-
Psychopharmacology Jun 2009Morphine relieves pain, in part, by acting on neurons within the periaqueductal gray (PAG). Given that the PAG contains a subpopulation of dopamine neurons, dopamine may...
RATIONALE
Morphine relieves pain, in part, by acting on neurons within the periaqueductal gray (PAG). Given that the PAG contains a subpopulation of dopamine neurons, dopamine may contribute to the antinociceptive effects mediated by the PAG.
METHODS
This hypothesis was tested by measuring the behavioral and electrophysiological effects of administering dopamine agonists and antagonists into the ventrolateral PAG (vPAG). An initial histological experiment verified the existence of dopamine neurons within the vPAG using dopamine transporter and tyrosine hydroxylase antibodies visualized with confocal microscopy.
RESULTS
Microinjection of cumulative doses of morphine into the vPAG caused antinociception that was dose-dependently inhibited by the dopamine receptor antagonist alpha-flupenthixol. alpha-Flupenthixol had no effect on nociception when administered alone. Injection of the dopamine receptor agonist (-) apomorphine into the vPAG caused a robust antinociception that was inhibited by the D2 antagonist eticlopride but not the D1 antagonist SCH-23390. The effects of dopamine on GABA(A)-mediated evoked inhibitory post-synaptic potentials (eIPSCs) were measured in PAG slices. Administration of met-enkephalin inhibited peak eIPSCs by 20-50%. Dopamine inhibited eIPSCs by approximately 20-25%. Administration of alpha-flupenthixol (20 muM) attenuated eIPSC inhibition by dopamine but had no effect on met-enkephalin-induced inhibition.
CONCLUSIONS
These data indicate that PAG dopamine has a direct antinociceptive effect in addition to modulating the antinociceptive effect of morphine. The lack of an effect of alpha-flupenthixol on opioid-inhibition of eIPSCs indicates that this modulation occurs in parallel or subsequent to inhibition of GABA release.
Topics: Analgesics; Analgesics, Opioid; Animals; Apomorphine; Dopamine; Dopamine Agonists; Dopamine Antagonists; Dopamine Plasma Membrane Transport Proteins; Flupenthixol; Immunohistochemistry; Male; Microinjections; Microscopy, Confocal; Morphine; Nerve Fibers; Neurons; Pain Measurement; Periaqueductal Gray; Rats; Rats, Sprague-Dawley; Receptors, Dopamine; Synaptic Transmission; Tyrosine 3-Monooxygenase; gamma-Aminobutyric Acid
PubMed: 19225762
DOI: 10.1007/s00213-009-1482-y -
Chemical & Pharmaceutical Bulletin Jul 2002In search of a dopamine D2 and serotonin 5-HT3 receptors dual antagonist as a potential broad antiemetic agent, a number of benzamides were prepared from...
Synthesis and structure-activity relationships of 4-amino-5-chloro-N-(1,4-dialkylhexahydro-1,4-diazepin-6-yl)-2-methoxybenzamide derivatives, novel and potent serotonin 5-HT3 and dopamine D2 receptors dual antagonist.
In search of a dopamine D2 and serotonin 5-HT3 receptors dual antagonist as a potential broad antiemetic agent, a number of benzamides were prepared from 4-amino-5-chloro-2-methoxybenzoic acid derivatives and 6-amino-1,4-dialkylhexahydro-1,4-diazepines and evaluated for their binding affinity for the dopamine D2 and the serotonin 5-HT3 receptors using rat brain synaptic and rat cortical membranes, respectively. From the results of both in vitro receptor binding and in vivo biological assays for the dopamine D2 receptor, 1-ethyl-4-methylhexahydro-1,4-diazepine ring was selected as an optimum amine moiety. Introduction of one methyl group on the nitrogen atom at the 4-position and/or modification of the substituent at the 5-position of the 4-amino-5-chloro-2-methoxybenzoyl moiety caused a marked increase in the dopamine D2 receptor binding affinity along with a potent 5-HT3 receptor binding affinity. Among the compounds, 5-chloro-N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)-2-methoxy-4-methylaminobenzamide (82), 5-bromo (110), and 5-iodo (112) analogues exhibited a much higher affinity for the dopamine D2 receptor than that of metoclopramide (IC50=17.5-61.0 nM vs. 483 nM). In particular, 82 showed a potent antagonistic activity for both receptors in vivo tests. Optical resolution of the racemate 82 brought about a dramatic change in the pharmacological profile with the (R)-enantiomer exhibiting a strong affinity for both the dopamine D2 and the 5-HT3 receptors, while the corresponding (S)-enantiomer had a potent and selective serotonin 5-HT3 receptor binding affinity.
