Sensitization and conditioned rotation: apomorphine, quinpirole and SKF-38393 compared.

Rats lesioned in one substantia nigra were treated on three consecutive days with the nonselective dopamine agonist, apomorphine (0.05 mg kg-1), the selective D2 agonist, quinpirole (0.025, 0.05, or 0.2 mg kg-1) or the selective D1 agonist, SKF-38393 (2.0, 4.0 or 8.0 mg kg-1). Each of these compounds resulted in acute contralateral rotation which increased significantly upon successive administrations. Two weeks after apomorphine treatment rats exhibited rapid contralateral rotation when placed, undrugged, in the drug-associated environment. Similar undrugged rotation was seen ten weeks after the lower doses of SKF-38393. No evidence of undrugged rotation was seen after quinpirole. The results show that sensitization does not necessarily predict development of a placebo effect, and suggest that persistent motor effects of dopamine agonists are associated with D1 receptor stimulation.     

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.     

Stimulation of both D1 and D2 dopamine receptors appears necessary for full expression of postsynaptic effects of dopamine agonists: a neurophysiological study

The abilities of 4 dopamine agonists to inhibit the tonic single unit activity of substantia nigra dopamine neurons and stimulate tonic activity of globus pallidus neurons were compared to study the agonists' effects on pre- and postsynaptic dopamine receptors, respectively. The agonists studied were apomorphine and pergolide, which interact with both D₁ and D₂ receptors, and the selective D₂ agonists quinpirole and RU 24926. Drugs were administered systematically. The 4 dopamine agonists were equipotent and equiefficacious at inhibiting the firing rates of dopamine neurons. In contrast, their effects on pallidal cells were not identical; apomorphine and pergolide induced significantly greater increases in pallidal cell activity than did quinpirole and RU 24926. In addition, pretreatment with a small dose of quinpirole did not attenuate the excitatory effect of apomorphine on globus pallidus cell activity, as low doses of apomorphine have previously been shown to do. Possible mechanisms underlying the differences in efficacy between the non-selective and D₂ selective dopamine agonists in the globus pallidus were investigated. Coadministering quinpirole with apomorphine did not significantly attenuate the effect of apomorphine, suggesting that quinpirole is not a partial agonist at postsynaptic dopamine receptors. In addition, prazosin pretreatment did not attenuate the stimulatory effect of pergolide on firing rates of pallidal cells, indicating that the greater efficacy of the non-selective agonists was not due to concurrent stimulation of ₁ adrenergic receptors and dopamine receptors. However, the effect of quinpirole on pallidal cell activity was significantly potentiated by pretreatment with the D₁ agonist RS-SKF 38393 but not its inactive enantiomer S-SKF 38393. These results suggest that concurrent D₁ and D₂ receptor stimulation may be necessary for the full expression of postsynaptic receptor-mediated effects of dopamine and dopamine agonists in the basal ganglia.     

Stimulation of D1-like or D2 dopamine receptors in the shell, but not the core, of the nucleus accumbens reinstates cocaine-seeking behaviour in the rat

Although increases in dopamine transmission in the brain are clearly involved in the reinstatement of cocaine seeking, the role of nucleus accumbens dopamine in cocaine priming-induced reinstatement remains controversial. The goal of these experiments was to evaluate the relative contributions of D1-like and D2-like dopamine receptors in the nucleus accumbens core and shell in the reinstatement of cocaine-seeking behaviour. Initially, rats were trained to press a lever for cocaine (0.25 mg, i.v.) using a fixed-ratio 5 (FR5) schedule of reinforcement. Responding was then extinguished by substituting saline for cocaine. During the reinstatement phase, subtype-specific dopamine receptor agonists were microinjected into the nucleus accumbens core or medial shell in order to assess their ability to induce cocaine seeking. Administration of the D1/D5 dopamine receptor agonist SKF-81297 (1.0 microg) into the nucleus accumbens shell, but not core, reinstated drug-seeking behaviour. Similarly, microinjection of quinpirole (3.0 microg), a D2/D3 dopamine receptor agonist, into the nucleus accumbens shell and not core reinstated drug-seeking behaviour. In contrast, administration of the D3- or D4-preferring dopamine receptor agonists PD 128,907 (1.5 and 3.0 microg) and PD 168,077 (0.3 and 3.0 microg), respectively, did not promote reinstatement when administered into either the core or the shell. Taken together, these results indicate that activation of D1/D5 or D2 dopamine receptors, in the limbic shell subregion of the nucleus accumbens but not the basal ganglia-orientated accumbens core, promotes the reinstatement of cocaine-seeking behaviour.     

