Topographical evaluation of the phenotype of spontaneous behaviour in mice with targeted gene deletion of the D1A dopamine receptor: paradoxical elevation of grooming syntax

The phenotype of spontaneous behaviour in mice with targeted gene deletion of the DIA dopamine receptor was investigated topographically. Via direct visual observation, individual elements of behaviour were resolved and quantified using an ethologically-based, rapid time-sampling behavioural check-list procedure. Relative to wildtypes (D1A+/+), D1A-null (-/-) mice evidenced over initial exploration significant reductions in rearing free, sifting and chewing, but significant increases in locomotion, grooming and intense grooming. Sniffing and rearing to a wall habituated less readily in D1A-null mice such that these behaviours occurred subsequently to significant excess: increases in locomotion were persistent. The ethogram of spontaneous behaviour in D1A-null mice was characterised by neither 'hypoactivity' or 'hyperactivity' but, rather, by prominent topographical shifts between individual elements of behaviour that could not be encapsulated by either term. Given the substantial body of evidence that grooming and particularly intense grooming constitute the most widely accepted behavioural index of D1-like receptor function, the elevation of such behaviour in D1A-null mice was paradoxical; it may reflect (over)compensatory processes subsequent to developmental absence of D1A receptors and/or the involvement of a D1-like receptor other than/additional to the D1A subtype.     

Spare receptors and intrinsic activity: studies with D1 dopamine receptor agonists

Anti-nitric oxide synthase antibody was used to study the distribution, cytoarchitecture, and synaptic relations of nitric oxide synthase-like immunoreactive neurons in the whole rostral-caudal length of the dorsal raphe nucleus of the rat and compared them with serotonergic neurons. Results showed that the distribution of the nitric oxide synthase in the dorsal raphe nucleus was similar to that of the serotonergic neurons at the rostral part of the dorsal raphe nucleus, including the mediodorsal and the medioventral cell groups, and changed at the middle and caudal parts of the dorsal raphe nucleus. The cytoarchitecture of the nitric oxide synthase-like immunoreactive neurons in the medioventral cell group of the dorsal raphe nucleus was similar to that of the serotonergic neurons. Similar to the serotonergic neurons there, nitric oxide synthase-like immunoreactive neurons also received synapses from axon terminals that contained round, or flattened vesicles, or both kinds. Different to the serotonergic neurons, the few nitric oxide synthase-like immunoreactive axon terminals that were in this area formed synapses.     

Differential expression of D1 and D5 dopamine receptors in the fetal primate cerebral wall

Previous film autoradiographic studies demonstrated that, during corticogenesis, dopamine receptors of the D1 class are abundant in the embryonic primate cerebral wall. In the present study, we expand these findings by identifying the cellular elements of the fetal occipital cerebral wall expressing D1 and D5 subtypes of the D1 dopamine receptor class. We have examined tissue from monkey fetuses collected at 70, 90 and 120 days of gestation using antibodies directed against C-termini of the D1 and D5 dopamine receptors. At all three embryonic ages studied, we found D1 and D5 receptors expressed by multiple cell types of the embryonic cerebral wall. Both D1 and D5 receptor proteins are produced by pyramidal neurons of the cortical plate and by a variety of interstitial neurons of the subplate and intermediate zones. D1 and D5 receptors are also present in cells of the proliferative ventricular and subventricular zones, some of which were identified as dividing cells. In addition, D1 and D5 receptors are detectable in the protoplasmic astroglial and ependymal cells distinguishable in monkey fetuses collected at 120 days of gestation. Some cellular elements of the embryonic monkey cerebral wall express only one subtype of the D1 dopamine receptor class. For example, embryonic Cajal-Retzius neurons in the marginal zone and migrating neurons in the intermediate zone are immunoreactive only to D5 antisera. In contrast, radial glia can be labeled only with D1 receptor-specific antisera. Finally, only D1 receptors are detectable in the blood vessels penetrating the embryonic monkey cerebral wall. Based on these observations, we propose that dopamine receptors of the D1 class play an important role in regulating cerebral cortical formation and that D1 and D5 receptor subtypes may participate in regulation of different aspects of this process.     

