Analysis of dopamine receptor antagonism upon feeding elicited by mu and delta opioid agonists in the shell region of the nucleus accumbens

The nucleus accumbens (NAcc) has been implicated as an important reward site for the mediation of unconditioned reinforcers such as food. Although both mu-selective and delta-selective opioid agonists in the NAcc induce spontaneous and palatable feeding, these effects are mediated by multiple opioid receptor subtypes within the nucleus. A role for dopaminergic mediation of feeding in the NAcc is based upon selective antagonist-induced suppression of feeding induced by systemic amphetamine. The present study investigated whether feeding elicited by infusion of either mu ([D-Ala(2), NMe-Phe(4), Gly-ol(5)]-enkephalin) or delta(2) ([D-Ala(2), Glu(4)]-deltorphin) opioid receptor subtype agonists in the shell region of the NAcc would be modified by intra-accumbens pretreatment with equimolar (12-100 nmol) doses of either D(1)-selective (SCH23390) or D(2)-selective (raclopride) antagonists. Both opioid agonists displayed comparable magnitudes and durations of feeding responses in the NAcc. SCH23390 significantly and dose-dependently reduced mu agonist-induced feeding in the NAcc with significant reductions noted following the two higher, but not two lower doses. In contrast, raclopride pretreatment produced inconsistent effects upon mu agonist-induced feeding with limited actions across doses and test times. Further, neither SCH23390 nor raclopride pretreatment in the NAcc affected feeding elicited by the delta(2) opioid agonist. These data indicate that the role of dopamine receptors in mediating opioid-induced feeding within the shell region of the NAcc is both dependent upon the dopamine receptor subtype that was blocked (D(1) vs. D(2)) as well as the opioid receptor subtype which was being stimulated mu vs. delta(2)).     

Antagonism of the discriminative stimulus effects of cocaine at two training doses by dopamine D2-like receptor antagonists

RATIONALE: The relative contributions of different dopamine receptor subtypes to the discriminative stimulus effects of cocaine may be influenced by the training dose of cocaine. Substitution tests with dopamine receptor agonists have suggested that the role of dopamine D2-like receptors is diminished relative to that of D1-like receptors at a training dose of 3 mg/kg cocaine compared with a training dose of 10 mg/kg. OBJECTIVES: To test whether dopamine D2-like receptor antagonists were differentially effective at attenuating cocaine's discriminative stimulus effects at different training doses, and to test for the first time an antagonist that is selective for the dopamine D2 receptor within the D2-like receptor subfamily. METHODS: Rats were trained to press one lever after receiving cocaine and another after receiving saline (maintaining >95% drug-appropriate responding). Three dopamine D2-like receptor antagonists (haloperidol, raclopride and L-741,626) were tested in rats trained at 3 mg/kg or 10 mg/kg cocaine. At the lower training dose, the D1-like receptor antagonist SCH 39166 was also tested. RESULTS: The antagonists were not differentially effective between training groups: they all produced parallel, rightward shifts in cocaine's dose-effect function, indicating surmountable antagonism. CONCLUSIONS: The results demonstrate that D2-like receptor antagonists with different affinities for the various D2-like receptors can antagonise the discriminative stimulus effects of cocaine at two training doses. Importantly, antagonism by L-741,626 implies that stimulation of D2 receptors alone (not D3 or D4 receptors) is sufficient to mediate cocaine's discriminative stimulus effects. Finally, the claim that D1-like receptors are preferentially involved at low training doses of cocaine is only consistent with the current findings if indirect stimulation of D2 receptors by low doses of cocaine remains necessary for the expression of the D1-like receptor-mediated effect.     

Effects of dopamine agonists and antagonists on cocaine-induced operant responding for a cocaine-associated stimulus

