Low dopamine striatal D2 receptors are associated with prefrontal metabolism in obese subjects: possible contributing factors

Dopamine's role in inhibitory control is well recognized and its disruption may contribute to behavioral disorders of discontrol such as obesity. However, the mechanism by which impaired dopamine neurotransmission interferes with inhibitory control is poorly understood. We had previously documented a reduction in dopamine D2 receptors in morbidly obese subjects. To assess if the reductions in dopamine D2 receptors were associated with activity in prefrontal brain regions implicated in inhibitory control we assessed the relationship between dopamine D2 receptor availability in striatum with brain glucose metabolism (marker of brain function) in ten morbidly obese subjects (BMI > 40 kg/m²) and compared it to that in twelve non-obese controls. PET was used with [¹¹C]raclopride to assess D2 receptors and with [¹⁸F]FDG to assess regional brain glucose metabolism. In obese subjects striatal D2 receptor availability was lower than controls and was positively correlated with metabolism in dorsolateral prefrontal, medial orbitofrontal, anterior cingulate gyrus and somatosensory cortices. In controls correlations with prefrontal metabolism were not significant but comparisons with those in obese subjects were not significant, which does not permit to ascribe the associations as unique to obesity. The associations between striatal D2 receptors and prefrontal metabolism in obese subjects suggest that decreases in striatal D2 receptors could contribute to overeating via their modulation of striatal prefrontal pathways, which participate in inhibitory control and salience attribution. The association between striatal D2 receptors and metabolism in somatosensory cortices (regions that process palatability) could underlie one of the mechanisms through which dopamine regulates the reinforcing properties of food.     

Brain dopamine receptors. Interactions between D1 and D2 receptors, and dopamine mediated behaviour]

The review begins by a brief presentation of the present state of knowledge on the multiplicity of brain dopamine receptors. The molecular basis of their distinction is reported, as well as the most specific ligands for each receptors type: D1, D2 (their isoforms A and B), D3, the putative D4 and autoreceptors. Then the review focuses on the respective location of D1 receptors (mainly linked positively to an adenylate cyclase) and of so-called D2 (lacking precision for distinguishing D2, D3 or D4), at the cellular level. The theoretical aspects of the functional interactions between these D1 and D2 receptors suggest four possibilities: Antagonism, indifference, additive synergy and potentiation. The effects resulting from the simultaneous administration of either D1 and D2 dopamine agonists or D1 and D2 dopamine antagonists were considered on various behaviours or functions. The four predicted types of interactions were found: D1/D2 antagonism on thermoregulation, D1/D2 indifference on nociception, additive synergy on the traction test, on anorexia or on the latency of the acoustic startle response, and finally potentiation on stereotypies or climbing behaviour. These data are completed by many other reported in an abundant literature about these interactions, which appear as modalities of regulation: their alterations might take part in several pathological states.     

Striatal dopamine D1 and D2 receptors in burning mouth syndrome

Animal studies have indicated that the nigrostriatal dopaminergic system is involved in central pain modulation. In a recent positron emission tomography (PET) study, we demonstrated presynaptic dysfunction of the nigrostriatal dopaminergic pathway in burning mouth syndrome, which is a chronic pain state. The objective of the present study was to examine striatal dopamine D1 and D2 receptors in these patients. We used 11C-NNC 756 and 11C-raclopride to study D1 and D2 receptor binding in a PET study in ten burning mouth patients and 11 healthy controls. Patients underwent a structured psychiatric evaluation and an electrophysiological test for the excitability of the blink reflex. The striatal uptake of 11C-NNC 756 did not differ between patients and controls. In a voxel-level analysis, the uptake of 11C-raclopride was statistically significantly higher in the left putamen in burning mouth patients (corrected P-value 0.038 at cluster-level). In the region of interest analysis, the D1/D2 ratio was 7.7% lower in the right putamen (0.64+/-0.04 vs. 0.69+/-0.04, P=0.01) and 6.4 % lower in the left putamen (0.65+/-0.05 vs. 0.70+/-0.05, P=0.05) when compared to controls. Increased 11C-raclopride uptake and the subsequent decrease in the D1/D2 ratio may indicate a decline in endogenous dopamine levels in the putamen in burning mouth patients.     

