Impairments of exploration and memory after systemic or prelimbic D1-receptor antagonism in rats

D1-receptor antagonism is known to impair rodent memory but also inhibits spontaneous exploration of stimuli to be remembered. Hypo-exploration could contribute to impaired memory by influencing event processing. In order to explore this effect, the D1 receptor antagonist, SCH23390, was administered to rats via routes that either did or did not affect spontaneous exploration: systemic or prelimbic administration, respectively. Effects were tested in spatial and non-spatial memory tasks selected for their requirements for self-initiated exploration of stimuli to be remembered in order to examine the effects on memory: cross-maze and object recognition task. Systemic administration reduced spatial exploration in cross-maze as well as in an open field test, and also reduced object exploration. Spatial (hippocampus-dependent) short-term memory was inhibited in the cross-maze and non-spatial short-term object retention was also impaired. In contrast to these systemic effects, bilateral injections of SCH23390 into the prelimbic cortices altered neither spatial nor object exploration, but did inhibit short-term memory in both cross-maze and object recognition task. Therefore, the inhibiting effects of SCH23390 on both spatial and non-spatial memory were not mediated indirectly via reduced exploration of stimuli to be remembered, but through antagonism of a prelimbic D1-R function that is directly involved in memory formation. Finally, a cooperative regulation of spatial exploration between D1-R and mGlu5 was indicated by a synergistic effect of the antagonists SCH23390 and MPEP.     

Dopaminergic modulation of the caudal photoreceptor in crayfish

In our study we investigated the influence of dopamine (DA) on the caudal photoreceptor (CPR) in crayfish. Here we report the following: (a) the chromatographic determination of DA in the sixth abdominal ganglion (6th AG) shows a variation in the content during a 24‐h cycle with the maximum value at dawn. (b) There are possibly dopaminergic neurons in the 6th AG with antityrosine hydroxylase antibodies. Immunopositive neurons (164) were located in the anterior and posterior regions of the 6th AG with the mean (± SE) diameter of their somata 23 ± 1 μm. In addition, there is immunopositive staining in axons, neuropilar fibers, and varicosities. (c) We also identified, using immunohistochemistry, 108 neurons in the sixth AG that contain dopamine D1‐like receptors, with the mean (±SE) diameter of their somata 18 ± 1 μm. (d) We examined the exogenous action of DA on the electrical activity of the CPR in the isolated sixth AG by conventional extracellular‐recording methods. This CPR displays spontaneous activity and phasic‐tonic responses to light pulses. Topical application of dopamine to ganglia kept in the dark increased the spontaneous firing rate of the CPR, whereas the photoresponse of the CPR remained unchanged. The effect on the spontaneous activity is dose‐dependent with an ED₅₀ of 33 μM, and is blocked by the dopamine D1‐like antagonist SCH23390. These observations suggested that the DA is playing the role of a neurotransmitter or a neuromodulator of the CPR in the 6th AG in both species of crayfish, Procambarus clarkii and Cherax quadricarinatus. Synapse, 2011. © 2010 Wiley‐Liss, Inc.     

Dopamine receptor blockade and synthesis inhibition during exaggerated natriuresis in spontaneously hypertensive rats

Hansell , P. & Sjöquist , M. 1992. Dopamine receptor blockade and synthesis inhibition during exaggerated natriuresis in spontaneously hypertensive rats. Acta Physiol Scand 144 , 269–276. Received 21 September 1990, accepted 11 October 1991. ISSN 0001–6772. Department of Physiology and Medical Biophysics, Biomedical Centre, University of Uppsala, Sweden. The influence of dopamine receptor blockade and synthesis inhibition on natriuresis induced by isotonic saline volume expansion was investigated in anaesthetized spontaneously hypertensive rats and normotensive Wistar-Kyoto rats. The aim of the study was to elucidate the mechanisms underlying the phenomenon of exaggerated natriuresis during volume expansion that has been observed in spontaneously hypertensive rats. Volume expansion, at 5 % of body weight, resulted in a larger and faster natriuretic response in spontaneously hypertensive rats than in Wistar-Kyoto rats. Sixty minutes after commencement of volume expansion the natriuretic response (accumulated sodium excretion) in Wistar-Kyoto rats (n = 8) was only 24% of that in spontaneously hypertensive rats (n = 17). When spontaneously hypertensive rats were pretreated with the dopamine receptor blockers haloperidol (n= 14, 1 mg kg^-1), SCH23390 (n = 8, 30 μg h^-1 kg^-1) or the dopamine synthesis inhibitor benserazide (n = 8, 50 mg kg^-1; n = 5, 100 mg kg^-1), the natriuretic response to volume expansion was only 16, 35, 59 and 42%, respectively, of that in untreated SHR. The corresponding proportion in the haloperidol-treated (n= 8) compared with untreated Wistar-Kyoto rats was 22%. In conclusion, isotonic volume loading results in more pronounced natriuresis in spontaneously hypertensive than in Wistar-Kyoto rats. Dopamine receptor blockade and synthesis inhibition attenuate the expansion of exaggerated natriuresis in spontaneously hypertensive rats and reduces the volume expansion natriuresis in Wistar-Kyoto rats, indicating that the dopamine system plays an important role.     

