different effects of the dopamine D1-like and D2-like receptor antagonists SCH 23390 and raclopride on licking for sucrose, in particular the failure of the former to reduce bout size and the ability of the latter to induce a within-session decrement of bout number resembling either reward devaluation or neuroleptics on instrumental responding, we suggested that activation of reward-associated responses depends on dopamine D1-like receptor stimulation, and its level is updated on the basis of a dopamine D2-like receptor-mediated reward evaluation. Consistent results were obtained in a study examining the effect of dopamine D2-like receptor antagonism in rats licking for NaCl solutions and water. In this study, we examined the effects of the dopamine D1-like receptor antagonist SCH 23390 (0, 10, 20 and 40 μg/kg) on the microstructure of licking for water and sodium chloride solutions (0.075 M, 0.15 M, 0.3 M) in 12 h water deprived rats. Rats were exposed to each solution for 60 s either after the first lick or after 3 min that the animals were placed in the chambers. Bout size, but not bout number, was decreased at the highest NaCl concentration. SCH 23390 produced a decrease of bout number and of lick number mainly due to the decreased number of subjects engaging in licking behaviour, and failed to reduce bout size for Na Cl and water at a dose which increased the latency to the 1st lick but did not affect the intra-bout lick rate. In agreement with previous observations, these results suggest that dopamine D1-like receptors play an important role in the activation of reward-oriented responses.     

D-1 and D-2 dopaminergic receptors regulate protein phosphorylation in the rat neurohypophysis

Dopamine stimulates the phosphorylation of the neuron-specific synaptic vesicle proteins Synapsin I, Protein IIIa and Protein IIIb in the posterior pituitary gland of the rat [Tsou and Greengard (1982) Proc. natn. Acad. Sci. U.S.A. 79, 6075-6079]. This effect has been characterized in the present investigation. The stimulatory effect of dopamine was mimicked by the selective D-1 receptor agonist SKF 38393 and was competitively and potently inhibited by the selective D-1 receptor antagonist SKF 83509 as well as by the mixed D-1/D-2 antagonist fluphenazine. Conversely, the effect of dopamine was attenuated by a D-2 receptor agonist (LY 141865) and potentiated by a D-2 receptor antagonist (sulpiride). Norepinephrine also stimulated phosphorylation of the synaptic vesicle proteins, apparently through activation of the D-1 receptor. D-1 and D-2 dopaminergic receptors may play a role in the regulation of hormone secretion from the neurohypophysis. Evidence exists that in the isolated neurophypophysis activation of D-1 receptors facilitates, while activation of D-2 receptors inhibits, release of vasopressin. Further work will be required to determine whether the regulation by D-1 and D-2 receptors of the protein phosphorylation in the neurohypophysial peptidergic terminals is related to the regulation by those receptors of the neurohypophysial hormone secretion.     

Cooperative activation of D1-like and D2-like dopamine receptors in the nucleus accumbens shell is required for the reinstatement of cocaine-seeking behavior in the rat

Activation of D1-like (D1, D5) or D2-like (D1, D3, D4) dopamine receptors in the nucleus accumbens shell is sufficient to reinstate cocaine-seeking behavior in rats. The goal of these experiments was to assess whether cooperative activation of D1-like and D2-like dopamine receptors in the accumbens shell is required to promote cocaine reinstatement. Rats were initially trained to self-administer cocaine (0.25 mg, i.v.) using a fixed-ratio schedule of reinforcement for approximately 21 days. Animals subsequently underwent an extinction phase during which saline was substituted for cocaine. Once cocaine self-administration behavior was extinguished (defined as <15% of the total responses maintained during self-administration), dopamine receptor agonist-induced reinstatement of cocaine seeking was assessed. Administration of the selective D1/5 agonist R-(+)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF-81297) (1.0 microg) or the D2/3 receptor agonist trans-(-)-(4aR)-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo[3,4-g]quinoline hydrochloride (quinpirole) (3.0 microg) directly into the nucleus accumbens shell promoted reinstatement of cocaine seeking. In order to determine if endogenous dopamine tone in the accumbens shell is required for dopamine receptor agonist-induced reinstatement of cocaine seeking, D1/5 or D2/3 dopamine receptor antagonists were administered into the nucleus accumbens shell prior to a selective dopamine receptor agonist. Microinfusion of the D2/3 dopamine receptor antagonist sulpiride ((S)-5-aminosulfonyl-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2-methoxybenzamide) (1.0 microg) into the nucleus accumbens shell 10 minutes prior to SKF-81297 (1.0 microg) blocked the ability of this D1-like dopamine receptor agonist to reinstate cocaine seeking. Similarly, administration of the selective D1/5 dopamine receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH-23390) (1.0 microg) into the nucleus accumbens shell prior to quinpirole (3.0 microg) blocked reinstatement of drug-seeking behavior elicited by this D2/3 dopamine receptor agonist. Moreover, intra-accumbal shell co-administration of subthreshold doses of quinpirole (1.5 microg) and SKF-81297 (0.1 microg) promoted cocaine-seeking behavior. Collectively, these results indicate that cooperative activation of D1-like and D2-like dopamine receptors in the nucleus accumbens shell is necessary to reinstate cocaine seeking in rats.