Methylphenidate-induced increases in vesicular dopamine sequestration and dopamine release in the striatum: the role of muscarinic and dopamine D2 receptors

Methylphenidate (MPD) administration alters the subcellular distribution of vesicular monoamine transporter-2 (VMAT-2)-containing vesicles in rat striatum. This report reveals previously undescribed pharmacological features of MPD by elucidating its receptor-mediated effects on VMAT-2-containing vesicles that cofractionate with synaptosomal membranes after osmotic lysis (referred to herein as membrane-associated vesicles) and on striatal dopamine (DA) release. MPD administration increased DA transport into, and decreased the VMAT-2 immunoreactivity of, the membrane-associated vesicle subcellular fraction. These effects were mimicked by the D2 receptor agonist quinpirole and blocked by the D2 receptor antagonist eticlopride. Both MPD and quinpirole increased vesicular DA content. However, MPD increased, whereas quinpirole decreased, K(+)-stimulated DA release from striatal suspensions. Like MPD, the muscarinic receptor agonist, oxotremorine, increased K(+)-stimulated DA release. Both eticlopride and the muscarinic receptor antagonist scopolamine blocked MPD-induced increases in K(+)-stimulated DA release, whereas the N-methyl-d-aspartate receptor antagonist (-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) was without effect. This suggests that D2 receptors mediate both the MPD-induced redistribution of vesicles away from synaptosomal membranes and the MPD-induced up-regulation of vesicles remaining at the membrane. This results in a redistribution of DA within the striatum from the cytoplasm into vesicles, leading to increased DA release. However, D2 receptor activation alone is not sufficient to mediate the MPD-induced increases in striatal DA release because muscarinic receptor activation is also required. These novel findings provide insight into the mechanism of action of MPD, regulation of DA sequestration/release, and treatment of disorders affecting DA disposition, including attention-deficit hyperactivity disorder, substance abuse, and Parkinson's disease.     

Stimulation of D1 and D2 dopamine receptors produces additive anorectic effects

In food-deprived mice the D1 dopamine agonist SKF 38393 induced dose dependent anorexia (ED50 = 2.6 mg/kg). This effect was reversed by the D1 antagonist SCH 23390. In similar conditions, the D2 dopamine agonist RU 24926 also induced dose dependent anorexia (ED50 = 0.19 mg/kg). This effect was reversed by the D2 antagonist (+/-) sulpiride. The mixed D1/D2 agonist apomorphine also induced an anorectic effect (150 micrograms/kg sc) which was completely reversed by (+/-) sulpiride (25 mg/kg, ip) but unaffected by SCH 23390 (5-30 micrograms/kg). The dose response curve obtained by associating SKF 38393 (2.5 mg/kg) with increasing doses of RU 24926 was roughly parallel to that obtained with RU 24926 alone. This indicates that effects of two drugs were additive. Although both D1 and D2 receptors regulate food consumption, the anorectic effect of apomorphine appears to involve only D2 receptors.     

Dopamine D1 and D2 receptors influence dopamine transporter synthesis and degradation in the rat.

Neurotransmitter transporters play an important role in maintaining synaptic homeostasis and in the actions of many drugs. Utilizing a technique for measuring the kinetics (synthesis, degradation, and half-life) of the dopamine transporter (DAT) protein in the rat striatum and nucleus accumbens, we have investigated the effects of systemic administration of dopamine receptor agonists and antagonists upon DAT kinetics in these brain regions. In the striatum, the dopamine D1 receptor agonist SKF38393 and the dopamine D1 receptor antagonist SCH23390 were without effect. However, the dopamine D2 receptor agonists R-(-)-propylnorapomorphine hydrochloride (NPA) and quinpirole decreased the half-life of DAT. This effect was blocked by the dopamine D2 antagonist eticlopride, which, by itself, increased the half-life of DAT. In the nucleus accumbens, the agonist SKF38393 increased the DAT half-life, whereas the antagonist SCH23390 decreased the half-life. In contrast to the striatum, NPA and quinpirole increased the DAT half-life, which was blocked by eticlopride and by itself had no effect on DAT kinetics. Cocaine increased the half-life of DAT in both the striatum and the nucleus accumbens. The results of the present study suggest that, through dopamine receptors, dopamine indirectly influences DAT protein turnover in the striatum and in the nucleus accumbens, but in different ways.     