Dopamine receptor agonists mediate neuroprotection in malonate-induced striatal lesion in the rat

Mitochondrial bioenergetic defects are involved in neurological disorders associated with neuronal damage in the striatum, such as Huntington's disease and cerebral ischemia. The striatal release of neurotransmitters, in particular dopamine, may contribute to the development of the neuronal damage. Recent studies have shown that dopamine agonists may exert neuroprotective effects via multiple mechanisms, including modulation of dopamine release from nigrostriatal dopaminergic terminals. In rats, intrastriatal injection of malonate, a reversible inhibitor of the mitochondrial enzyme succinate dehydrogenase, induces a lesion similar to that observed following focal ischemia or in Huntington's disease. In this study, we used the malonate model to explore the neuroprotective potential of dopamine agonists. Sprague-Dawley rats were injected systemically with increasing concentrations of D(1), D(2), or mixed D(1)/D(2) dopamine agonists prior to malonate intrastriatal insult. Administration of increasing doses of the D(2)-specific agonist quinpirole resulted in increased protection against malonate toxicity. Conversely, the D(1)-specific agonist SKF-38393, as well as the mixed D(1)/D(2) agonist apomorphine, conferred higher neuroprotection at lower than at higher concentrations. Our data suggest that malonate-induced striatal toxicity can be attenuated by systemic administration of dopamine agonists, with D(1) and D(2) agonists showing different profiles of efficacy.     

Effects of D1 and D2 dopamine receptor stimulation on the activity of substantia nigra pars reticulata neurons in 6-hydroxydopamine lesioned rats: D1/D2 coactivation induces potentiated responses

Extracellular single unit recording techniques were used to compare the effects of selective and non-selective dopamine agonists on substantia nigra pars reticulata activity in rats with 6-hydroxydopamine induced lesions of the nigrostriatal dopamine pathway. As previously shown, apomorphine (0.32 mg/kg), a dopamine agonist that interacts with both D1 and D2 dopamine receptor subtypes, produced consistent inhibitions of substantia nigra pars reticulata activity in these animals. The D1-receptor agonist, SKF 38393 (RS-SKF 38393, 10 mg/kg), also induced significant inhibitions in the activity of these neurons in 6-hydroxydopamine lesioned rats, although less consistently than did apomorphine. The effects of SKF 38393 were reversed by the D1-antagonist, SCH 23390. The D2 selective agonist quinpirole was considerably less effective than apomorphine at inhibiting substantia nigra pars reticulata activity at doses up to 1 mg/kg. Since comparable experiments have shown that quinpirole is as effective as apomorphine at producing dopamine D2-autoreceptor-mediated effects on dopamine neuron activity, quinpirole's lack of efficacy in the present study relative to that of apomorphine does not appear to be related to differences in relative potency for central D2-receptors using this route of administration. Rather, the relative effectiveness of SKF 38393 on pars reticulata activity suggests that selective stimulation of D1-receptors is at least, if not more, efficacious than selective stimulation of D2-receptors at inducing alterations in the activity of substantia nigra pars reticulata neurons in 6-hydroxydopamine lesioned rats. The simultaneous stimulation of both receptors, however, was considerably more effective than selective stimulation of either receptor subtype: doses of SKF 38393 and quinpirole which had no significant effect on nigral activity when administered alone brought about marked inhibition of the firing of these cells when administered simultaneously. No such inhibition was seen when the inactive enantiomer, S-SKF 38393, was substituted for the racemic form of SKF 38393 in this protocol. These observations in 6-hydroxydopamine lesioned rats support other recent findings indicating that the two dopamine receptor subtypes can interact in a synergistic way to affect basal ganglia output.     