The present study examined the effects of receptor subtype-selective dopamine agonists and antagonists on (i) cocaine-induced responding for a cocaine-associated stimulus and (ii) on responding for food and cocaine reinforcement. Rats implanted with intravenous catheters were trained to lever-press for food or cocaine reinforcers on an FR5-FR5 multiple schedule, which was preceded by a 5-min component during which only stimuli previously associated with the primary reinforcers were available response-contingently. (i) Non-contingent delivery of cocaine at the beginning of the stimulus component significantly increased responding for the cocaine-associated stimulus, compared to responding for the food-associated cue. Changes in the dose of cocaine administered non-contingently before the stimulus component resulted in an inverted U-shaped dose-effect curve in responding for the cocaine-associated cue. In subsequent experiments, pretreatment with the dopamine D₂ receptor agonist bromocriptine (4.0–16.0 mg/kg IP) attenuated the cocaine-induced increase in responding for the cocaine-associated cue. In contrast, pretreatment with low doses of SDZ 208–911, a dopamine D₂ partial agonist (0.025–0.1 mg/kg SC), further potentiated the cocaine-induced response. Pretreatment with low and medium doses of the dopamine D₁ and D₂ receptor subtype-selective antagonists SCH 23390 (D₁; 5–10 µg/kg SC) and raclopride (D₂; 100–200 µg/kg SC) blocked responding for cocaine-associated cues, with SCH 23390 acting more selectively than raclopride. At higher doses (SCH 23390: 20 µg/kg SC; raclopride: 400 µg/kg SC), both drugs produced nonselective effects by inhibiting responses for the food-associated cue. (ii) Varying the dose of cocaine self-administered during the multiple schedule resulted in an inverted U-shaped dose-effect curve during the cocaine components, while the number of food pellets earned remained unchanged. Pretreatment with bromocriptine selectively reduced the number of cocaine infusions obtained. The compensatory increases in responding for cocaine typically associated with SCH 23390, raclopride or SDZ 208–911 pretreatment were also observed under the present schedule conditions, although the effect did not reach statistical significance in the case of SCH 23390 and raclopride, possibly due to methodological constraints. The results indicate that the present rat model of cocaine-seeking behavior is sensitive to pharmacological manipulations and may yield important information regarding the neurobiological mechanisms underlying conditioned and unconditioned reinforcing aspects of cocaine addiction.     

Chronic treatment with the D1 receptor antagonist,SCH 23390, and the D2 receptor antagonist,raclopride, in cebus monkeys withdrawn from previous haloperidol treatment

The effects of chronic treatment with dopamine (DA) D₁ and D₂ receptor antagonists were evaluated in eightcebus apella monkeys with mild oral dyskinesia after previous haloperidol treatment. SCH 23390 (D₁ antagonist) was given daily to investigate the direct behavioural effect during long-term treatment and the subsequent supersensitivity to DA agonists. Raclopride (D₂ antagonist) was investigated for comparison. All drugs were given subcutaneously. SCH 23390 and raclopride induced dystonic syndromes, catalepsy, sedation and reduced locomotor activity. The monkeys developed marked tolerance to the dystonic effect of SCH 23390, while they showed increased sensibility to the dystonic effect of raclopride. Baseline oral dyskinesia (24 h after injection) remained unchanged during D₁ antagonist treatment, while it increased during D₂ antagonist treatment. SCH 23390 induced supersensitivity to the oral dyskinesia- and grooming-inducing effects of SKF 81297 (D₁ agonist) after 9 weeks, while the subsequent treatment with raclopride induced supersensitivity to the reactivity- and stereotypy-inducing effects of quinpirole (D₂ receptor agonist) after 3 weeks. Because of the possibility of a carry-over effect (SKF 81297-induced oral hyperkinesia and grooming), other changes in raclopride-induced behaviours cannot be ruled out. The development of tolerance to the dystonic effect of SCH 23390 and the unchanged baseline oral dyskinesia during SCH 23390 treatment indicate an advantageous profile of side effects of DA D₁ receptor blockade.     

Dopamine D2/D3 receptor agonist quinpirole impairs spatial reversal learning in rats: investigation of D3 receptor involvement in persistent behavior