Topics: Animals; Antiemetics; Apomorphine; Benzamides; Brain; Chemical Phenomena; Chemistry, Physical; Chromatography, High Pressure Liquid; Dogs; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Emetics; In Vitro Techniques; Indicators and Reagents; Rats; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Serotonin Antagonists; Structure-Activity Relationship
PubMed: 12130853
DOI: 10.1248/cpb.50.941 -
Neuroscience Letters Aug 2013Anxiety-related behaviors increase histamine and dopamine release in the brain. On the other hand, central histamine counteracts reward and reinforcement processes...
Anxiety-related behaviors increase histamine and dopamine release in the brain. On the other hand, central histamine counteracts reward and reinforcement processes mediated by the mesolimbic dopamine system. We investigated the effects of the histaminergic system and dopamine D2 receptors agents and their interactions on anxiety-related behaviors using the elevated plus-maze (EPM). The intra-hippocampal (Intra-CA1) microinjection of histamine (10 μg/mouse) decreased the percentage of open arm time (%OAT) and open arm entries (%OAE) but not the locomotor activity, indicating an anxiogenic-like response. Quinpirole (0.5 and 2 μg/mouse) or sulpiride (0.3 and 1 μg/mouse) when injected into the dorsal hippocampus also induced anxiety-like behavior, however, the drugs reversed the anxiogenic response induced by the effective dose of histamine (10 μg/mouse). Taken together and under the present experimental design, our results indicate that activation of the dorsal hippocampal histaminergic receptors causes anxiety-like behaviors altered by dopamine D2 receptor agonist and antagonist. Histamine can decrease dopaminergic tone in the dorsal hippocampus through decreasing the endogenous dopamine release, whereas quinpirole does the same via the postsynaptic DA receptors' activation. Sulpiride however renders the same effect through autoreceptors' blockade and potentiated dopamine transmission. Thus, quinpirole and sulpiride seem to compensate the effects of the intra-CA1 injection of exogenous histamine, and tend to exert anxiolytic effects in the presence of histamine.
Topics: Animals; Anxiety; Behavior, Animal; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Hippocampus; Histamine; Male; Mice; Motor Activity; Quinpirole; Receptors, Dopamine D2; Sulpiride
PubMed: 23872092
DOI: 10.1016/j.neulet.2013.07.009 -
British Journal of Pharmacology May 2001The anti-emetic and pharmacological profile of AS-8112 ((R)-5-bromo-N-(1-ethyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-2-methoxy-6-methylamino-3-pyridinecarboxamide.2...
The anti-emetic and pharmacological profile of AS-8112 ((R)-5-bromo-N-(1-ethyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-2-methoxy-6-methylamino-3-pyridinecarboxamide.2 fumarate), a novel and potent dopamine D2, D3 and 5-hydroxytryptamine-3 (5-HT3) receptors ligand, was investigated in the present study. In guinea-pig isolated colon, AS-8112 produced a rightward shift of the concentration-response curves of 2-methyl-5HT, a 5-HT3 receptor agonist (pA2 value of 7.04). Other 5-HT3 receptor antagonists also produced such a shift in the following antagonistic-potency order: granisetron> ondansetron=AS-8112>>metoclopramide. In mice, AS-8112 (1.0 - 3.0 mg kg(-1) s.c.) potently inhibited hypothermia induced by the dopamine D3 receptor agonist; R(+)-7-OH-DPAT (R(+)-7-hydroxy-2-(N,N-di-n-propylamino)tetraline) (0.3 mg kg(-1) s.c.). Domperidone and haloperidol, which have affinity for dopamine D3 receptor, also inhibited R(+)-7-OH-DPAT-induced hypothermia. In ferrets or dogs, AS-8112 dose-dependently inhibited emesis induced by R(+)-7-OH-DPAT, apomorphine, morphine or cisplatin with ID50 values of 2.22 microg kg(-1) s.c., 10.5 microg kg(-1) s.c., 14.2 microg kg(-1) i.v. and 17.6 microg kg(-1) i.v., respectively. Moreover, oral administration of AS-8112 significantly inhibited emesis induced by these emetogens. AS-8112 (0.3 mg kg(-1) i.v.) significantly inhibited emesis induced by cyclophosphamide and doxorubicin. In conclusion, AS-8112 is a potent dopamine D2, D3 and 5-HT3 receptors antagonist, and a novel anti-emetic agent with a broad-spectrum of anti-emetic activity. These results suggest that this compound is worthy of clinical investigation.
