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PubMed1993

Effects of dopamine D1 and D2 receptor blockade on MK-801-induced hyperlocomotion in rats.

Blocking glutamatergic transmission at the N-methyl-D-aspartate (NMDA) receptor complex with MK-801 (0.15-0.5 mg/kg, IP) was found to induce a robust, dose-dependent increase in locomotor activity. This behavioural activation was similar in intensity to that observed after d-amphetamine (1 mg/kg, SC). The locomotor stimulation induced by MK-801 at 0.3 mg/kg was significantly inhibited by the D2 dopamine receptor antagonist raclopride (0.1-0.3 mg/kg, SC) and by the D1 receptor antagonist SCH 23390 (0.04 mg/kg, SC). The locomotor activity induced by a higher dose of MK-801 (0.5 mg/kg) was reduced by higher doses of raclopride or SCH 23390 administered alone (0.3 and 0.08 mg/kg, respectively), and was inhibited by simultaneous administration of ineffective doses. Raclopride significantly reduced d-amphetamine-induced locomotor activity at a dose (0.2 mg/kg) that also blocked the effects of a low dose of MK-801. In contrast, SCH 23390 blocked the effects of d-amphetamine at a dose (i.e. 0.01 mg/kg) lower than that needed to block MK-801. These results suggest that the dopaminergic system may in part mediate the locomotor effects induced by the NMDA antagonist, MK-801, in rats. However, the locomotor activity induced by MK-801 appears to be less sensitive to dopaminergic receptor blockade than that induced by d-amphetamine, suggesting that the underlying mechanisms, although similar, are not identical.

Animals↗
PubMed1993

Effect of clonidine on the responsiveness of infant rats to maternal stimuli.

Clonidine (0.1 mg/kg), an alpha 2-adrenoceptor agonist, stimulated ultrasonic callings in 10-day-old rats. Unlike normal isolated rat pups, the vocalizations of clonidine-treated rats appeared resilient to maternal cues. Thus, clonidine-induced vocalizations did not decrease during intraoral infusions with 10% sucrose, exposure to home cage bedding or tactile stimulation of the skin. Clonidine (0.05; 0.1; 0.2 mg/kg) also disrupted the attraction normally shown by infant rats to home cage odours in an olfactory place preference test. This effect by clonidine was not shared by raclopride (1-4 mg/kg), naltrexone (0.5-2.0 mg/kg) or propranolol (2.5-10.0 mg/kg). Clonidine-treated infants (0.05; 0.1; 0.2 mg/kg) also failed to apprehend and attach to the anaesthetized mother's nipple. The results raise the possibility that alpha 2-adrenoceptor activation blunts the infant's receptivity to maternal olfactory incentives and intensifies separation-induced responses.

Animals↗
PubMed1996

Mu opioid receptor mRNA in nucleus accumbens is elevated following dopamine receptor activation.

We have previously demonstrated that continuous cocaine treatment for three days induces a marked but transient increase in mu opioid receptor (MOR) mRNA in nucleus accumbens (n. acc.); SCH 23390 and eticlopride, selective antagonists of D1- and D2-like dopamine (DA) receptors, respectively, blocked this cocaine-induced upregulation of MOR mRNA in n. acc. suggesting involvement of both subfamilies of DA receptors in the effect of cocaine (1,2). In the present study the ability of the selective DA D3 receptor antagonist, nafadotride (3,4), to prevent the cocaine-induced upregulation of MOR mRNA in n. acc. has been examined. Also, regulation of MOR mRNA following chronic administration of the DA agonists, SKF 38393, R(+)-6-Bromo-APB hydrobromide, or bromocriptine, has been studied. Male Sprague-Dawley rats were treated for 3 days with saline, cocaine, the DA receptor agonists or antagonist delivered by osmotic minipump. Expression of MOR mRNA in n. acc. was estimated by quantitative competitive polymerase chain reaction (PCR) assays following reverse transcription. Nafadotride (1.0 mg/kg/day) prevented the cocaine-induced upregulation of MOR mRNA in n. acc. When administered alone, nafadotride did not change the expression of MOR mRNA. The levels of MOR mRNA were elevated in n. acc. after 3 days treatment with each of the DA agonists, SKF 38393 (4.0 mg/kg/day), R(+)-6-Bromo-APB hydrobromide (4.0 mg/kg/day), or bromocriptine (5.0 mg/kg/day). Thus, DA agonists mimick the effect of cocaine on the expression of MOR mRNA in n. acc. These data confirm the involvement of dopaminergic mechanisms in the mediation of cocaine effects, indicate the comparability of actions of indirect and direct DA agonists, and point to the usefulness of cocaine as a tool to expose interaction between dopaminergic and opioid systems. The results suggest that activation of more than one type of DA receptor is required for the increased expression of MOR mRNA.