G protein coupling and ligand selectivity of the D2L and D3 dopamine receptors

The human dopamine D(2L) receptor couples promiscuously to multiple members of the Galpha(i/o) subfamily. Despite the high homology of the D(2L) and D(3) receptors, the G protein coupling specificity of the human D(3) receptor is less clearly characterized. The primary aim of this study, then, was the parallel characterization of the G protein coupling specificity of the D(2L) and D(3) receptors. By using both receptor-G protein fusion proteins and stable cell lines in which pertussis toxin-resistant mutants of individual Galpha(i)-family G proteins were expressed in an inducible fashion, we demonstrated highly selective coupling of the D(3) receptor to Galpha(o1). Furthermore, by using the fusion proteins to ensure identical stoichiometry of receptor to G protein for each pairing, a range of ligands displayed higher potency and, for partial agonists, higher efficacy at the D(3) receptor when coupled to Galpha(o1) compared with the D(2L) receptor. The second aim of this study was to investigate the molecular basis of the above differential G protein coupling specificity. The importance of a 12-amino acid sequence from the C-terminal end of the third intracellular loop of the D(2L) receptor in providing promiscuity in G protein coupling was demonstrated using a chimeric D(3)/D(2) receptor in which the equivalent region of the D(3) receptor was exchanged for this sequence. This chimera displayed D(3)-like affinity for [(3)H]spiperone and potency for agonists but gained D(2)-like ability to couple to each of Galpha(i1-3) as well as Galpha(o1).     

Antagonist‐D2S‐dopamine receptors interactions in intact Chinese recombinant ovary cells

D₂‐type dopamine receptors are major recognition sites for antipsychotic drugs. There are two splice variants: D_2S and D_2L with an additional 29 amino acid sequence in the third intracellular loop. Only little comparative information is hitherto available about their pharmacological properties and none of these studies dealt with intact cell systems. This prompted us to investigate the binding properties of [³H]‐raclopride, a hydrophilic benzamide, and [³H]‐spiperone, a highly hydrophobic butyrophenone, to intact CHO cells expressing recombinant human D_2L‐receptors. Presently, we have repeated and extended this experimental approach to the human D_2S‐receptors in the same cell system. Except for a slower dissociation of [³H]‐spiperone from D_2S, the binding properties of these and other antagonists were not significantly different for both isoforms (P > 0.05). The very slow dissociation of the atypical antipsychotic clozapine was surprising in light of its low affinity. Two experiments pointed out the existence of non‐competitive interactions between raclopride and spiperone for D_2S as well as D_2L (A. Packeu, J. P. De Backer & G. Vauquelin, in preparation). Alongside the different physicochemical properties of these ligands, this finding fits with a model wherein the hydrophilic raclopride approaches the D_2L‐receptor from the aqueous phase, while the hydrophobic spiperone approaches the receptor by lateral diffusion between the membrane lipids. These different modes of approach could imply the existence of topologically distinct ligand binding sites at D₂‐receptors.     

全脑缺血再灌注小鼠额叶和海马c-fos基因的表达

目的:探讨c-fos基因表达在全脑缺血再灌注后不同时间的变化规律。方法:实验动物全部采用由白求恩医科大学实验动物中心提供的雄性昆明小鼠,6～7周龄,体质量25～28g。①动物分组:第1批:40只小鼠随机分为假手术组5只,脑缺血再灌注组35只,根据再灌注不同时间提取标本,分别为术后1h,1d,3d,7d,2周,4周,6周,每个时间点5只。第2批:40只小鼠用于反转录-聚合酶链反应,分组同上。②模型制备及检测方法:制备全脑缺血再灌注损伤模型,假手术组不阻断颈总动脉亦不放血。采用卒中指数对各组小鼠神经病学症状进行评价。于小鼠双侧颈总动脉阻断再灌注后1h,1d,3d,7d,2周,4周,6周取小鼠额叶皮质、海马区脑组织采用免疫组织化学染色、反转录-聚合酶链反应技术,对c-fos基因表达变化进行检测。结果:80只小鼠均进入结果分析,无脱落。①免疫组化检测c-fos基因表达产物Fos蛋白结果:假手术组Fos蛋白有较弱表达,免疫组化染色假手术组未见Fos蛋白阳性神经元;再灌注1h在额叶皮质与海马区即可见Fos蛋白表达升高,与假手术组差异显著,再灌注1dFos蛋白表达达最高峰,并持续至2周(P<0.01),以后随时间延长逐渐下降,到6周达假手术组水平。②反转录聚合酶链反应检测c-fos表达结果:假手术组海马区有少量c-fosmRNA表达。再灌注1hc-fosmRNA转录水平显著升高,与假手术组差异有显著性意义(P<0.01),至5周时仍呈现较高转录水平(P<0.05),随后下降,至4周时达假手术组水平。结论:全脑缺血再灌注可诱导中枢神经系统c-fos基因的持续表达。     