Rationale  Dopamine is strongly implicated in the ability to shift behavior in response to changing stimulus-reward contingencies. Objectives  We investigated the effects of systemic administration of the D2/D3 receptor agonist quinpirole (0.1, 0.3 mg/kg), the D2/D3 receptor antagonist raclopride (0.1, 0.3 mg/kg), the selective D3 antagonist nafadotride (0.3, 1.0 mg/kg), and combined administration of raclopride (0.1 mg/kg) or nafadotride (1.0 mg/kg) with quinpirole (0.3 mg/kg) on spatial discrimination and reversal learning. Materials and methods  Rats were trained on an instrumental two-lever spatial discrimination and reversal learning task. Both levers were presented, only one of which was reinforced. The rat was required to respond on the reinforced lever under a fixed ratio 3 schedule of reinforcement. Following attainment of criterion, a reversal was introduced. Results  None of the drugs altered performance during retention of the previously reinforced contingencies. Quinpirole (0.3 mg/kg) significantly impaired reversal learning by increasing both trials and incorrect responses to criterion in reversal phase, a pattern of behavior manifested as increased perseverative responding on the previously reinforced lever. In contrast, neither raclopride nor nafadotride when administered alone altered reversal performance. However, raclopride blocked the quinpirole-induced reversal deficit, whereas combined administration of nafadotride and quinpirole affected not only performance during the reversal but also the retention phase. The reversal impairment resulting from co-administration of nafadotride and quinpirole was associated with both perseverative and learning errors. Conclusions  Our data indicate distinct roles for D2 and D3 receptors in the capacity to modify behavior flexibly in the face of environmental change.     

11C-Raclopride的快速制备及生物学评价

目的 建立快速制备11C-雷氯必利(Raclopride)的方法,并对其进行生物学评价.方法 采用固相萃取法制备11C-Raclopride,即用11C-三氟甲基磺酰基甲烷(CH3-Triflate)与去甲基(Nor)-Raclopride反应得粗产品,用水稀释粗产品,将其转移到Sep-Pak C18反相柱,冲洗反相柱,再用乙醇淋洗得11C-Raclopride.研究正常SD大鼠体内11C-Raclopride分布,并行阻断剂(螺环哌啶酮)阻断后显像.制备食蟹猴帕金森病(PD)模型,行PET显像.结果 11C-Raclopride放化纯＞95%,比活度＞8 GBq/μmol,合成效率为60%,从11CO2到11C-Raclopride的合成时间为16 min.大鼠注射11C-Raclo pride 30 min后纹状体/小脑、纹状体/额叶皮质放射性摄取比值分别为4.67和6.20.Raclopride和螺环哌啶酮明显阻断了纹状体摄取11C-Raclopride,而Nor-Raclopride则不明显.PD模型猴11C-Raclo-pride PET显像示实验侧放射性高于对侧,出现D2受体上调.结论 固相萃取法制备11C-Raclopride速度快,放化纯高.动物显像表明11C-Raclopride能满足临床需求.     

Differential labeling of dopamine and sigma sites by [H]nemonapride and [H]raclopride in postmortem human brains

The difference between the binding of [³H]nemonapride and [³H]raclopride has been used to quantify dopamine D₄ receptors in postmortem schizophrenic brain studies. Recent work, however, has suggested that at least part of the differential between [³H]nemonapride and [³H]raclopride binding may represent σ rather than D₄ receptor sites. We applied the nemonapride-raclopride subtraction method to postmortem, non-schizophrenic human striatum to examine the variation in dopaminergic receptor binding labeled by these ligands. Variation in σ receptor binding labeled by [³H]nemonapride was studied in frontal cortex, striatum and cerebellum. Specific binding was defined by sulpiride (dopamine receptor ligand), PPAP (σ receptor ligand) and haloperidol (mixed dopaminergic/σ agent), respectively. Haloperidol defined a combination of sites, which were approximately the sum of the dopaminergic and σ components defined by sulpiride and PPAP, respectively. Significant inter-individual variation in the amount of specific binding for dopaminergic and σ receptor sites was observed. However, no significant nor consistent observation of striatal dopamine D₄ receptors or D₄-like binding sites was observed in the striatum even though two independent sets of tissues, with different dissections were used. The inconsistencies in some previous postmortem studies appear to be at least partially explained by the inclusion of both σ and dopaminergic components in [³H]nemonapride binding and the inherent high inter-individual variability of the different components.     