Animals↗
PubMed1992

Comparative biochemical pharmacology of central nervous system dopamine D1 and D2 receptors.

The biochemical properties of central nervous system (CNS) dopamine (DA) D1 and D2 receptors were examined using the specific antagonists [3H]SCH23390 and [3H]raclopride, respectively. There is a different participation of sulfhydryl (-SH) and disulfide (-SS-) groups in the binding site and/or coupling to second messenger systems of D1 and D2 receptors. The ionic studies with [3H]SCH23390 showed slight agonist and antagonist affinity shifts for the D1 receptor. On the other hand, the D2 receptor is very sensitive to cations; even if lithium and sodium influence specific [3H]raclopride binding in a similar manner, there appear to be quantitative differences between these two ions that cannot be explained by surface charge mechanisms. The distribution of D1 and D2 receptors was heterogenous in both species, with the greatest densities in the neostriatum, where the highest concentrations of DA and metabolites were measured. Regions with low endogenous DA content (cerebral cortex and hippocampus) had lower densities of DA receptors. Furthermore, these binding sites were differentially localized within the various regions, and there were substantially more D1 than D2 receptors. The functional significance and heterogeneities in the distribution of D1 and D2 receptors can be related to dopaminergic innervation and turnover.

Aging↗
PubMed1992

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.

Animals↗
PubMed2005

Synthesis and anti-inflammatory testing of some new compounds incorporating 5-aminosalicylic acid (5-ASA) as potential prodrugs.

This work includes the synthesis of 15 final compounds (6a-h and 7b-h) as prodrugs of 5-ASA in the form of the acid itself, esters and amides linked by an amide linkage through a spacer to the endocyclic ring N of nicotinamide. Also, 15 new intermediate compounds were prepared. The target compounds (6b, 6f, 7b, and 7e-h) revealed potent analgesic and anti-inflammatory activities in comparison to sulfasalazine and 5-ASA. In addition, ulcerogenicity, LD50, in vivo and in vitro metabolism of compound 7f were determined.

Analgesics↗
PubMed1999

Comparison of three PET dopamine D2-like receptor ligands, [11C]raclopride, [11C]nemonapride and [11C]N-methylspiperone, in rats.

We studied the tracer kinetics of three dopamine D2-like receptor ligands, [11C]raclopride ([11C]RAC), [11C]nemonapride ([11C]NEM) and [11C]N-methylspiperone ([11C]MSP), in anesthetized rats by tissue dissection, ex vivo ARG and PET in order to clarify their characteristics for PET imaging. The in vivo affinity of the three ligands for the striatum ([11C]MSP > [11C]NEM > [11C]RAC) obeyed the in vitro affinity for dopamine D2 receptors. The affinity of [11C]RAC and [11C]MSP for the cerebellum was very low, but the affinity of [11C]NEM for the cerebellum was compatible to that for the cortex and was not to be ignored. Also the affinity of [11C]MSP for the cortex was relatively high. [11C]RAC showed the highest selectivity. The striatal PET image with [11C]RAC was clearer than that with [11C]NEM or [11C]MSP, but the activity decreased much faster than that measured by tissue dissection because of the partial volume effect. The striatal activity with [11C]NEM remained high and that with [11C]MSP gradually increased. [11C]RAC and [11C]MSP, but not [11C]NEM, showed a high accumulation in the periorbital region.