D1 and D2 dopamine receptors independently regulate spontaneous blink rate in the vervet monkey.

Previous studies have revealed the involvement of a dopaminergic link in the regulation of spontaneous eye blink rate in primates. Based on the effect of dopamine D2 receptor-selective drugs and the anecdotal failure of the partial D1 agonist, SKF 38393, to alter blink rate in monkeys, it was assumed that D1 dopamine receptors did not control blink rate. The recent availability of dihydrexidine, a full D1 agonist, prompted us to reevaluate the role of D1 and D2 receptors in the regulation of blink rate. African green monkeys (n = 5) were used in all studies. Dihydrexidine produced a rapid and dose-dependent (up to 1 mg/kg, i.m.) increase in blink rate. The elevation in blink rate elicited by 0.3 mg/kg dihydrexidine was completely reversed by prior administration of a specific D1 antagonist, SCH 23390 (0.01 mg/kg, i.m.), but was unaffected by prior administration of a specific D2 antagonist, remoxipride (1 mg/kg, i.m.). Treatment with the specific D2 agonist, (+)-4-propyl-9-hydroxynaphthoxazine, led to a rapid and dose-dependent (up to 0.01 mg/kg, i.m.) increase in blink rate. The raised blink rate produced by (+)-4-propyl-9-hydroxynaphthoxazine (0.001 mg/kg) was abolished by pretreatment with remoxipride, but was not influenced by pretreatment with SCH 23390. These data indicate that spontaneous blink rate in the primate can be regulated by both D1 and D2 dopamine receptors. Furthermore, the receptor subtypes appear to affect blink rate in the same direction, yet function independently. Measurement of blink rate may provide a noninvasive method to assess the potency and selectivity of dopamine agonists and antagonists in primates.     

全脑缺血再灌注小鼠额叶和海马c-fos基因的表达

目的：探讨c-fos基因表达在全脑缺血再灌注后不同时间的变化规律。方法：实验动物全部采用由白求恩医科大学实验动物中心提供的雄性昆明小鼠，6～7周龄，体质量25～28g。①动物分组：第1批：40只小鼠随机分为假手术组5只，脑缺血再灌注组35只，根据再灌注不同时间提取标本，分别为术后1h，1d，3d，7d，2周，4周，6周，每个时间点5只。第2批：40只小鼠用于反转录-聚合酶链反应，分组同上。②模型制备及检测方法：制备全脑缺血再灌注损伤模型，假手术组不阻断颈总动脉亦不放血。采用卒中指数对各组小鼠神经病学症状进行评价。于小鼠双侧颈总动脉阻断再灌注后1h，1d，3d，7d，2周，4周，6周取小鼠额叶皮质、海马区脑组织采用免疫组织化学染色、反转录-聚合酶链反应技术，对c-fos基因表达变化进行检测。结果：80只小鼠均进入结果分析，无脱落。①免疫组化检测c-fos基因表达产物Fos蛋白结果：假手术组Fos蛋白有较弱表达，免疫组化染色假手术组未见Fos蛋白阳性神经元；再灌注1h在额叶皮质与海马区即可见Fos蛋白表达升高，与假手术组差异显著，再灌注1dFos蛋白表达达最高峰，并持续至2周（P〈0．01），以后随时间延长逐渐下降，到6周达假手术组水平。②反转录聚合酶链反应检测c-fos表达结果：假手术组海马区有少量c-fos mRNA表达。再灌注1hc-fos mRNA转录水平显著升高，与假手术组差异有显著性意义（P〈0．01），至5周时仍呈现较高转录水平（P〈0．05），随后下降，至4周时达假手术组水平。结论：全脑缺血再灌注可诱导中枢神经系统c-fos基因的持续表达。     