大鼠主动脉和肠系膜动脉多巴胺受体DA1 亚型和年龄变化的关系

目的和方法　采用离体血管环方法 ,用DA1受体的特异性激动剂Fenoldpam(FODA)和特异性拮抗剂Sch 2 3390 ,检测和分析了DA1受体在大鼠不同年龄段的生长发育和演变情况 ,借以阐明外周DA1受体与年龄变化的关系。结果　FODA引起的离体主动脉的舒张反应 ,以 3月龄大鼠的舒张反应最强 ,10d龄和 18月龄大鼠主动脉较 3月龄大鼠的主动脉的舒张百分比均有明显下降趋势 ,三组大鼠的最大舒张百分比 (Emax)分别为 10d龄 4 8.77± 6 .0 3(P <0 .0 5 )、3月龄 98.11± 7.0 2、18月龄 5 6 .2 3± 5 .79(P <0 .0 5 )。 10d龄及 18月大鼠的FODA累积浓度 -舒张反应曲线均明显右移。其主动脉的ED50 分别为5 6 2× 10 -4mol/L和 1.5 8× 10 -4mol/L明显大于 3月龄组大鼠的ED50 (P <0 .0 5 )。 10d龄及 18月龄大鼠肠系膜动脉的最大舒张百分比 (Emax)显著小于 3月龄大鼠 ,分别为 6 0 .32± 7.0 2 (P <0 .0 5 )和 6 9.5 9± 10 .71(P <0 .0 5 ) ,ED50 分别为 6 6 5×10 -4(P <0 .0 5 )和 3.98× 10 -5(P <0 .0 5 ) ,明显大于 3月龄组大鼠的ED50 。结论　①外周DA1受体在新生及幼鼠数量较少 ,可能与个体发育尚未成熟有关。②外周DA1受体与中枢多巴胺受体相似 ,也有明显的年龄依赖性特征 ,也随着老龄化而有明显下调趋势。③外周多     

Age-related changes in human D1 dopamine receptors measured by positron emission tomography

The effects of age on the binding parameters of¹¹C-SCH23390, the highly selective ligand for central D1 dopamine receptors, at specific binding sites in the brain were studied. Seventeen healthy male volunteers (20–72 years old) participated. Regional radioactivity in the brain was followed for 40 min by positron emission tomography (PET). A high accumulation of radioactivity was observed in the striatum and there was a conspicuous accumulation in the neocortex. A two-compartment model was used to obtain quantitative estimates of rate constants of association (k₃) and dissociation (k₄). The binding potential (k₃/k₄) of the dopamine D1 receptors in the striatum and frontal cortex decreased by 35% and 39%, respectively, with age. The value of k₃ decreased by 58% in the striatum and 83% in the frontal cortex, whereas the value of k₄ decreased by 35% in the striatum and 72% in the frontal cortex with age.     

