Dopamine receptors modulate ethanol's locomotor‐activating effects in preweanling rats

Near the end of the second postnatal week motor activity is increased soon after ethanol administration (2.5 g/kg) while sedation‐like effects prevail when blood ethanol levels reach peak values. This time course coincides with biphasic reinforcement (appetitive and aversive) effects of ethanol determined at the same age. The present experiments tested the hypothesis that ethanol‐induced activity during early development in the rat depends on the dopamine system, which is functional in modulating motor activity early in ontogeny. Experiments 1a and 1b tested ethanol‐induced activity (0 or 2.5 g/kg) after a D1‐like (SCH23390; 0, .015, .030, or .060 mg/kg) or a D2‐like (sulpiride; 0, 5, 10, or 20 mg/kg) receptor antagonist, respectively. Ethanol‐induced stimulation was suppressed by SCH23390 or sulpiride. The dopaminergic antagonists had no effect on blood ethanol concentration (Experiments 2a and 2b). In Experiment 3, 2.5 g/kg ethanol increased dopamine concentration in striatal tissue as well as locomotor activity in infant Wistar rats. Adding to our previous results showing a reduction in ethanol induced activity by a GABA B agonist or a nonspecific opioid antagonist, the present experiments implicate both D1‐like and D2‐like dopamine receptors in ethanol‐induced locomotor stimulation during early development. According to these results, the same mechanisms that modulate ethanol‐mediated locomotor stimulation in adult rodents seem to regulate this particular ethanol effect in the infant rat. © 2009 Wiley Periodicals, Inc. Dev Psychobiol 52: 13–23, 2010     

Subthalamic high frequency stimulation induced rotations are differentially mediated by D1 and D2 receptors

High frequency stimulation (HFS) of the subthalamic nucleus (STN) has clinically emerged as a promising approach in the treatment of Parkinson's disease, epilepsy, dystonia as well as compulsive and possibly other mood disorders. The underlying mechanisms are incompletely understood, but are definitely related to high frequency and likely to involve the dopamine (DA)-system. To further test this hypothesis the present study investigated the modulation of STN-HFS-induced circling by systemic and intracerebral injection of drugs acting on DA receptors in naive freely moving rats. Within this experimental setup, unilateral STN-HFS alone induced intensity-dependent circling. Systemic injections of selective D1- (SCH-23390) and D2-((-)-sulpiride) antagonists as well as the mixed D1 and D2 agonist apomorphine dose-dependently reduced STN-HFS-induced rotational behavior. Intracerebral microinjections of (-)-sulpiride but not SCH-23390 decreased circling when injected intrastriatally and increased the number of rotations when injected intranigrally (pars reticulata (SNr)). These data reveal that STN-HFS-induced contralateral circling is differentially modulated by D1 and D2 receptors. While D2 receptor-mediated effects involve the dorso-/ventrolateral striatum and the SNr, D1 receptors probably exert their actions via brain areas outside the striatum and SNr. These findings suggest the nigrostriatal DA-system to be specifically involved in the mediation of STN-HFS-induced motor effects.     

Therapeutic potential of adenosine receptor antagonists and agonists

The adenosine receptors (A₁, A_2A, A_2B and A₃) are important and ubiquitous mediators of cellular signalling, which play vital roles in protecting tissues and organs from damage. Launched drugs include the adenosine receptor antagonists theophylline and doxofylline (both used as bronchodilators in respiratory disorders such as asthma), while several compounds are presently in clinical trials for a range of indications, including heart failure, Parkinson's disease, rheumatoid arthritis, cancer, pain and chronic obstructive pulmonary disease. A host of companies and institutions are addressing the huge potential for the development of selective adenosine receptor agonists and antagonists, so that it appears we are on the verge of a new wave of compounds approaching the market for many unmet medical needs. This review presents an analysis of the patenting activity in the area for 2006 and an interpretation and reflection on the developments that we can expect in the future.     

Cocaine facilitation of prefrontal cortex self-stimulation: a microstructural and pharmacological analysis

A novel self-stimulation methodology involving a fixed-interval (FI-5 s) schedule of reinforcement, microanalysis and threshold evaluation was used to investigate the effects of cocaine on rats lever pressing for electrical stimulation of the prefrontal cortex. Cocaine (15 mg/kg) increased medial prefrontal cortex (MPC) self-stimulation rates under FI-5 by a mean of 269% and reduced current thresholds for self-stimulation. A similar facilitation was evident with self-stimulation of the sulcal prefrontal cortex. Microanalysis showed that cocaine decreased inter-response times and post-reinforcement pauses, increased responding in the second and third quartiles of the inter-reinforcement interval (IRI) and decreased responding in the fourth IRI quartile. Schedule control of responding was still evident following cocaine despite the profound facilitation of response rates. Increased response rates were seen up to 48 h following a single dose of cocaine, suggesting sensitization of the PFC reinforcement substrate. The acute effects of cocaine on MPC self-stimulation were completely reversed by the dopamine (DA) D₁ antagonist SCH 23390 0.02 mg/kg) and the D₂ antagonist raclopride (0.3 mg/kg) but not by naloxone (0.5 mg/kg). These results are consistent with previous studies demonstrating the PFC as part of the neural substrate mediating cocaine reward. Further, these results implicate DA receptors in the reinforcing properties of both cocaine and MPC self-stimulation.     