Differential regulation of dopamine D2 and D3 receptors by chronic drug treatments

Regulation of the expression of dopamine D2 and D3 receptors in the rat brain was examined using quantitative autoradiography after chronic (14 day) drug treatments designed to increase or decrease dopamine receptor stimulation. Reserpine treatment depleted endogenous dopamine by more than 90% and significantly increased the binding of [(125)I]NCQ 298 to D2 receptors in the nucleus accumbens, ventral pallidum, and substantia nigra. In contrast, this treatment significantly decreased the binding of [(125)I]7-OH-PIPAT to D3 receptors in each of these regions. Chronic stimulation of D2-like receptors with quinpirole (1 mg/kg/day) or 7-OH-DPAT (1 mg/kg/day) produced decreases in [(125)I]NCQ 298 binding in the nucleus accumbens, ventral pallidum, and substantia nigra as expected. As with depletion, chronic stimulation elicited an opposite response from D3 receptors with significant increases observed in the ventral pallidum and substantia nigra. D3 receptor expression in the nucleus accumbens was unchanged. Baclofen (30 mg/kg/day) or continuous administration of the psychomotor stimulant cocaine (20 mg/kg/day) produced no significant changes in D2 or D3 receptor binding in any region examined. Acute administration of the irreversible antagonist EEDQ (10 mg/kg) nearly eliminated D2 receptor binding in all regions, but inactivated D3 receptors only in the VP and SN, suggesting subtype-specific and region-specific differences in receptor occupancy. The existence of regional and subtype-specific heterogeneities in the regulation of these receptors supports the contention that despite their similar pharmacological profiles, D2 and D3 receptors may mediate different functional responses.     

Memory of music: roles of right hippocampus and left inferior frontal gyrus

We investigated neural correlates of retrieval success for music memory using event-related functional magnetic resonance imaging. To minimize the interference from MRI scan noise, we used sparse temporal sampling technique. Newly composed music materials were employed as stimuli, which enabled us to detect regions in absence of effects of experience with the music stimuli in this study. Whole brain analyses demonstrated significant retrieval success activities in the right hippocampus, bilateral lateral temporal regions, left inferior frontal gyrus and left precuneus. Anatomically defined region-of-interests analyses showed that the activity of the right hippocampus was stronger than that of the left, while the activities of the inferior frontal gyri showed the reverse pattern. Furthermore, performance-based analyses demonstrated that the retrieval success activity of the right hippocampus was positively correlated with the corrected recognition rate, suggesting that the right hippocampus contributes to the accuracy of music retrieval outcome.     

Zinc modulates antagonist interactions with D2-like dopamine receptors through distinct molecular mechanisms

Recently, zinc has been shown to modulate antagonist drug interactions with the D1 dopamine receptor (Schetz and Sibley, 1997) and the dopamine transporter (Norregaard et al., 1998). We now demonstrate that zinc also reversibly and dose-dependently modulates the specific binding of the butyrophenone antagonist [3H]methylspiperone to all D2-like dopamine receptors: D2L, D3, and D4. The molecular mechanisms of zinc regulation of these D2-like receptor subtypes are distinct because zinc inhibition of [3H]methylspiperone binding to the D4 receptor is noncompetitive by both equilibrium and kinetic measures (lower Bmax and essentially no change in koff), whereas the corresponding inhibition of zinc at D2L and D3 receptors is primarily characterized by competitive allosterism (increases in KD and koff). Interestingly, thermodynamic measurements reveal that the macroscopic properties of zinc binding are entropy-driven for all receptor subtypes, despite their having distinct molecular mechanisms. Zinc also reduces the binding affinity of the D2L receptor for [3H]raclopride, a structurally different antagonist of the substituted benzamide class. Sodium ions negatively modulate zinc inhibition of both sodium-insensitive [3H]methylspiperone binding and sodium-sensitive [3H]raclopride binding. In addition to its demonstrated effects on antagonist binding in membrane preparations, zinc also retards the functional effects of antagonist at the D2L receptor in intact cells. These findings suggest that synaptic zinc may be a factor influencing the effectiveness of therapies that rely on dopamine receptor antagonists.     