Oral administration of NNC 756 — a placebo controlled PET study of D1-dopamine receptor occupancy and pharmacodynamics in man

NNC 756 is a new benzazepine with high affinity and selectivity for D₁-dopamine receptors. In a double-blind, placebo controlled, cross-over study, positron emission tomography and the radioligand [¹¹C]SCH 23390 were used to determine central D₁-do-pamine receptor occupancy after a single oral dose of 80 mg NNC 756 in three healthy men. NNC 756 induced 75, 66 and 47% occupancy of D₁-dopamine receptors in the putamen of at 1.5 h after drug administration and 46, 36 and 24% after 7.5 h. There was a hyperbolic relationship between the occupancy values and the serum concentrations. The K_i value for the hyperbola was 6.4 ng/ml (±SD 1.4). The occupancy at 1.5 h is on the same level as that shown to induce effects in animal models for prediction of antipsychotic effect. Restlessness (akathisia) appeared in two subjects and nausea in one subject at time of peak drug concentration in serum. The oral dose level of 80 mg should be appropriate to investigate the potential antipsychotic effect of NNC 756.     

Human dopamine receptor subtypes—in vitro binding analysis using3H-SCH 23390 and3H-raclopride

Summary Affinities and regional densities of the D₁- and D₂-dopamine receptor subtypes were studied in the human post-mortem brain in vitro using the two selective radioligands³H-SCH23390 and³H-raclopride.³H-Raclopride binding was confined to the caudate nucleus, the putamen and the substantia nigra, while³H-SCH23390 bound to cortical regions as well. The binding of³H-SCH 23390 was reduced by a low concentration of ketanserin, indicating binding to 5-HT₂ receptors in addition to the D₁dopamine receptors. The endogenous neurotransmitter dopamine interacted potently both with the D₁-dopamine receptor and the D₂-dopamine receptor, displaying two affinity states for each subtype. The distribution of the dopamine receptor subtypes obtained in the present in vitro investigation is in agreement with data obtained with¹¹C-SCH 23390 and¹¹C-raclopride in positron emission tomographic studies in human volunteers.     

Differential tolerance to cataleptic effects of SCH 23390 and haloperidol after repeated administration

The development of tolerance to the cataleptic effect of the selective D-1 antagonist SCH 23390 (0.5 mg/kg/day SC or 0.1 mg/kg/day SC) and haloperidol (1 mg/kg/day SC) during repeated administration was investigated. Catalepsy in rats was measured using the horizontal bar method. SCH 23390 induced a dose-related cataleptic effect of short duration, whereas the cataleptic effect of haloperidol appeared more slowly and lasted longer.Marked tolerance to the cataleptic effect of haloperidol developed already 6 days from the beginning of the treatment. The cataleptic effect of the higher dose regimen of SCH 23390 was also significantly reduced after 6 days' treatment. However, unlike haloperidol, this subacute tolerance was gradually reversed and was no longer significant after 12 and 18 days. The cataleptic response to the lower dose of SCH 23390 (0.1 mg/kg/day) was not significantly altered during the treatment and no initial catalepsy tolerance was observed with this dose regimen. These results suggest that different mechanisms are involved in the expression of cataleptic behaviour during chronic treatment with SCH 23390 and classical antipsychotics, such as haloperidol.     

The effects of changes in intracellular calcium on rat synaptosomal cyclic adenosine monophosphate

Cyclic adenosine monophosphate (cAMP) concentration was measured in rat striatal and hippocampal synaptosomes. Incubation in 50 mM K+ medium caused a decrease in both striatal and hippocampal cAMP: this effect was dependent on extracellular Ca2+. Replacement of NaCl with sucrose in the incubation medium increased cAMP. Incubation with 0.5 mM ouabain was without effect.     

Neurotransmitter signaling pathways required for normal development in Xenopus laevis embryos: a pharmacological survey screen

Neurotransmitters are not only involved in brain function but are also important signaling molecules for many diverse cell types. Neurotransmitters are widely conserved, from evolutionarily ancient organisms lacking nervous systems through man. Here, results are reported from a loss‐ and gain‐of‐function survey, using pharmacological modulators of several neurotransmitter pathways to examine possible roles for these pathways in normal embryogenesis. Applying reagents targeting the glutamatergic, adrenergic and dopaminergic pathways to embryos of Xenopus laevis from gastrulation to organogenesis stages, we observed and quantified numerous malformations, including craniofacial defects, hyperpigmentation, muscle mispatterning and miscoiling of the gut. These data implicate several key neurotransmitters in new embryonic patterning roles, reveal novel earlier stages for processes involved in eye development, suggest new targets for subsequent molecular‐genetic investigation, and highlight the necessity for in‐depth toxicology studies of psychoactive compounds to which human embryos might be exposed during pregnancy.