Animals↗
PubMed1999

An alternative synthesis of [11C]raclopride for routine use.

The standard method of [11C]raclopride synthesis requires a large amount of its desmethyl precursor. We prepared [11C]raclopride by methylation of a small amount of desmethyl derivative (0.3-0.5 mg) with [11C]methyl iodide in a DMF solution containing NaH, with a decay-corrected radiochemical yield of 11-14% based on [11C]methyl iodide and with a specific activity of 48 TBq/mmol for 25 min from EOB. The reaction was reproducible and reliable.

Dopamine Antagonists↗
PubMedDate not supplied

Trapezoidal area method for simulating physiological pharmacokinetics of drugs in animals.

A trapezoidal area method for simulating physiological pharmacokinetics of drugs in animals is proposed. Concentrations of ethoxybenzamide in rat tissues and diazepam in human plasma were simulated. The results showed that profiles of concentrations vs time in the body with this method were in a good agreement with those obtained with the Rang-Katta method. As compared with the Rang-Katta method, the present method has two special advantages: the time course of drug concentration in tissue can be estimated using simple equations and the speed for simulation is faster.

Animals↗
PubMed1997

Developmental differences in dopamine synthesis inhibition by (+/-)-7-OH-DPAT.

Dopamine synthesis modulation by the D2-family agonist (+/-)-7-OH-DPAT was explored in striatum, accumbens, and prefrontal cortex of 10-40 day old rats using the gamma-butyrolactone (GBL) autoreceptor model. GBL produced an age-dependent increase in dopamine synthesis that was inhibited by (+/-) 7-OH-DPAT (0.1-13.5 mg/kg) at all ages and antagonized by eticlopride in the nucleus accumbens and striatum. The ID50 of (+/-) 7-OH-DPAT increased with age, suggesting decreased autoreceptor sensitivity with maturation. In prefrontal cortex, (+/-) 7-OH-DPAT inhibited synthesis between 10-30 days, with no evidence of autoreceptor function at 40 days. Dopamine synthesis was also inhibited with the D3/D2 agonist quinpirole at 15 days of age in vivo and yielded similar results to those obtained with (+/-) 7-OH-DPAT. Finally, under conditions that result in low D2 receptor affinity, D3 specificity was examined in vitro at 15 days with (+/-) 7-OH-DPAT, which produced comparable (yet more potent) effects to those observed in vivo. These findings illustrate D3 autoreceptor-like activity in ascending dopamine regions and provide further support for transient prefrontal cortex autoreceptor-like function that recedes by puberty.

Age Factors↗
PubMed1998

Stimulation of forward locomotion by SCH-23390 and raclopride in d-amphetamine-treated rats.

In d-amphetamine-treated (4.0 mg kg(-1) s.c.) rats the selective dopamine D1 and D2/3 receptor antagonists SCH-23390 (2.5-20.0 microg kg(-1) s.c.) and raclopride (12.5-100.0 microg kg(-1) s.c.), respectively, produced a biphasic pattern of effects on forward locomotion, as observed in an open-field arena (approximately 0.5 m2). Thus, at the low doses of SCH-23390 (2.5-10.0 microg kg(-1)) or raclopride (12.5-50.0 microg kg(-1)), there was a statistically significant increase in forward locomotion, followed by suppression of the behavior at the higher doses. The SCH-23390-induced (5.0 microg kg(-1)) stimulation of forward locomotion was partially antagonized by concomitant raclopride treatment (12.5-25.0 microg kg(-1)) and the corresponding raclopride-induced (12.5 microg kg(-1)) stimulation was fully antagonized by treatment with SCH-23390 (2.5-5.0 microg kg(-1)). Furthermore, the SCH-23390- or raclopride-induced stimulation of forward locomotion was also antagonized by treatment with the alpha1-adrenoceptor antagonist prazosin (1.0 mg kg(-1) s.c.). These observations suggest that under conditions of an increased general tone at brain dopamine receptors, there is a mutual inhibitory synergy between dopamine D1 and D2/3 receptors.