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 D2-like receptor agonists induce penile erection in male rats: differential role of D2, D3 and D4 receptors in the paraventricular nucleus of the hypothalamus

Pramipexole, a dopamine D3/D2 receptor agonist, induces penile erection when administered subcutaneously (s.c.) or into the paraventricular nucleus of the hypothalamus of male rats, like apomorphine, a mixed D1/D2 receptor agonist, and PD 168,077, a D4 receptor agonist. A U-inverted dose-response curve was found with pramipexole and apomorphine, but not with PD 168,077 (0.025-0.5 mg/kg s.c.). Pramipexole effect was abolished by L-741,626, a D2 receptor antagonist (2.5 and 5 mg/kg s.c.) and raclopride, a D2/D3 receptor antagonist (0.025 and 0.1 mg/kg s.c.), but not by SB277011A (2.5 and 10 mg/kg s.c.) or FAUC 365 (1 and 2 mg/kg s.c.), two D3 receptor antagonists, or L-745,870 (1 and 5 mg/kg i.p.), a D4 receptor antagonist. Similar results were found with apomorphine (0.08 mg/kg s.c.), although its effect was also partially reduced by L-745,870. In contrast, PD 168,077 effect was abolished by L-745,870, but not L-741,626, SB277011A, FAUC 365 or raclopride. Similar results were found when dopamine agonists (5-200 ng/rat) and antagonists (1-5 μg/rat) were injected into the paraventricular nucleus. However, no U-inverted dose-response curve was found with any of the three dopamine agonists injected into this nucleus. As pramipexole- and apomorphine-induced penile erection was reduced mainly by D2, but not D3 or D4 antagonists, D2 receptors are those that mediate the pro-erectile effect of these dopamine agonists. Although the selective stimulation of paraventricular D4 receptors induces penile erection, D4 receptors seem to play only a modest role in the pro-erectile effect of the above dopamine agonists.     

D(3) dopamine receptors are down-regulated in amphetamine sensitized rats and their putative antagonists modulate the locomotor sensitization to amphetamine

D(3) dopamine receptor agonists inhibit locomotor activity in rodents and modulate the reinforcing effect of psychostimulants; however, their functional role during behavioral sensitization remains unclear. In the present study, we intend to investigate if D(3) dopamine receptors alter during the amphetamine sensitization and test if manipulation of D(3) receptors would affect the development of locomotor sensitization to amphetamine. We have found that D(3) dopamine receptors are down-regulated in the limbic forebrain in chronic amphetamine-treated (5 mg/kg x 7 days) animals. The levels of both D(3) receptor protein (B(max) value) and mRNA decreased significantly in the behaviorally sensitized rats compared to the saline-treated controls. When animals were co-administered a putative D(3) receptor antagonist (U99194A or GR103691; 20 microg x 7 days; intracerebroventricle) and amphetamine (5 mg/kg x 7 days, i.p.), the locomotor sensitization to amphetamine was significantly inhibited. However, when the putative D(3) receptor antagonist U99194A was administered during the amphetamine withdrawal period at day 10, it did not affect the development of locomotor sensitization. Furthermore, pretreatment with the preferential D(3) agonist 7-hydroxydipropylaminotetralin partially blocked the inhibitory effect of U99194A on locomotor sensitization. These data prove the participation of D(3) dopamine receptors in the development of amphetamine sensitization and, in addition, suggest a potential application for D(3) antagonists in the prevention of amphetamine addiction.     