Identification of two novel polymorphisms and a rare deletion variant in the human dopamine D4 receptor gene

PURPOSE: To compare turning by an oscillating bed to standard 2-hour turning. Outcomes were survival, length of stay (LOS), duration of mechanical ventilation, and incidence of pneumonia. METHODS: One hundred and three intensive care patients were randomly assigned to standard turning or turning by an oscillating bed. Data, collected at baseline, daily for 7 days, and then three times weekly until study discharge, included demographics, initial Acute Physiology and Chronic Health Evaluation (APACHE II) score, ventilatory/gas exchange parameters, indicators of pneumonia, nursing measures, and chest roentgenograph. RESULTS: There were no significant differences for LOS, duration of ventilation, nor incidence of pneumonia. Higher survival for subjects on the oscillating bed reached borderline significance (P = .056) for subjects with APACHE II greater than or equal to 20. Longitudinal data were analyzed using the random effects model. No differences in ventilatory or gas exchange parameters were identified. Among subjects who developed pneumonia there was a significantly higher respiratory score (nursing acuity scale) for subjects on the oscillating bed. CONCLUSIONS: In selected critically ill patients oscillating therapy may improve survival and improve airway clearance. The frequency and degree of turning needed to prevent complications and improve outcome remains unclear. These newer beds should be used with discrimination so as to not increase hospital costs unnecessarily.     

Review the role of dopamine D4 receptors in schizophrenia and antipsychotic action

Syncope is by definition a transient event, and its cause has usually resolved by the time the patient is examined. Electrophysiologic testing provides a method for assessing a patient's risk for future arrhythmias based on the known sensitivity and specificity of the analyses of sinus node function, atrioventricular conduction, and responses to programmed atrial and ventricular stimulation. Interpretation of these data must always be made in the context of the patient's total clinical situation.     

Spatial learning deficits in mice with a targeted glucocorticoid receptor gene disruption

Previous studies in rats using the Morris water maze suggested that the processing of spatial information is modulated by corticosteroid hormones through mineralocorticoid and glucocorticoid receptors in the hippocampus. Mineralocorticoid receptors appear to be involved in the modulation of explorative behaviour, while additional activation of glucocorticoid receptors facilitates the storage of information. In the present study we used the water maze task to examine spatial learning and memory in mice homozygous and heterozygous for a targeted disruption of the glucocorticoid receptor gene. Compared with wild-type controls, homozygous and heterozygous mice were impaired in the processing of spatial but not visual information. Homozygous mutants performed variably during training, without specific platform-directed search strategies. The spatial learning disability was partly compensated for by increased motor activity. The deficits were indicative of a dysfunction of glucocorticoid receptors as well as of mineralocorticoid receptors. Although the heterozygous mice performed similarly to wild-type mice with respect to latency to find the platform, their strategy was more similar to that of the homozygous mice. Glucocorticoid receptor-related long-term spatial memory was impaired. The increased behavioural reactivity of the heterozygous mice in the open field points to a more prominent mineralocorticoid receptor-mediated function. The findings indicate that (i) the glucocorticoid receptor is of critical importance for the control of spatial behavioural functions, and (ii) mineralocorticoid receptor-mediated effects on this behaviour require interaction with functional glucocorticoid receptors. Until the development of site-specific, inducible glucocorticoid receptor mutants, glucocorticoid receptor-knockout mice present the only animal model for the study of corticosteroid-mediated effects in the complete absence of a functional receptor.     

D1 and D2 dopamine receptor function in the striatum: coactivation of D1- and D2-dopamine receptors on separate populations of neurons results in potentiated immediate early gene response in D1-containing neurons