Animals↗
PubMed1999

Effects of antidepressant drugs on the dopamine D2/D3 receptors in the rat brain differentiated by agonist and antagonist binding--an autoradiographic analysis.

In the present study the effect of antidepressant drugs on the density of dopamine D2/D3 receptors in the rat forebrain was examined using autoradiography, since this technique provides the appropriate anatomical resolution. Male Wistar rats were treated with three various antidepressant drugs: imipramine, citalopram and mianserin in a dose of 10 mg/kg p.o., acutely (single dose) or repeatedly (twice a day for 14 days). To estimate the distribution of D2/D3 receptors, we chose following radioligands: [3H]raclopride, a non-selective antagonist of D2/D3 receptors, and [3H]quinpirole, a non-selective D2/D3 agonist. When [3H]raclopride was used as a radioligand, no significant differences in the density of D2/D3 receptors were observed after administration of the investigated drugs. However, following repeated administration of imipramine, citalopram and mianserin, a significant increase in the binding of [3H]quinpirole was observed, both in the nucleus caudatus and nucleus accumbens septi. In some cases the increase of [3H]quinpirole binding was also observed after acute treatment with antidepressant drugs. Thus, using an agonist as a radioligand, we were able to see upregulation of dopamine D2/D3 receptors in the rat forebrain following administration of antidepressant drugs, which might be interpreted as the biochemical correlative for the postsynaptic dopamine D2/D3 receptor supersensitivity observed in previous behavioral studies.

Animals↗
PubMed2005

Biochemical characterization of trinitrotoluene transforming oxygen-insensitive nitroreductases from Clostridium acetobutylicum ATCC 824.

The genes that encode oxygen-insensitive nitroreductases from Clostridium acetobutylicum possessing 2,4,6-Trinitrotoluene (TNT) transformation activity were cloned, sequenced and characterized. The gene products NitA (MW 31 kDa) and NitB (MW 23 kDa) were purified to homogeneity. The NitA and NitB are oxygen-insensitive nitroreductases comprised of a single nitroreductase domain. NitA and NitB enzymes show spectral characteristics similar to flavoproteins. The biochemical characteristics of NitA and NitB are highly similar to those of NfsA, the major nitroreductase from E. coli. NitA exhibited broad specificity similar to that of E. coli NfsA and displayed no flavin reductase activity. NitB showed broad substrate specificity toward nitrocompounds in a pattern similar to NfsA and NfsB of Escherichia coli. NitB has high sequence similarity to NAD(P)H nitroreductase from Archaeoglobus fulgidus. NitA could utilize only NADH as an electron donor, whereas NitB utilized both NADH and NADPH as electron donors with a preference for NADH. The activity of both nitroreductases was high toward 2,4-Dinitrotoluene (2,4-DNT) as a substrate. Both the nitroreductases were inhibited by dicoumarol and salicyl hydroxamate. The nitroreductases showed higher relative expression on induction with TNT, nitrofurazone and nitrofurantoin compared to the uninduced control.

Amino Acid Sequence↗
PubMed2001

Nicotine potentiation of brain stimulation reward reversed by DH beta E and SCH 23390, but not by eticlopride, LY 314582 or MPEP in rats.