Dopaminergic involvement in the discriminative-stimulus effects of methamphetamine in rats

Rationale: Dopamine plays a major role in the behavioral effects of methamphetamine. Objective: In the present experiments, the effects of different dopaminergic agonists, antagonists, and uptake inhibitors were evaluated in rats discriminating methamphetamine from saline. Methods: In Sprague-Dawley rats trained to discriminate 1.0 mg/kg methamphetamine, i.p., from saline under a fixed-ratio schedule of food delivery, the ability of various dopaminergic agonists and uptake inhibitors to substitute for methamphetamine was evaluated. Subsequently, the ability of various dopaminergic antagonists to block the discriminative-stimulus effects of the training dose of methamphetamine was tested. Results: The dopamine-uptake inhibitors cocaine (10.0 mg/kg), nomifensine (3.0 mg/kg), GBR-12909 (18.0 mg/kg), and bupropion (30.0 mg/kg) fully substituted for the 1.0 mg/kg training dose of methamphetamine. Chloro-APB (SKF-82958), a full agonist at D1 dopamine receptors, produced about 85% methamphetamine-appropriate responding, but the dose required (0.18 mg/kg) markedly decreased rates of responding. Chloro-PB (SKF-81297), another agonist at D1 receptors with a lower intrinsic activity than Chloro-APB, produced only partial generalization (maximum about 55%) at a dose of 1.0 mg/kg. Full substitution for the training dose of methamphetamine was observed with 0.03 mg/kg of the D2 agonist NPA and 0.56 mg/kg of the D3/D2 agonist 7-OH-DPAT. Both NPA and 7-OH-DPAT markedly decreased rates of responding at these doses. The D1 antagonist SCH-23390 (0.056 mg/kg), the D2 antagonist spiperone (0.18 mg/kg), and the mixed D1,D2 antagonist cis-flupenthixol (0.56 mg/kg) all completely blocked the discriminative-stimulus actions of the training dose of methamphetamine. Conclusions: The present findings in rats support previous research findings in other species indicating a major role of dopamine in the discriminative-stimulus effects of methamphetamine. These findings further indicate involvement of dopamine uptake sites as well as D1 and D2 receptors. Received: 2 July 1999 / Final version: 17 September 1999     

Selective D1- and D2-dopamine receptor blockade both induces akathisia in humans — a PET study with [11C]SCH 23390 and [11C]raclopride

Pharmacological effects were recorded and time course for receptor binding in brain was followed by positron emission tomography after IV injection of the selective D₁-dopamine receptor antagonist SCH 23390 in four healthy subjects in doses of 310–810 µg. Akathisia, the syndrome of motor restlessness, appeared after the three highest doses. The akathisia was transient and occurred only when [¹¹C]SCH 23390 binding in the basal ganglia was at a high level with a central D₁-dopamine receptor occupancy of 45–59%. The D₂-dopamine receptor antagonist [¹¹C]raclopride was injected IV into 20 healthy subjects and 13 schizophrenic patients. Akathisia appeared in 14 healthy subjects and 7 patients and coincided with maximal [¹¹C]raclopride binding in the basal ganglia. The findings for [¹¹C]raclopride and [¹¹C]SCH 23390 are the first demonstration of a relationship between time courses for radioligand binding in the human brain and simultaneously induced pharmacological effects.     

Effects of blockade of central dopamine D1 and D2 receptors on thermoregulation,metabolic rate and running performance

To assess the effects of a blockade of central D₁- and D₂-dopaminergic receptors on metabolic rate, heat balance and running performance, 10 nmol (2 μl) of a solution of the D₁ antagonist SCH-23390 hydrochloride (SCH,n= 6), D₂ antagonist eticlopride hydrochloride (Eti, n = 6), or 2 μl of 0.15 MNaCl (SAL, n = 6) was injected intracerebroventricularly into Wistar rats before the animals began graded running until fatigue (starting at i0 m/min, increasing by 1 m/min increment every 3 min until fatigue, 5% inclination). Oxygen consumption and body temperature were recorded at rest, during exercise and following 30 min of recovery. Control experiments with injection of two doses (10 and 20 nmol/rat) of either SCH or Eti solution were carried out in resting rats as well. Body heating rate, heat storage, workload and mechanical efficiency were calculated. Although SCH and Eti treatments did not induce thermal effects in resting animals, they markedly reduced running performance (–83%, SCH; -59% Eti, p < 0.05) and decreased maximal oxygen uptake (–79%, SCH; -45%, Eti, p < 0.05) in running rats. In addition, these treatments induced a higher body heating rate and persistent hyperthermia during the recovery period. Our data demonstrate that the alteration in dopamine transmission induced by the central blockade of dopamine- D₁ and D₂ receptors impairs running performance by decreasing the tolerance to heat storage. This blockade also impairs the dissipation of exercise-induced heat and metabolic rate recovery during the post-exercise period. Our results provide evidence that central activation of either dopamine- Di or D₂ receptors is essential for heat balance and exercise performance.     