D2 dopamine receptors modulate Galpha-subunit coupling of the CB1 cannabinoid receptor

CB(1) cannabinoid (CB(1)) and D(2) dopamine (D(2)) receptors are known to couple to the G protein Galpha(i/o). It has been reported that concurrent activation of D(2) receptors and CB(1) receptors, in primary striatal neuronal culture, promotes functional CB(1) receptor coupling to Galpha(s) resulting in elevations in intracellular cyclic AMP levels. We now report that in the absence of D(2) receptors, acute activation of CB(1) receptors inhibits cyclic AMP accumulation, whereas the presence of D(2) receptors promotes CB(1)-stimulated cAMP accumulation, presumably through Galpha(s). This Galpha(s) subunit switching was not prevented by pertussis toxin treatment and occurred in the presence and absence of D(2) receptor activation. Thus, coexpression of the D(2) receptor with the CB(1) receptor was sufficient to switch the coupling of the CB(1) receptors from Galpha(i/o) to Galpha(s). Persistent activation of D(2) receptors resulted in heterologous sensitization of adenylate cyclase to subsequent stimulation by forskolin, whereas the persistent activation of CB(1) receptors did not. Additional studies in human embryonic kidney cells cotransfected with D(2) and CB(1) receptors revealed that persistent activation (18 h) of D(2) receptors induced a switch of CB(1) receptor coupling from Galpha(s) to Galpha(i/o). This D(2) receptor-induced effect allowed for CB(1) receptor-mediated inhibition of cyclic AMP accumulation. The present studies suggest D(2) receptors may have a significant modulatory role in determining the G protein coupling specificity of CB(1) receptors.     

Effects of chronic SCH23390 treatment on the biochemical and behavioral properties of D1 and D2 dopamine receptors: potentiated behavioral responses to a D2 dopamine agonist after selective D1 dopamine receptor upregulation

Chronic treatment of rats with SCH23390 (0.5 mg/kg/day s.c.), a D1 dopamine receptor antagonist, for 21 days resulted in an increase in D1 dopamine receptors but produced no change in D2 dopamine receptors. During habituation to locomotor activity cages the rats treated chronically with SCH23390 showed significantly higher locomotor activity than controls treated chronically with saline. When injected with the selective D1 dopamine receptor agonist SKF38393 (3 mg/kg), rats treated chronically with SCH23390 showed significantly greater stereotypy and locomotor activity responses. Surprisingly, rats treated chronically with SCH23390 also showed significantly higher locomotor activity and stereotypy responses when treated with the selective D2 dopamine receptor agonist, quinpirole (LY171555) (0.3 mg/kg). These results indicate that a selective increase in D1 receptors may not be necessary, but is sufficient, to lead to an enhanced behavioral response to either selective D1 or D2 dopamine receptor agonists. If, indeed, an enhanced stereotypy and locomotor activity response to dopaminergic agonists in rats after a brief chronic treatment with a neuroleptic drug is predictive of tardive dyskinesia potential in the clinical setting, these results can suggest that SCH23390 may also induce tardive dyskinesia in humans. Adenylate cyclase activity stimulated by guanine nucleotides, forskolin or dopamine was enhanced after chronic treatment with SCH23390. However, dopamine-stimulated adenylate cyclase activity was not potentiated detectably by the increase in receptor number over the more general increase in guanine nucleotide-stimulated cyclic AMP production. Additionally, no change was observed in dopamine competition for [3H]SCH23390 binding, with dopamine's RH/RL ratio remaining unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)     

Multisecond oscillations in firing rate in the globus pallidus: synergistic modulation by D1 and D2 dopamine receptors.