D1- and D2-dopamine receptor-mediated regulation of immediate early gene levels in identified populations of neurons in the striatum was examined with quantitative in situ hybridization histochemical techniques. Levels of messenger RNA (mRNA) encoding the immediate early genes zif268 and c-fos were examined in two experiments in rats with unilateral lesions of the nigrostriatal dopamine pathway. In a dose-response study, animals were treated with doses of 0.5, 1.0, and 1.5 mg/kg of the D1 agonist SKF-38393 either alone or in combination with the D2 agonist quinpirole (1 mg/kg). Levels of immediate early gene mRNAs 60 min following drug treatments showed a dose-related increase to the D1 agonist alone and a potentiation to combined D1 and D2 against treatment. In a second experiment, in animals receiving 1 mg/kg SKF-38393 either alone or in combination with 1 mg/kg quinpirole, the level of zif268 mRNA was measured with a double-labeling method in striatal neurons containing enkephalin mRNA, a marker of D2-containing neurons, and in neurons not containing enkephalin, putative D1-containing neurons. In the dopamine-depleted striatum, D1 agonist treatment alone did not affect enkephalin-positive neurons but significantly elevated zif268 mRNA levels in nearly all enkephalin-negative neurons. Combined D1 and D2 agonist treatment further increased zif268 mRNA levels in this population of enkephalin-negative neurons and decreased zif-268 mRNA levels in enkephalin-positive neurons. These data indicate that the synergistic response to combined D1- and D2-receptor stimulation is mediated by interneuronal interactions involving the activation of D1 and D2 receptors on separate populations of striatal neurons.     

D2 dopamine receptor antisense oligodeoxynucleotide inhibits the synthesis of a functional pool of D2 dopamine receptors

In vivo administration of an antisense oligonucleotide targeted toward the D2 dopamine (DA) receptor mRNA (D2 AS) markedly inhibited D2 receptor-mediated behaviors but produced only a relatively small reduction in the levels of D2 DA receptors in mouse striatum. This apparent dissociation between DA receptor-mediated behaviors and the levels of D2 DA receptors was addressed by inhibiting the total number of D2 DA receptors by intraperitoneal administration of the selective, irreversibly acting D2 DA receptor antagonist fluphenazine-N-mustard (FNM) and then determining the effects of D2 AS, administered intracerebroventricularly, on the rate of synthesis of D2 DA receptors and on the recovery of D2 receptor-mediated behaviors. FNM inactivated approximately 90% of D2 DA receptors within 4 hr of treatment, after which the receptors returned to normal levels by approximately 8 days. D2 AS treatment significantly inhibited the rate of recovery of D2 DA receptors in striatum of FNM-treated mice. FNM treatment also produced a number of behavioral alterations, including catalepsy, and the inhibition of stereotypic behavior induced by the D2/D3 DA receptor agonist quinpirole. Both of these behaviors returned to normal within 8 days after FNM treatment. D2 AS treatment delayed the restoration of these FNM-induced behaviors. Thus, it reduced the rate of disappearance of the cataleptic behavior induced by FNM and significantly delayed the restoration of the stereotypic behavior induced by quinpirole. The changes induced by D2 AS on D2 receptor-mediated behaviors were reversed on cessation of D2 AS treatment. A random oligomer given in the same amount and for the same length of time as that of the D2 AS had no significant effects on either D2 DA receptor synthesis or DA receptor-mediated behaviors. These studies demonstrate that in vivo administration of D2 AS decreased the rate of recovery of D2 DA receptors and inhibited the recovery of D2 DA receptor-mediated behaviors after irreversible receptor inactivation and suggest that D2 AS treatment inhibits the synthesis of a functional pool of D2 DA receptors.     

Effects of chronic neuroleptic treatments on dopamine D1 and D2 receptors: homogenate binding and autoradiographic studies

The antipsychotic effects of neuroleptics are believed to be mediated via dopamine D2 receptor blockade; however, the anatomical and pharmacological targets of these drugs remain somewhat controversial. The purpose of this study was to examine the effects of chronic clozapine (CLZ) and haloperidol (HAL) treatments on the densities of DA D1 and D2 receptors. Adult male Sprague-Dawley rats (300-350 g) were treated for 21 days with either HAL (1 mg/kg/day, i.p.), CLZ (20 mg/kg/day, i.p.) or saline. Three days after ending the treatments, the brains were removed and used for biochemical assays of tissue DA and metabolites as well as for receptor studies. DA D1 and D2 receptors were labelled with [3H]SCH23390 and [3H]raclopride, respectively, and measured in the neostriatum by binding studies, and in autoradiograms of forebrain sections by quantitative densitometry. The autoradiographic measurements revealed significant increases in the densities of D2 receptors in nucleus accumbens, in the medio-ventral, latero-dorsal and latero-ventral quadrants of the rostral neostriatum, in caudal neostriatum and in globus pallidus of both HAL-(28-44%) and CLZ-treated (15-85%) animals. The HAL-induced up-regulation of D2 receptors in rostral and caudal neostriatum was homogenous, but CLZ produced a more uneven increase, with the highest absolute densities measured in latero-dorsal neostriatum, as well as with changes in the medio-dorsal rostral neostriatum. For D1 receptors, only CLZ and not HAL, produced significant increases in five regions, namely nucleus accumbens (43%) latero-dorsal rostral neostriatum (16%), caudal neostriatum (30%), globus pallidus (67%) and substantia nigra (12%). The observation that CLZ, contrary to HAL, also has an effect on D1 receptor densities may explain the greater therapeutic and selective efficacy with fewer side-effects of this agent, in comparison to other neuroleptics.     