SCH-56592对新型隐球菌体内外抗真菌活性

目的评价新的唑类抗真菌药物SCH-56592体内外抗临床分离的新型隐球菌活性.方法依照美国国家临床试验标准化委员会推荐的M27-A方案的微量稀释法测定26株新型隐球菌对SCH-56592及氟康唑、伊曲康唑和两性霉素B的MICs.比较SCH-56592与氟康唑治疗免疫功能抑制的鼠肺隐球菌病的疗效.结果SCH-56592对于临床分离的26株新型隐球菌的体外抗菌活性是氟康唑的16～64倍,对氟康唑耐药的新型隐球菌的MIC(0.05μg@mL-1)是伊曲康唑MIC(2μg@mL-1)的1/40倍.SCH-56592不仅明显降低氟康唑敏感新型隐球菌株感染小鼠的肺内菌数(P＜0.05)[SCH-56592组为(2.90±1.90)×107CFU@mL-1,对照组为(46.60±29.58)×107CFU@mL-1];而且明显降低氟康唑耐药的新型隐球菌株感染的小鼠肺内菌数[SCH-56592组为(5.30±2.36)×107CFU-mL-1,对照组为(197.70±10.37)×107CFU@mL-1,氟康唑治疗组为(190.60±97.63)×107CFU@mL-1,与后2组比较,均为P＜0.05].肺隐球菌感染的小鼠经SCH-56592治疗后生存时间延长,生存率提高.结论SCH-56592具有良好的体内、体外抗临床分离的新型隐球菌活性;对于氟康唑耐药的新型球菌具有极好的抗真菌活性.     

SCH 23390 blocks drug-conditioned place-preference and place-aversion: anhedonia (lack of reward) or apathy (lack of motivation) after dopamine-receptor blockade?

The influence of the D₁ antagonist SCH 23390 on the motivational properties of rewarding (morphine, nicotine and diazepam) and aversive (naloxone, phencyclidine and picrotoxin) drugs was studied in the rat in a two-compartment place-conditioning paradigm, which included a pre-conditioning test for spontaneous place-preference. The specific D₁ dopamine-receptor antagonist SCH 23390 (0.05 mg/kg SC), paired with both compartments or, separately, with the preferred or with the non-preferred compartment, failed to affect the spontaneous unconditioned preference of the animal. Pairing of morphine (1.0 mg/kg SC), nicotine (0.6 mg/kg SC) or diazepam (1.0 mg/kg IP) with the less preferred compartment induced significant preference for that compartment. Pairing of SCH 23390 (0.05 mg/kg SC) with both compartments completely blocked the place-preference induced by morphine, nicotine and diazepam. Naloxone (0.8 mg/kg SC), phencyclidine (2.5 mg/kg SC) or picrotoxin (2.0 mg/kg IP) paired with the preferred compartment elicited place-aversion. Pairing of SCH 23390 (0.05 mg/kg SC) with both compartments abolished also the place-aversion induced by naloxone, phencyclidine and picrotoxin. The results indicate that blockade of dopamine transmission blocks the motivational properties of rewarding as well as aversive stimuli. It is suggested that neuroleptics rather than simply blocking the rewarding impact of positive reinforcers (anhedonia, lack of pleasure) exert a more general influence on conditioned behaviour by blocking the affective impact of negative as well as positive reinforcers (apathy, lack of motivation).     

Effects of selective D-1 and D-2 dopamine antagonists on development of methamphetamine-induced behavioral sensitization

The present study examined effects of selective antagonists of D-1 and D-2 dopamine receptors on the development of behavioral sensitization produced by repeated methamphetamine (MAP) administration. Male Sprague-Dawley rats were divided into four groups. Each group received a daily injection of saline (control group), 4 mg/kg MAP (MAP group), 1 mg/kg YM-09151-2 plus 4 mg/kg MAP (YM+MAP group) or 0.5 mg/kg SCH 23390 plus 4 mg/kg MAP (SCH+MAP group) for 14 days. During daily injection for 14 days, the MAP group exhibited a progressive augmentation in locomotor and stereotyped behavior, whereas the progression of such behaviors in the YM+MAP and SCH+MAP group was completely prevented. After an abstinence period of 7 days, all groups received a challenge of 2 mg/kg MAP. The MAP challenge reproduced hyperlocomotion and intense stereotyped behavior only in the MAP group. However, neither the YM+MAP group nor the SCH+MAP group showed sterotypy. The manner in which both groups showed only hyperlocomotion was similar to that observed in the control group. These results indicate that both selective D-1 antagonists and selective D-2 antagonists not only reverse MAP-induced motor effects at each injection but also prevent the development of behavioral sensitization induced by repeated MAP administration.