Dopamine D3 receptor-preferring agonists increase dendrite arborization of mesencephalic dopaminergic neurons via extracellular signal-regulated kinase phosphorylation

Clinical improvements in Parkinson's disease produced by dopamine D3 receptor-preferring agonists have been related to their neuroprotective actions and, more recently, to their neuroregenerative properties. However, it is unclear whether dopamine agonists produce their neurotrophic effects by acting directly on receptors expressed by the mesencephalic dopaminergic neurons or indirectly on receptors expressed by astrocytes, via release of neurotrophic factors. In this study, we investigated the effects of the dopamine D3 receptor-preferring agonists quinpirole and 7-hydroxy-N,N-di-propyl-2-aminotetralin (7-OH-DPAT), as well as of the indirect agonist amphetamine, on dopaminergic neurons identified by tyrosine hydroxylase immunoreactivity (TH-IR). Experiments were performed on neuronal-enriched primary cultures containing less than 0.5% of astrocytes prepared from the mouse embryo mesencephalon. After 3 days of incubation, both quinpirole (1-10 microm) and 7-OH-DPAT (5-500 nm) dose-dependently increased the maximal dendrite length (P < 0.001), number of primary dendrites (P < 0.01) and [3H]dopamine uptake (P < 0.01) of TH-IR-positive mesencephalic neurons. Similar effects were observed with 10 microm amphetamine. All neurotrophic effects were blocked by the unselective D2/D3 receptor antagonist sulpiride (5 microm) and by the selective D3 receptor antagonist SB-277011-A at a low dose (50 nm). Quinpirole and 7-OH-DPAT also increased the phosphorylation of extracellular signal-regulated kinase (ERK) within minutes, an effect blocked by pretreatment with SB-277011-A. Inhibition of the D2/D3 receptor signalling pathway to ERK was obtained with PD98059, GF109203 or LY294002, resulting in blockade of neurotrophic effects. These data suggest that dopamine agonists increase dendritic arborizations of mesencephalic dopaminergic neurons via a direct effect on D2/D3 receptors, preferentially involving D3 receptor-dependent neurotransmission.     

Repeated D1 dopamine receptor agonist administration prevents the development of both D1 and D2 striatal receptor supersensitivity following denervation.

Following 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal dopamine (DA) pathway, rat caudate-putamen (CPu) neurons are supersensitive to the inhibitory effects of both D1 and D2 dopamine (DA) receptor selective agonists. In addition, both the necessity of D1 receptor stimulation for D2 agonist-induced inhibition and the synergistic inhibitory effects of D1 and D2 agonists are abolished by denervation. The present study attempted to determine the relative roles of D1 and D2 DA receptors in the development of denervation supersensitivity to DA agonists and the "uncoupling" of functional interactions between the receptors following 6-OHDA lesions of the nigrostriatal DA pathway. Beginning on the day after an intraventricular 6-OHDA (or vehicle) injection, groups of rats received daily injections of either the selective D1 receptor agonist SKF 38393 (8.0 mg/kg, s.c.), the D2 agonist quinpirole (0.5 mg/kg, s.c.), or saline for 7 days. On the day following the last agonist injection, rats were anesthetized and prepared for extracellular single cell recording with iontophoretic drug administration. Daily administration of quinpirole selectively prevented the development of D2 receptor supersensitivity, whereas daily administration of SKF 38393 prevented the development of both D1 and D2 receptor supersensitivity. In addition, D1, but not D2, agonist treatment prevented the loss of synergistic inhibitory responses typically produced by 6-OHDA lesions. Behavioral observations revealed similar effects; daily injections of SKF 38393, but not quinpirole, prevented contralateral rotational responses to the mixed D1/D2 agonist apomorphine (1.0 mg/kg, s.c.) in rats with unilateral 6-OHDA lesions of the nigrostriatal pathway. After a 4-week withdrawal from repeated D1 agonist treatment, both supersensitive inhibitory responses of CPu neurons and contralateral rotations to apomorphine were evident, indicating that the preventative effects on DA receptor supersensitivity were not permanent. These findings indicate that continued agonist occupation of striatal D1 DA receptors following DA denervation not only prevents the development of D1 DA receptor supersensitivity but also exerts a similar regulation of D2 receptor sensitivity.     