Functional implications of multiple dopamine receptor subtypes: the D1/D3 receptor coexistence

The D3 dopamine receptor, a D2-like receptor, is selectively expressed in the ventral striatum, particularly in the shell of nucleus accumbens and islands of Calleja, where it is found in medium sized substance P neurons. The latter co-express the D1 receptor whose interaction with the D3 receptor was studied by treating rats with selective agonists and antagonists. In agreement with the opposite cAMP response, they mediate in cultured neuroblastoma cells, the D1 and D3 receptors exerted opposite influences on c-fos expression in islands of Calleja. However, in agreement with the synergistic influence of cAMP on D3 receptor-mediated mitogenesis on the same cultured cells, D1 and D3 receptor stimulation in vivo synergistically enhanced preprotachykinin mRNA in the shell of accumbens. This indicates that the two receptor subtypes may affect neurons in either synergy or opposition according to the cell or signal generated. Levodopa-induced behavioral sensitization in hemiparkinsonian rats is another example of D1/D3 receptor interaction. Hence repeated levodopa administration induces the ectopic appearance of the D3 receptor in substance P/dynorphin, striatonigral neurons of the dorsal striatum. This induction is secondary to D1 receptor stimulation in neurons of the denervated side and fully accounts for the sensitization, i.e. the increased behavioral responsiveness to levodopa. During brain development, a similar process could operate to control the late appearance of the D3 receptor in D1-receptor bearing neurons of the ventral striatum at a time at which they start to be innervated by dopamine neurons. Finally, taking into account a variety of genetic, developmental, neuroimaging and pharmacological data, we postulate that imbalances between the levels of D1 and D3 receptors in the same neurons could be responsible for schizophrenic disorders.     

The effects of anandamide on memory consolidation in mice involve both D1 and D2 dopamine receptors

Post-training administration of anandamide (1.5, 3, 6 mg/kg) dose-dependently impairs the retention of an inhibitory avoidance response in mice. The effects on retention performance induced by the drug appear to be due to an effect on memory consolidation, as they were observed when drugs were given at short, but not long, periods of time after training, i.e. when the memory trace was susceptible to modulation. Pretreatment with either selective D1 or D2 dopamine (DA) receptor agonists, SKF 38393 and quinpirole, at doses that were ineffective when given alone (5 and 0.25 mg/kg, respectively), antagonized the effects of anandamide on memory consolidation, suggesting that D1 and D2 receptors are similarly involved in the effects of anandamide on memory consolidation. These results are discussed in terms of a possible inverse relationship between the modulation of memory processes by endogenous cannabinoid and DA systems.     

Rearing conditions alter social reactivity and D1 dopamine receptors in high- and low-aggressive mice

As a result of selective breeding, NC900 mice exhibit isolation-induced attacks in a social interaction test, whereas NC100 mice do not attack but freeze instead. Administration of the D1 receptor agonist dihydrexidine was previously shown to reduce aggression in NC900 mice and nonagonistic approaches in NC100 mice. This resulted from induction of a marked social reactivity in both selected lines. Because isolation rearing also induces social reactivity, the present experiment was designed to test the hypothesis that D1 dopamine receptors mediate isolation-induced social reactivity. Isolation was expected to potentiate the effects of a D1 agonist and to increase D1 dopamine receptor density. Thus, isolated and group-reared mice were administered dihydrexidine, and their social behavior was compared to vehicle-injected controls. Dihydrexidine induced higher levels of reactivity among isolated than among group-reared animals, especially in NC900 mice. In independent experiments, increased densities of D1 dopamine receptors in the striatum of isolated animals were found, with no change in affinity. These studies suggest an important role for the D1 dopamine receptor as a mediator of isolation-induced social reactivity.     