Topics: Animals; Antiemetics; Antineoplastic Agents; Apomorphine; Azepines; Colon; Dogs; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Ferrets; Guinea Pigs; Hypothermia; In Vitro Techniques; Male; Mice; Morphine; Muscle Contraction; Muscle, Smooth; Narcotics; Pyridines; Receptors, Dopamine D3; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Serotonin Antagonists; Tetrahydronaphthalenes; Vomiting
PubMed: 11350861
DOI: 10.1038/sj.bjp.0704078 -
The Journal of Pharmacology and... Sep 2015The chronic and relapsing nature of addiction presents unique challenges for ensuring the safety of a potential medication. A patient may use cocaine, for example, while...
The chronic and relapsing nature of addiction presents unique challenges for ensuring the safety of a potential medication. A patient may use cocaine, for example, while taking the medication or take more medication than prescribed. Thus, a potential medication must be safe and not exacerbate the effects of cocaine. Multiple published studies support antagonism of brain dopamine D3 receptor function as a potential mechanism of action for an anti-addiction medication. Dopamine D3 receptors are widely distributed outside the central nervous system, however; for example, dopamine D3 receptors in the kidneys are implicated in regulating blood pressure. The selective dopamine D3 receptor antagonist GSK598809 [1-(2-fluoro-4-trifluoromethyl-phenyl)-3-{3-[4-methyl-5-(4-methyl-oxazol-5-yl)-4H-[1,2,4]triazol-3-ylsulfanyl]-propyl}-3-aza-bicyclo[3.1.0]hexane] has been proposed as a medication to treat cocaine and other substance use disorders. The US Food and Drug Administration has established guidelines recommending safety studies to investigate potential undesirable pharmacodynamic effects of a substance in relation to exposure in the therapeutic range and above. Hence, we assessed the interaction between this selective dopamine D3 receptor antagonist and cocaine on hemodynamics and cardiac function in freely-moving, telemetered dogs before conducting a clinical trial. GSK598809 increased the hemodynamic effect of cocaine in this model. Thus, the increase in blood pressure after intravenous cocaine was greater in animals that had been pretreated with GSK598809 compared with vehicle. This finding suggests that GSK598809 in particular, and perhaps dopamine D3 receptor antagonists as a class, may produce unacceptable cardiovascular risks as medications to treat cocaine use disorder.
Topics: Animals; Azabicyclo Compounds; Behavior, Addictive; Blood Pressure; Cardiovascular Diseases; Cocaine; Cocaine-Related Disorders; Dogs; Dopamine Antagonists; Male; Oxazoles; Receptors, Dopamine D3
PubMed: 26177654
DOI: 10.1124/jpet.115.224121 -
Pharmaceutical Biology Dec 2017Guibourtia tessmannii (Caesalpiniaceae) is a plant traditionally used as aphrodisiac. We previously reported the pro-ejaculatory effects of the aqueous and methanol...
CONTEXT
Guibourtia tessmannii (Caesalpiniaceae) is a plant traditionally used as aphrodisiac. We previously reported the pro-ejaculatory effects of the aqueous and methanol extracts of G. tesmannii in spinal male rat. However, the mechanism underlying such effects has not been elucidated.
OBJECTIVE
This study characterizes the dopaminergic sub-type receptors involved in G. tesmannii-induced ejaculation in male Wistar rat.
MATERIALS AND METHODS
Urethane-anesthetized spinal male rats were intravenously treated with saline solution (1 mL/kg, control); dopamine (0.1 μmol/kg, reference); aqueous or methanol extracts of G. tesmannii (20 mg/kg) in the absence or presence of haloperidol (0.26 μmol/kg), a nonspecific dopaminergic receptor antagonist, Sch23390 (0.26 μmol/kg), a specific D1-like receptor antagonist or, sulpiride (0.26 μmol/kg), a specific D2-like receptor antagonist. Electromyography of the bulbospongiosus muscles and intraseminal pressure were recorded after urethral, penile and drug stimulations.