Time dependence and role of N-methyl- -aspartate glutamate receptors in the priming of D2-mediated rotational behavior and striatal Fos expression in 6-hydroxydopamine lesioned rats

Administration of dopamine agonists to 6-hydroxydopamine (6-OHDA) lesioned rats enhances the rotational response to subsequent administration of dopamine agonist, an effect called ‘priming'. Previously, we have shown that 6-OHDA rats primed with three injections of the D1/D2 dopamine agonist apomorphine (0.5 mg/kg) permitted a challenge with an otherwise inactive dose of the D2 agonist quinpirole (0.25 mg/kg) to elicit robust rotational behavior and to induce Fos expression in striatoentopeduncular neurons. In this study, the time-course and role of N-methyl- -aspartate (NMDA) glutamate receptors on apomorphine-priming of these D2 responses were investigated. The enhanced rotational behavior and striatal Fos expression observed following challenge with quinpirole (0.25 mg/kg) peaked 1 day following the third apomorphine priming injection and persisted, in reduced form, for at least 4 months. Pretreatment with the NMDA antagonists MK-801 or 3-[(+)-2-carboxypiperazin-4-yl]-propyl-1-phosphonate (CPP) dose-dependently attenuated apomorphine-priming of quinpirole-mediated rotational behavior and striatal Fos induction compared to 6-OHDA rats primed with apomorphine alone. Taken together, these data suggest that priming of these D2-mediated responses in 6-OHDA rats develops rapidly, persists for several months, and is dependent on concomitant NMDA receptor stimulation. Since this priming effect resembles response fluctuations observed in patients with Parkinson's disease receiving long-term -dihydroxyphenylalanine therapy, the results of the present study suggest that interventions that prevent the development of this enhanced response, such as NMDA antagonists, could prove useful in reducing the incidence these response fluctuations.     

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.     

D1 dopamine receptor stimulation enables the postsynaptic, but not autoreceptor, effects of D2 dopamine agonists in nigrostriatal and mesoaccumbens dopamine systems

Possible functional interactions between D1 and D2 dopamine (DA) receptors were examined using extracellular single-cell recording with microiontophoretic application of selective D1 and D2 receptor agonists both postsynaptically, in the rat nucleus accumbens (NAc) and caudate-putamen (CPu), and presynaptically, at impulse-regulating somatodendritic DA autoreceptors in the ventral tegmental area (A10) and substantia nigra pars compacta (A9). In addition, synthesis-modulating nerve terminal DA autoreceptors were studied in both the CPu and NAc using the gamma-butyrolactone (GBL) neurochemical model of isolated nerve terminal autoreceptor function in vivo. In both the NAc and CPu, the inhibition of neurons produced by iontophoresis of the D2 receptor agonists quinpirole or RU-24213 was attenuated by acute DA depletion via the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (AMPT). However, during iontophoresis of the selective D1 DA receptor agonist SKF 38393, the inhibitory effects of the D2 agonists were again evident, suggesting that the attenuation of D2 agonist-induced inhibition was due to decreased D1 receptor activation. In contrast, the inhibitory effects produced by the non-selective D1/D2 agonist apomorphine or by SKF 38393 were unaffected by AMPT pretreatment. Thus, D1 receptor activation appears necessary for D2 receptor-mediated inhibition of NAc and CPu neurons, whereas D2 receptor activation is not required for the inhibition produced by D1 receptor stimulation. In contrast to postsynaptic D2 receptors, the ability of DA agonists to stimulate D2 DA autoreceptors was not altered by manipulations of D1 receptor occupation. Enhancing D1 receptor stimulation with SKF 38393 or reducing D1 receptor occupation with either the selective D1 receptor antagonist SCH 23390 or AMPT failed to alter the rate-inhibitory effect of i.v. quinpirole on A9 or A10 DA neurons. Similarly, iontophoresis of SKF 38393 failed to alter the inhibitory effects of iontophoretic quinpirole. SKF 38393 also failed to affect the inhibition of GBL-induced increases in DOPA accumulation (tyrosine hydroxylase activity) produced by quinpirole in either the NAc or CPu. Furthermore, reversal of GBL-induced increases in DOPA accumulation by apomorphine or quinpirole was unaffected by pretreatment with SCH 23390. Therefore, D1 receptor occupation appears to be necessary for the expression of the functional effects of postsynaptic D2 receptor stimulation but not presynaptic D2 DA autoreceptor stimulation.     