RATIONALE: Systemic nicotine administration increases dopamine and glutamate levels in reward-related brain areas. Nicotine-induced increases of dopamine in the nucleus accumbens are in part mediated by glutamatergic projections to the ventral tegmental area dopamine neurons. OBJECTIVES: To assess the effects of actions at acetylcholine, dopamine, presynaptic (mGluR(2/3)) and postsynaptic (mGluR(5)) metabotropic glutamate receptors (mGluRs) on the potentiation of brain stimulation reward induced by systemically administered nicotine (0.125-0.5 mg/kg; free base) in rats. METHODS: A discrete-trial current-threshold s stimulation reward procedure (electrodes placed in the posterior lateral hypothalamus) was used to assess the effects of DH beta E (0.5-5 mg/kg), an acetylcholine nicotinic receptor antagonist, SCH 23390 (1.25-5 microg/kg), a dopamine D(1) receptor antagonist, eticlopride (2.5-20 microg/kg), a dopamine D(2) receptor antagonist, LY 314582 (1-20 mg/kg), an mGluR(2/3) agonist, and MPEP (1-9 mg/kg), an mGluR(5) antagonist, on the reward potentiating effects of nicotine (0.25 mg/kg). RESULTS: DH beta E had no effect on reward thresholds when administered alone, but dose-dependently reversed the nicotine-induced potentiation of brain stimulation reward. SCH 23390 (5 microg/kg) elevated thresholds when administered alone, and reversed the nicotine-induced potentiation of brain stimulation reward even at a dose (2.5 microg/kg) that had no effect on reward thresholds. Eticlopride (10-20 microg/kg), LY 314582 (10-20 mg/kg) and MPEP (9 mg/kg) elevated thresholds when administered alone but had no effect on the nicotine-induced potentiation of brain stimulation reward. CONCLUSIONS: These results indicate that nicotinic and dopamine D(1) receptors are involved in the nicotine-induced potentiation of brain stimulation reward, while actions at dopamine D(2), mGlu(2/3) and mGlu(5) receptors did not modulate this effect of nicotine.

Animals↗
PubMed2002

Effects of SCH 23390 and eticlopride on cocaine-seeking produced by cocaine and WIN 35,428 in rats.

RATIONALE: Exposure to a small amount of cocaine can trigger relapse, and so an understanding of the mechanisms underlying cocaine-seeking are important for the development of effective anti-relapse treatments. OBJECTIVES: The present study sought to compare the contributions of dopamine D(1)- and D(2)-like receptors in drug-seeking produced by cocaine and WIN 35,428. METHODS: Reinstatement of extinguished cocaine self-administration was measured for rats that received injections of cocaine (5.0-20.0 mg/kg) or WIN 35,428 (0.1-1.0 mg/kg) following extinction. Prior to the injection of cocaine or WIN 35,428, rats received an injection of the D(1)-like antagonist, SCH 23390 (0.001-0.010 mg/kg) or the D(2)-like antagonist, eticlopride (0.01-0.30 mg/kg). Effects of SCH 23390 (0.01 mg/kg) on cocaine-produced locomotor activation were also measured in separate groups of rats. RESULTS: The ability of both cocaine and WIN 35,428 to produce cocaine-seeking was dose-dependent. Within the range of doses tested, SCH 23390 failed significantly to attenuate the ability of either cocaine or WIN 35,428 to reinstate extinguished cocaine self-administration, although cocaine-produced locomotor activation was significantly attenuated by pretreatment with the highest dose of SCH 23390. Eticlopride attenuated both cocaine and WIN 35,428 produced cocaine-seeking but lower doses were required to decrease WIN 35,428-produced cocaine-seeking. CONCLUSIONS: These results suggest that dopamine D(2) mechanisms are involved in cocaine-seeking produced by both cocaine and WIN 35,428. The lower potency of eticlopride in attenuating cocaine-produced cocaine-seeking suggest that cocaine's effects at sites other than the dopamine transporter contribute to its ability to elicit drug-seeking.

Animals↗
PubMed2003

Ability of dopamine antagonists to inhibit the locomotor effects of cocaine in sensitized and non-sensitized C57BL/6 mice depends on the challenge dose.