Altered feeding responses in mice with targeted disruption of the dopamine-3 receptor gene.

Dopamine signaling has been implicated in the control of food intake and body weight. In particular, dopamine is important in the control of meal size and number and is thought to mediate the response to metabolic deprivation states. In the present experiments, the authors assessed the role of the dopamine-3 receptor (D?R) in the feeding responses to 2-deoxy-D-glucose, mercaptoacetate, and peripheral insulin. All 3 compounds increased food intake in wild-type mice, but the hyperphagic responses were blunted in D?R-/- mice. In other experiments, D?R-/- mice were hyperresponsive to the administration of amylin and leptin relative to wild-type mice. These results support the hypothesis that D?Rs chronically inhibit the effects of adiposity hormones, thereby contributing to a net anabolic state. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Opposing roles for dopamine D1 and D2 receptors in the regulation of hypothalamic tuberoinfundibular dopamine neurons

The purpose of the present study was to characterize pharmacologically dopamine D1 receptor-mediated inhibition of tuberoinfundibular dopamine neurons in males rats, and to determine if inhibitory dopamine D1 receptors oppose stimulatory dopamine D2 receptors and account for the inability of mixed dopamine receptor agonists to alter the activity of these neurons. Tuberoinfundibular dopamine neuronal activity was estimated by measuring the concentrations of the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the median eminence, the region of the hypothalamus containing terminals of these neurons. Administration of the dopamine D1 receptor agonist (+/-)-1 phenyl-2,3,4,5-tetrahydro-(1 H)-3-benzazepine-7,8-diol (SKF38393) decreased median eminence DOPAC and increased plasma prolactin concentrations, whereas administration of the dopamine D1 receptor antagonist ((-)-trans,6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5H -benzo[d]naphtho-[2,1 b]azepine (SCH39166) increased median eminence DOPAC concentrations but had not effect on plasma prolactin. The inhibitory effect of SKF38393 on median eminence DOPAC concentrations was blocked by SCH39166. These results demonstrate that acute activation of dopamine D1 receptors inhibits the activity of tuberoinfundibular dopamine neurons and thereby increases prolactin secretion, and that under basal conditions dopamine D1 receptor-mediated inhibition of tuberoinfundibular dopamine neurons is tonically active. Administration of the dopamine D2 receptor agonist (5aR-trans)-5,5a,6,7,8,9,9a,10-octahydro-6-propyl-pyridol[2, 3-g]quinazolin-2-amine (quinelorane) increased median eminence DOPAC concentrations, and SKF38393 caused a dose-dependent reversal of this effect. Administration of the mixed dopamine D1/D2 receptor agonist R(-)-10,11-dihydroxy-apomorphine (apomorphine) had no effect per se, but blocked quinelorane-induced increases in DOPAC concentrations in the median eminence. These results reveal that concurrent activation of dopamine D1 and D2 receptors nullifies the actions of each of these receptors on tuberoinfundibular dopamine neurons, which likely accounts for the lack of an acute effect of mixed dopamine D1/D2 receptor agonists on these hypothalamic dopamine neurons.     

Circadian changes in PACAP type 1 (PAC1) receptor mRNA in the rat suprachiasmatic and supraoptic nuclei

A receptor for pituitary adenylate cyclase activating polypeptide (PACAP), denoted as PAC1, is expressed in the suprachiasmatic nuclei (SCN). Since the circadian clock demonstrates phase-dependent sensitivity to PACAP, we have used in situ hybridization histochemistry to examine whether PAC1 mRNA is differentially expressed in the rat SCN across the 24-h cycle. There was a significant variation in PAC1 mRNA within the SCN and supraoptic nuclei during the light-dark cycle and in constant darkness, with peaks at the middle of both the real and subjective day and night; no significant variation was observed in the cingulate cortex. The results suggest that the phase-dependent actions of PACAP on the clock may involve phase-specific changes in the availability of PAC1 receptors within the SCN.