Functional Fast Scan Cyclic Voltammetry Assay to Characterize Dopamine D2 and D3 Autoreceptors in the Mouse Striatum

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Alterations in D1/D2 synergism may account for enhanced stereotypy and reduced climbing in mice lacking dopamine D2L receptor

Concurrent activation of dopamine D1 and D2 receptors (D1 and D2) is required for the expression of certain dopamine (DA)-mediated responses, such as climbing and stereotyped behaviors. Such interactions between D1 and D2 (i.e. D1/D2 synergism) represent an important aspect of dopaminergic function and plasticity. The D2 receptor exists in two isoforms: D2L and D2S. We have generated mice that selectively lack D2L (D2L-/-). Here we showed that treatment with the indirect DA agonist amphetamine, the direct DA agonist apomorphine, or combination of D1 and D2 agonists elicited intense climbing in wild type mice (which express predominantly D2L in the striatum), but this behavior was absent or reduced in D2L-/- mice. On the other hand, apomorphine, the D2 agonist quinpirole, or combination of quinpirole and the D1 agonist SKF 81297 induced more stereotyped behavior such as biting or head movements in D2L-/- mice (which express only D2S) than in wild type mice. The D1 receptor functioned normally in D2L-/- mice. Taken together, these results suggest that D2L and D1 interactions may play a greater role in DA agonist-induced climbing, whereas D2S and D1 interactions may have a larger impact on DA agonist-induced stereotypy (and possibly psychosis). DA agonists, which are clinically used to treat Parkinson's disease and attention-deficit hyperactivity disorder (ADHD), are known to induce psychotic side effects. Thus, our findings may provide novel insights for designing anti-parkinsonian, anti-ADHD and antipsychotic drugs with greater therapeutic efficacy and fewer side effects.     

Dopamine D3 receptor ligands show place conditioning effect but do not influence cocaine-induced place preference

The importance of dopamine D3 receptors in reward related processes, especially in cocaine addiction, has been investigated extensively. However, in the reported studies a combination of different experimental conditions and different ligands have been used which renders the interpretation and comparison of the diverse results extremely difficult. Here, we report one comparative study investigating a wide range of dopamine D3 receptor ligands in one model of cocaine abuse: the place conditioning paradigm in rats. Of the antagonists tested, the moderately D3 selective nafadotride and the more selective SB-277011 did not produce any place conditioning effect while U-99194A caused place-preference. The most D3 selective agonist PD-128907, the less selective 7-OH-DPAT and the moderately selective partial agonist BP-897 all caused significant place aversion. None of the compounds influenced the cocaine-induced place preference. Results suggest the D3-preferring agonists could affect the reward mechanisms of the brain, however, modulation of D3 receptor function does not appear to be a significant mechanism for modifying the place conditioning effect of cocaine.     

Neuroprotective effects mediated by dopamine receptor agonists against malonate-induced lesion in the rat striatum

Abstract. In rats, intrastriatal injection of malonate, a reversible inhibitor of the mitochondrial enzyme succinate dehydrogenase, induces a lesion similar to that observed following focal ischemia or in Huntingtons disease. In this study we used the malonate model to explore the neuroprotective potential of dopamine agonists. Rats were injected intraperitoneally with increasing concentrations of D₁, D₂, or mixed D₁/D₂ dopamine agonists prior to intrastriatal injection of malonate. Administration of increasing doses of the D₂-specific agonist quinpirole resulted in increased protection against malonate toxicity. Conversely, the D₁-specific agonist SKF-38393, as well as the mixed D₁/D₂ agonist apomorphine, conferred higher neuroprotection at lower than at higher drug concentrations. Our data suggest that malonate- induced striatal toxicity can be attenuated by systemic administration of dopamine agonists, with D₁ and D₂ agonists showing different profiles of efficacy.