RESULTS
Urethral and penile stimulations, intravenous injection of dopamine or, aqueous and methanol extracts of G. tesmannii always triggered the expression of rhythmic contraction of the bulbospongiosus muscles with an average mean of 3.33 ± 0.43; 7.83 ± 0.85; 9.80 ± 0.86; 0.83 ± 0.54 and 2.67 ± 0.95 contractions, respectively. The intraseminal pressure was more expressed after urethral and penile stimulations (15.66 ± 1.58 and 13.60 ± 2.40 mmHg, respectively). In rats pretreated with haloperidol, Sch23390 or sulpiride, no ejaculation was recorded after intravenous injection of G. tesmannii extracts or dopamine.
DISCUSSION AND CONCLUSION
Guibourtia tesmannii-induced ejaculation requires the integrity of D and D-like receptors. These findings further justify the ethno-medicinal claims of G. tesmannii as an aphrodisiac.
Topics: Animals; Dopamine Antagonists; Ejaculation; Fabaceae; Male; Plant Extracts; Rats; Rats, Wistar; Receptors, Dopamine D1; Receptors, Dopamine D2; Spinal Injuries
PubMed: 28218041
DOI: 10.1080/13880209.2017.1291692 -
Acta Neurobiologiae Experimentalis 1996Antagonism of the discriminative stimulus properties of 10 mg/kg cocaine was studied in rats by use of the dopamine D1 antagonist SCH 23390 and the D2 antagonist...
Antagonism of the discriminative stimulus properties of 10 mg/kg cocaine was studied in rats by use of the dopamine D1 antagonist SCH 23390 and the D2 antagonist haloperidol. Whereas SCH 23390 and haloperidol were by themselves unable to antagonize the cueing properties of cocaine, the combination of both dopamine antagonists resulted in a complete blockade of the cocaine cue. In the presence of a fixed dose of 0.01 and 0.04 mg/kg haloperidol, the ED50's (it is the effective dose in 50% of the animals) of SCH 23390 for cocaine antagonism were 0.043 and 0.012 mg/kg, respectively. Similarly, the ED50's of haloperidol in combination with 0.01 and 0.04 mg/kg SCH 23390 were 0.021 and 0.024 mg/kg. The combined treatment of haloperidol and SCH 23390 resulted in strong response-rate reductions. At all combination regimens resulting in a complete blockade of the cocaine cue, response rate was reduced to less than 20% of the control values. These results indicate that the cueing properties of cocaine are both dopamine D1- and D2-mediated and that a combined antagonism of both receptor subtypes can lead to a complete antagonism of the cueing properties of cocaine which is associated with severe attenuation of response rate.
Topics: Animals; Benzazepines; Cocaine; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Haloperidol; Male; Rats; Rats, Wistar; Receptors, Dopamine D1
PubMed: 9033125
DOI: 10.55782/ane-1996-1197 -
Psychopharmacology Mar 2017Animal models with predictive and construct validity are necessary for developing novel and efficient therapeutics for psychiatric disorders.
RATIONALE
Animal models with predictive and construct validity are necessary for developing novel and efficient therapeutics for psychiatric disorders.
OBJECTIVES
We have carried out a pharmacological characterization of the Roman high- (RHA-I) and low-avoidance (RLA-I) rat strains with different acutely administered propsychotic (DOI, MK-801) and antipsychotic drugs (haloperidol, clozapine), as well as apomorphine, on prepulse inhibition (PPI) of startle and locomotor activity (activity cages).
RESULTS
RHA-I rats display a consistent deficit of PPI compared with RLA-I rats. The typical antipsychotic haloperidol (dopamine D2 receptor antagonist) reversed the PPI deficit characteristic of RHA-I rats (in particular at 65 and 70 dB prepulse intensities) and reduced locomotion in both strains. The atypical antipsychotic clozapine (serotonin/dopamine receptor antagonist) did not affect PPI in either strain, but decreased locomotion in a dose-dependent manner in both rat strains. The mixed dopamine D1/D2 agonist, apomorphine, at the dose of 0.05 mg/kg, decreased PPI in RHA-I, but not RLA-I rats. The hallucinogen drug DOI (5-HT2A agonist; 0.1-1.0 mg/kg) disrupted PPI in RLA-I rats in a dose-dependent manner at the 70 dB prepulse intensity, while in RHA-I rats, only the 0.5 mg/kg dose impaired PPI at the 80 dB prepulse intensity. DOI slightly decreased locomotion in both strains. Finally, clozapine attenuated the PPI impairment induced by the NMDA receptor antagonist MK-801 only in RLA-I rats.
