Inhibitory effects of MK-801 on contextual sensitization to climbing behavior and on development of tolerance to hypothermia induced by a single high dose of apomorphine

A single high dose of apomorphine (10 mg x kg(-1)) produced not only contextual sensitization to and conditioning of climbing behavior, but also context-independent tolerance to hypothermia. MK-801 (0.15 and 0.3 mg x kg(-1)) inhibited contextual sensitization to and conditioning of climbing behavior. Development of tolerance to hypothermia was also inhibited by MK-801. Dopamine D1 antagonist, SCH23390 (0.5 mg x kg(-1)), but not D2 antagonist, sulpiride, inhibited sensitization to and conditioning of climbing behavior. D2 antagonist, sulpiride (50 mg x kg(-1)), but not D1 antagonist, SCH23390, inhibited development of tolerance to hypothermia. These results suggest that MK-801 inhibited contextual sensitization to climbing behavior and development of tolerance to hypothermia through glutamatergic modulation of dopaminergic functions at dopamine receptors.     

Intact discrimination reversal learning but slowed responding to reward-predictive cues after dopamine D1 and D2 receptor blockade in the nucleus accumbens of rats

Rationale The prediction error hypothesis of dopamine action states that dopamine signals are necessary for the brain to update the predictive significance of cues. Yet, little is known whether D1 or D2 receptor-mediated signals in the nucleus accumbens core (AcbC) are required to learn a reversal of the predictive significance of cues. Objective Here we examined the effects of a selective D1 or D2 receptor blockade in the AcbC on learning a reversal of previously acquired cue–reward magnitude contingencies. Materials and methods Rats were trained on a reaction time (RT) task demanding conditioned lever release with discriminative visual cues signalling in advance the upcoming reward magnitude (one or five food pellets). After acquisition, RTs were guided by cue-associated reward magnitudes, i.e. RTs of responses were significantly shorter for expected high vs low reward. Thereafter, cue–reward magnitude contingencies were reversed. Reversal learning was tested for 12 daily sessions with intra-AcbC micro-infusions being given on sessions 1–6. Subjects received pre-trial infusions of the selective D1 or D2 receptor antagonists, SCH23390 (0.5, 2 μg per side) or raclopride (1, 4 μg per side), or vehicle (0.5 μl). Results Intra-AcbC infusion of SCH23390 (0.5, 2 μg) or raclopride (1, 4 μg) did not inhibit discrimination reversal learning, but the higher dose of each drug increased RTs of instrumental responses. Conclusions In a visual discrimination task as used here, D1 and D2 receptor-mediated signals in the AcbC seem to be unnecessary in updating the reward-predictive significance of cues, rather, they serve to activate instrumental behaviour.     

Pharmacological studies of the opioids, mood stabilizer and dopaminergic drugs on pilocarpine-induced seizures and status epilepticus

This work was designed to study the influence of drugs during seizures and status epilepticus (SE) induced by pilocarpine and mortality in adult rats. Morphine (0.1 and 0.2 mg/kg), SCH 23390 (0.1 and 0.2 mg/kg), haloperidol (5 and 10mg/kg) and lithium (30 and 60 mg/kg) were administered intraperitoneally (i.p.), 30 min before to pilocarpine (400 mg/kg, s.c.). The animals were observed (24 h) to determine: number of peripheral cholinergic signs, tremors, stereotyped movements, seizures, SE, latency to first seizure and number of deaths after pilocarpine treatment. Morphine and haloperidol had proconvulsant effects in both doses tested. Smaller and higher doses of these drugs no protected and increased pilocarpine-induced seizures, SE and/or mortality. SCH 23390 protected against seizures, increased the latency to first seizure and reduced the mortality of the animals treated with pilocarpine Theses results suggest that dopamine receptor system receptor subtypes exert opposite functions on the regulation of convulsive activity. The morphine is proconvulsant in lower doses. The opioids in high doses tested exert an action proconvulsant during the establishment of epileptic activity induce by pilocarpine. The lithium no protected the animals against seizures induced by pilocarpine and is used which a model of epilepsy associated with lower doses of pilocarpine in several studies, suggesting absence of the effect anticonvulsants in rodents.     

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     

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.     

Lack of genotype effect on D1, D2 receptors and dopamine transporter binding in triple MOP‐, DOP‐, and KOP‐opioid receptor knockout mice of three different genetic backgrounds

We investigated D1, D2 receptors and dopamine transporter (DAT) binding levels in mice lacking all three opioid receptors and wild‐type (WT) mice on three different genetic backgrounds. Quantitative autoradiography was used to determine the level of radioligand binding to the D1 and D2 receptors and DAT labeled with [³H]SCH23390, [³H]raclopride, and [³H]mazindol, respectively in triple‐opioid receptor knockout (KO) and WT maintained on C57BL/6 (B6) and 129/SvEvTac (129) as well as C57BL/6 × 129/SvPas (B6 × 129) strains. No significant genotype effect was observed in D1, D2 receptors and DAT binding in any regions analyzed in any of the strains studied, suggesting that a lack of all three opioid receptors does not influence D1, D2 receptors and DAT expression, irrespective of their genetic strain background. However, strain differences were observed in D1 binding between the three strains of mice studied. Lower levels of D1 binding were observed in the substantia nigra of B6 × 129 WT mice compared with the 129 WT mice and in the olfactory tubercle of B6 × 129 WT compared with B6 WT and 129 WT mice. Lower levels of D1 binding were observed in the caudate putamen of B6 × 129 KO mice compared with 129 KO mice. In contrast, no significant strain differences were observed in D2 and DAT binding between the three strains of mice in any regions analyzed. Overall, these results indicate a lack of modulation of the dopaminergic system by the deletion of all three opioid receptors regardless of different background strains. Synapse 64:520–527, 2010. © 2010 Wiley‐Liss, Inc.     

Responding for brain stimulation reward in the bed nucleus of the stria terminalis in alcohol-preferring rats following alcohol and amphetamine pretreatments

The bed nucleus of the stria terminalis (BNST) has been reported to release increased levels of extracellular dopamine (DA) following the systemic administration of abused drugs in outbred rats. This study examined the BNST as a novel locus for supporting operant responding for brain stimulation reward (BSR) in rats bred for alcohol preference while determining any potentiating effects of ethanol (EtOH) (0.125-1.25 g/kg, i.p.) and amphetamine (0.25-1.60 mg/kg, i.p.) on BSR within the BNST. Also examined was the capability of D1 receptor blockade to attenuate any observed potentiation. Following surgical implantation, alcohol-preferring (P) and non-preferring (NP) rats responded to a range of descending frequencies (300-20 Hz) as evaluated by a rate-frequency paradigm. The results revealed that the BNST was capable of supporting BSR in P but not NP rats. Also, amphetamine pretreatment produced a significant leftward shift in the rate-frequency function in P rats with significant reductions observed in three other measures of reward threshold, while EtOH only lowered the minimum frequency needed to produce responding. The effects of systemic amphetamine were successfully attenuated by the unilateral infusion of the D1 receptor antagonist SCH 23390 (5.0 microg) into the contralateral nucleus accumbens. The results suggest the BNST is capable of supporting BSR performance in P, but not NP rats, possibly due to increased sensitivity to the electrical stimulation-induced DA release of BSR in the innately DA "deficient" limbic system of P rats.     

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.     

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     

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.