RATIONALE: Studies in rats examining the ability of selective dopamine D(2) receptor class antagonists to attenuate the effects of a cocaine challenge have suggested that these agents are less potent in attenuating sensitized as opposed to non-sensitized locomotion. A potential issue with these studies is that the same challenge dose is used in sensitized and control conditions even though that dose may occupy different positions on the respective dose-response curves. OBJECTIVES: To examine whether the ability of dopamine antagonists to attenuate cocaine-induced locomotion differs between sensitized and non-sensitized animals if they are challenged with the same dose of cocaine, and with the lowest dose to maximally increase locomotion, which is lower in sensitized than in non-sensitized animals. METHODS: Mice were treated repeatedly with 20 mg/kg cocaine or saline (for 3 consecutive days) and then challenged (after an 11-day drug-free interval) with different challenge doses of cocaine after pretreatment with a dopamine antagonist or saline. RESULTS: Using the same challenge dose of cocaine in both repeated treatment conditions (i.e. 20 mg/kg), the D(2 )class antagonists eticlopride and raclopride were less potent in attenuating the locomotor effects of cocaine in sensitized than those in non-sensitized animals. In contrast, when the lowest doses to maximally increase locomotion in each of the repeated treatment conditions were used (10 and 40 mg/kg), the D(2 )class antagonists attenuated the locomotor effects of cocaine in sensitized and non-sensitized animals with similar potencies. The ability of the D(1) class antagonist SCH23390 to attenuate the effects of cocaine demonstrated a similar dependency on the challenge dose. CONCLUSIONS: These results show that, under the present conditions, the ability of dopamine antagonists to attenuate cocaine-induced locomotion is similar in sensitized and non-sensitized animals when challenged with pharmacologically equivalent doses of cocaine, but not when challenged with the same dose.

Animals↗
PubMed2004

Effects of dopamine D1- or D2-like receptor antagonists on the hypermotive and discriminative stimulus effects of (+)-MDMA.

RATIONALE: Both dopamine (DA) and serotonin (5-HT) release are evoked by (+)-MDMA; however, little is known of the contribution of DA D1- and D2-like receptors (D1R and D2R, respectively) in the behavioral effects of (+)-MDMA. OBJECTIVES. To test the hypothesis that a D1R or D2R antagonist would attenuate the hypermotive or discriminative stimulus effects of (+)-MDMA. METHODS: Male Sprague-Dawley rats (n=164) were pretreated with the D1R antagonist SCH 23390 (3.125-50 microg/kg, s.c.) or the D2R antagonist eticlopride (12.5-50 microg/kg, s.c.) prior to treatment with (+)-MDMA (3 mg/kg, s.c.) and locomotor activity was recorded using photobeam monitors. Twelve additional rats trained to discriminate (+)-MDMA (1 mg/kg, i.p.) from saline in a two-lever water-reinforced FR20 task were administered SCH 23390 (6.25 microg/kg, i.p.) or eticlopride (12.5 microg/kg, i.p.) prior to (+)-MDMA (0.375-1.0 mg/kg, i.p.). Rats were then placed in the drug discrimination chambers and the percent (+)-MDMA appropriate responding and response rate were measured. RESULTS: Both SCH 23390 and eticlopride blocked (+)-MDMA-evoked hyperactivity in a dose-related manner; the highest doses of the antagonists also effectively suppressed basal locomotor activity. In rats trained to discriminate (+)-MDMA from saline, SCH 23390 (6.25 microg/kg), but not eticlopride (12.5 microg/kg), blocked the stimulus effects of (+)-MDMA without altering response rate. CONCLUSION. These data indicate that DA released indirectly by (+)-MDMA administration results in stimulation of D1R and D2R to enhance locomotor activity. Furthermore, the D1R appears to play a more prominent role than the D2R in the discriminative stimulus properties of (+)-MDMA.

Animals↗