CONCLUSIONS
These results add experimental evidence to the view that RHA-I rats represent a model with predictive and construct validity of some dopamine and 5-HT2A receptor-related features of schizophrenia.
Topics: Amphetamines; Animals; Antipsychotic Agents; Apomorphine; Avoidance Learning; Clozapine; Dizocilpine Maleate; Dopamine Agonists; Dopamine Antagonists; Excitatory Amino Acid Antagonists; Haloperidol; Locomotion; Male; Prepulse Inhibition; Rats; Receptor, Serotonin, 5-HT2A; Reflex, Startle; Schizophrenia; Serotonin 5-HT2 Receptor Agonists; Serotonin Antagonists
PubMed: 28154892
DOI: 10.1007/s00213-017-4534-8 -
ACS Chemical Neuroscience May 2013Simultaneous electrochemical and electrophysiological data were recorded to evaluate the effects of controlled local application of dopaminergic agonists and antagonists...
Simultaneous electrochemical and electrophysiological data were recorded to evaluate the effects of controlled local application of dopaminergic agonists and antagonists in awake rats. Measurements were made with a probe consisting of a carbon-fiber microelectrode fused to three iontophoretic barrels used to introduce the drugs of interest. The probe and the manipulator used to position it in the brain of behaving animals were optimized to improve their performance. The effect of the dopamine autoreceptor on electrically stimulated release was demonstrated. Dopamine inhibited the release of endogenous dopamine whereas raclopride, a D2 antagonist, enhanced it, with similar responses in anesthetized and awake animals. We also examined changes in the firing rate of nucleus accumbens (NAc) neurons in awake animals during and after brief (15 s) iontophoretic ejections of SCH 23390 (D1 receptor antagonist) or raclopride. Changes in response to these antagonists were seen both immediately and on a prolonged time scale. Application of raclopride increased the firing rate in 40% of medium spiny neurons (MSNs), of which half responded immediately. Decreases in firing rate were observed in 46% of MSNs after SCH 23390 application. Only 11% of MSNs responded to both antagonists and one MSN (3%) showed no response to either drug. The same prolonged response in firing rate was seen for electrically stimulated and locally applied dopamine in 75% of MSNs. These results are in agreement with previously reported distributions for dopamine receptor subtypes on MSNs and probe the effects of dopamine on these cell populations.
Topics: Animals; Behavior, Animal; Benzazepines; Dopamine Agonists; Dopamine Antagonists; Electrochemical Techniques; Evoked Potentials; Iontophoresis; Male; Microelectrodes; Neurons; Nucleus Accumbens; Raclopride; Rats; Rats, Sprague-Dawley
PubMed: 23480099
DOI: 10.1021/cn400031v -
Japanese Journal of Pharmacology Oct 1980The inhibitory effect of sulpiride on dopamine receptors was investigated in the exocrine pancreas of dogs anesthetized with pentobarbital and with the stomach ligated...
The inhibitory effect of sulpiride on dopamine receptors was investigated in the exocrine pancreas of dogs anesthetized with pentobarbital and with the stomach ligated at the pylorus. All test substances were given intravenously. Dopamine, acetylcholine, histamine and secretin produced a dose-related increase in pancreatic juice secretion, though the dose-effect curves of these secretagogues differed in shape. Epinephrine, norepinephrine, isoproterenol, methamphetamine and serotonin had no secretagogue effects. The effects of acetylcholine and histamine were inhibited by atropine and cimetidine, respectively. The effect of dopamine was blocked by haloperidol, but not by atropine, cimetidine, phentolamine and propranolol. These results suggest that dopamine acts on specific dopamine receptors related to the exocrine pancreatic secretion. Haloperidol had no effect on the effects of acetylcholine and histamine, but did inhibit the secretin-induced secretion, though the inhibitory effect was to a lesser extent than on the dopamine response. Sulpiride and chlorpromazine also suppressed dose-dependently the dopamine-induced secretion. The inhibitory activity of sulpiride was almost the same as that of haloperidol, and 12 times more potent than that of chlorpromazine. Sulpiride was found to be a potent dopamine antagonist in the canine exocrine pancreas.
Topics: Acetylcholine; Animals; Atropine; Binding Sites; Cimetidine; Dogs; Dopamine Antagonists; Female; Histamine Antagonists; Male; Pancreas; Pancreatic Juice; Receptors, Dopamine; Stimulation, Chemical; Sulpiride
PubMed: 7206375
DOI: 10.1254/jjp.30.689