Decreases in Dopamine Receptors but not in Dopamine Transporters in Alcoholics

It has been hypothesized that ethanol's actions on the dopamine (DA) system may participate in addiction. The purpose of this study was to evaluate the DA system in the brain of alcoholics. We evaluated 10 alcoholics and 17 nonalcoholics using positron emission tomography and [¹¹C]raclopride to measure DA D2 receptors. In addition, in 5 of the alcoholics and 16 of the nonalcoholics, we also measured DA transporters with [¹¹C]d-threo methylphenidate. The ratio of the distribution volumes in striatum to that In cerebellum, which corresponds to B_max/K_d+ 1, was used as model parameter of DA D2 receptor and transporter availability. Dopamine D2 receptor availability (B_max/K_d) was significantly lower in alcoholics (2.1 ± 0.5) than in nonalcoholics (2.7 ± 0.6) (p < 0.05) and was not correlated with days since last alcohol use. Alcoholics showed DA transporter values similar to those in nonalcoholics. The ratio of DA D2 receptor to transporter availability was significantly higher in nonalcoholics (1.4 ± 0.1) than in alcoholics (1.1 ± 0.1) (p < 0.005). Alcoholics showed significant reductions in D2 receptors (postsynaptic marker) but not in DA transporter availability (presynaptic marker) when compared with nonalcoholics. Because D2 receptors in striatum are mainly localized in γ-aminobutyric acid (GABA) cells these results provide evidence of GABAergic involvement in the dopaminergic abnormalities seen in alcoholics.     

Effects of microinjection of the D2 dopamine antagonist raclopride into the ventral tegmental area on ethanol and sucrose self-administration

From previous microinjection studies, a reciprocal feedback between the nucleus accumbens and the ventral tegmental area (VTA) has been implicated in the reinforcing stimulus actions of ethanol and sucrose. In these studies, the effects of self administration of ethanol or sucrose solutions on maintained responding were similar when a dopamine antagonist was injected in the nucleus accumbens or a dopamine agonist was injected into the VTA. Our study was performed to determine if the effects on responding that had been observed when a dopamine agonist was injected into the nucleus accumbens would occur after an injection of a dopamine antagonist into the VTA. Male, Long-Evans rats were initially trained to lever press using either 10% ethanol or 75% sucrose solutions as the reinforcers. Bilateral guide cannulae were implanted to allow microinjection into the VTA of differing doses of the dopamine D2 antagonist, raclopride. Only at the highest dose tested (10 microg) was any effect observed on responding maintained by either reinforcer. The effect was minimal and different from that observed after the microinjection of a dopamine agonist into the nucleus accumbens. This suggests that either the actions of the nucleus accumbens agonist manipulation involved other processes or that the level of enhanced dopamine release in the nucleus accumbens from the VTA antagonist injection was not sufficient to mimic the effect of the nucleus accumbens agonist injections.     

轻型帕金森病D2受体的PET显像

目的利用[11C]-雷氯必利(raclopride,RAC)-正电子发射体层摄影术(PET)对早期帕金森病(PD)患者的D2受体进行功能显像,了解D2受体在PD早期的变化情况.方法PD组6例,男4例,女2例,平均年龄(66.60±7.19)岁,病程为Hoehn-Yahr分级1～2级.对照组4名,男2名,女2名,平均年龄(70.50±0.58)岁.PD组及对照组均进行RAC-PET检查.结果[11C]-RAC在尾状核和壳核显像明显,在皮质、小脑、丘脑、脑干等部位无明显显像,符合D2受体的分布特点;早期未经治疗的PD患者,在患肢对侧尾状核头、壳核前部和壳核后部,[11C]-RAC的结合指数分别为2.94±0.33、3.34±0.27和3.27±0.37,明显高于对照组的2.54±0.49、2.89±0.48和2.72±0.19,差异有统计学意义(P值分别为0.046,0.013和0.022);患肢同侧尾状核头、壳核前部和壳核后部[11C]-RAC的结合指数分别为2.78±0.31、3.22±0.38和3.10±0.29,也高于对照组的2.63±0.19、2.93±0.21和2.76±0.27,但未达到统计学差异;患肢同侧尾状核头、壳核前部和壳核后部[11C]-RAC的结合指数分别为2.94±0.33、3.34±0.27和3.27±0.37,高于对侧相应部位的2.78±0.31、3.22±0.38和3.10±0.29,但未达到统计学差异.在对照组,双侧基底结区相应部位[11C]-RAC结合指数为右侧2.54±0.49、2.89±0.48和2.72±0.19,左侧为2.63±0.19、2.93±0.21和2.76±0.27,双侧无差异;但在纹状体内的分布有区域性差异,即壳核前部[11C]-RAC结合指数为2.85±0.15,壳核后部[11C]-RAC结合指数为2.80±0.12,均高于尾状核的2.58±0.07,差异有统计学意义(P＜0.05).结论[11C]-RAC是D2受体的特异性示踪剂,可用于活体D2受体的评价;早期未经治疗的PD患者,D2受体有上调效应.