The firing rates of many basal ganglia neurons recorded in awake rats oscillate at seconds-to-minutes time scales, and the D1/D2 agonist apomorphine has been shown to robustly modulate these oscillations. The use of selective D1 and D2 antagonists suggested that both these receptor subfamilies are involved in apomorphine's effects. In the present study, spectral analysis revealed that baseline multisecond oscillations were significantly periodic in 71% of globus pallidus neurons. Baseline oscillations had a wide range of periods within the analyzed range, with a population mean of 32 +/- 2 s. Administration of the D1 agonist SKF 81297 (6-chloroPB) at 1.0 or 5.0 mg/kg significantly changed these oscillations, reducing means of spectral peak periods to 14 to 16 s (i.e., increasing oscillatory frequency). This effect was attenuated by D2 antagonist pretreatment. The D2 agonist quinpirole did not cause a significant population change in multisecond periodicities. The strongest effects on multisecond periodicities occurred after combined treatment with SKF 81297 and quinpirole. Low, ineffective doses of SKF 81297 and quinpirole, when combined, produced a significant increase in oscillatory frequency. Also, when quinpirole was administered after an already effective dose of SKF 81297, quinpirole shifted oscillations to an even faster range (typically to periods of <10 s). The dopaminergic control of multisecond periodicities in globus pallidus firing rate demonstrates D1/D2 receptor synergism, in that the effects of D1 agonists are potentiated by and partially dependent on D2 receptor activity. Modulation of multisecond oscillations in firing rate represents a novel means by which dopamine can influence globus pallidus physiology.     

Asymmetry in dopamine D(2/3) receptors of caudate nucleus is lost with age

Molecular and functional imaging techniques reveal evidence for lateralization of human cerebral function. Based on animal data, we hypothesized that asymmetry in dopamine neurotransmission declines during normal aging. In order to test this hypothesis, we measured dopamine D2/3 receptor availability with [18F]desmethoxyfallypride-PET (DMFP) in putamen and caudate nucleus (NC) of 21 healthy, right-handed males (24-60 years; 35+/-10). For volumetric analysis, high-resolution T1-weighted MR-images were obtained in 18 of the PET-subjects in order to assess possible age-related decreases in NC and putamen volume. The calculated DMFP binding potentials (BP) showed a right-ward asymmetry in NC of young subjects that decreased with age (r = 0.577, p = 0.006; Pearson correlation; two-tailed). An age-independent analysis showed a right-ward asymmetry in NC of the whole subject group (left: 1.49+/-0.35; right: 1.65+/-0.43 [mean+/-S.D.]; p = 0.020). No such side lateralization or age-effects could be found in the putamen. Volumes tended to be asymmetric in the putamen (right: 4.85+/-0.56 cm3; left: 4.64+/-0.86 cm3 [mean+/-S.D.]; p = 0.063), but not in NC. The decline of putamen volume during aging was significant in the right putamen (r = -0.613; p = 0.007; Pearson correlation; two-tailed). There were no other significant correlations between striatal volumes and age or BP. Because ventral striatal dopamine neurotransmission is involved in cognitive processes, this loss of physiological asymmetry in NC dopamine transmission during aging might be involved in age-related declines of cognitive performance.     

Discriminative stimulus properties of lisuride revisited: involvement of dopamine D2 receptors

Although the discriminative stimulus effects of the clinically useful ergot derivative lisuride have previously been related to dopamine (DA) neuronal systems, the involvement of DA D1 and D2 receptor subtypes in the lisuride cue has been characterized for the first time in the present experiment. In rats trained to discriminate lisuride (0.04 mg/kg) from saline, appropriate doses of the putative D2 agonist LY 171555 (0.008-0.063 mg/kg) substituted completely whereas the D1 agonist SKF 38393 (2.0-16.0 mg/kg) evoked primarily saline-lever responding. When given in combination with lisuride (0.04 mg/kg), the D2 antagonist (-)-sulpiride (5-30 mg/kg), but not the D1 antagonist SCH 23390 (0.125-0.5 mg/kg), blocked the lisuride cue. Combination tests also suggested that bromuride and pirenperone have DA antagonist properties. Although the specificity of these agents is not fully known, these results support the conclusion that D2 but not D1 receptors play an important role in the stimulus effects of lisuride. Although a role for serotonin in the similar stimulus properties of lisuride and SCH 23390 cannot be ruled out, partial substitution of SCH 23390 (0.0625-0.35 mg/kg; administered alone) for lisuride complements previous observations which suggest that the two DA subtypes may be functionally linked in vivo.