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The Journal of Pharmacology and... Apr 2001Antipsychotic drugs comprise a wide range of structurally diverse compounds and are considered to be antagonists at dopamine D2 receptors. High-resolution kinetic...
Antipsychotic drugs comprise a wide range of structurally diverse compounds and are considered to be antagonists at dopamine D2 receptors. High-resolution kinetic analyses of their antagonist properties was performed by monitoring dynamic dopamine (DA)-antagonist interactions at the recombinant human dopamine D(2short) receptor. Time-dependent Ca2+ responses were measured following activation of a chimeric G(alphaq/o) protein in Chinese hamster ovary-K1 cells. DA (10 microM) induced a rapid, high-magnitude Ca2+ response (T(max) = 13.2 +/- 0.7 s) followed by a low-magnitude phase, which continued throughout the recorded time period (15 min). Of a large series of putative DA antagonists, (+)-UH 232 and bromerguride demonstrated positive, DA-like intrinsic activity at the presumably unoccupied, DA-free receptor; the other antagonists being silent. Antagonists differed in terms of their abilities to prevent the high-magnitude Ca2+ phase in the antagonist-bound receptor state, and to reverse the low-magnitude Ca2+ phase in the DA-bound state. The benzamide derivatives tropapride and nemonapride fully antagonized both the high- and low-magnitude Ca2+ response. Haloperidol, risperidone, and S 14066 also antagonized both responses but with a maximal effect of only 62 to 79%. Although preventing the high-magnitude response (85-95%), the further putative antagonists (+)-butaclamol (6%), bromerguride (27%), and domperidone (41%) reversed the low-magnitude response only weakly and partially. These Ca2+ data indicate that putative DA antagonists act differently, in particular, at the DA-bound D(2short) receptor.
Topics: Animals; CHO Cells; Calcium; Cricetinae; Dopamine; Dopamine Antagonists; Dose-Response Relationship, Drug; Humans; Receptors, Dopamine D2; Recombinant Proteins
PubMed: 11259537
DOI: No ID Found -
Pharmacology, Biochemistry, and Behavior Dec 2013Human cocaine users report that the initial "high" produced by cocaine administration is followed by an anxiogenic "crash". Given that cocaine has such robust and...
Human cocaine users report that the initial "high" produced by cocaine administration is followed by an anxiogenic "crash". Given that cocaine has such robust and opposing properties, it is likely that both positive and negative effects of cocaine contribute to an individual's motivation to administer the drug. Despite this likelihood, the neurobiology underlying cocaine's dual processes remains unclear. While much literature supports a role for dopamine (DA) in cocaine reward, it is uncertain if DA also contributes to the drug's negative effects. Our laboratory has extensively utilized a modified conditioned place test to explore cocaine's opponent processes. In this paradigm rats develop conditioned place preferences (CPPs) for an environment paired with the immediate/positive effects of cocaine, and conditioned place aversions (CPAs) for an environment paired with the delayed/negative effects present 15-min after i.v. injection. In the current study rats were conditioned to associate an environment with either the immediate or delayed effects of i.v. cocaine (1mg/kg/0.1ml) 3h after i.p. pre-treatment with either the DA D1/D2 receptor antagonist cis-flupenthixol (0.5mg/kg/ml) or saline vehicle. As expected, vehicle-treated control animals developed the normal pattern of CPPs for cocaine's immediate effects or CPAs for the delayed effects of cocaine. However, while DA receptor antagonism prevented the expression of cocaine CPPs it did not alter the expression of cocaine-induced CPAs. These data confirm a role for DA transmission in cocaine reward but suggest that different neural pathways mediate the drug's negative/anxiogenic properties.
Topics: Animals; Cocaine; Dopamine Antagonists; Flupenthixol; Locomotion; Male; Motivation; Rats; Rats, Sprague-Dawley
PubMed: 24012795
DOI: 10.1016/j.pbb.2013.08.014 -
Behavioural Brain Research Jul 2016Genetically-modified mice without the dopamine transporter (DAT) are hyperdopaminergic, and serve as models for studies of addiction, mania and hyperactive disorders....
Genetically-modified mice without the dopamine transporter (DAT) are hyperdopaminergic, and serve as models for studies of addiction, mania and hyperactive disorders. Here we investigated the capacity for object recognition in mildly hyperdopaminergic mice heterozygous for DAT (DAT +/-), with synaptic dopaminergic levels situated between those shown by DAT -/- homozygous and wild-type (WT) mice. We used a classical dopamine D2 antagonist, haloperidol, to modulate the levels of dopaminergic transmission in a dose-dependent manner, before or after exploring novel objects. In comparison with WT mice, DAT +/- mice showed a deficit in object recognition upon subsequent testing 24h later. This deficit was compensated by a single 0.05mg/kg haloperidol injection 30min before training. In all mice, a 0.3mg/kg haloperidol injected immediately after training impaired object recognition. The results indicate that a mild enhancement of dopaminergic levels can be detrimental to object recognition, and that this deficit can be rescued by a low dose of a D2 dopamine receptor antagonist. This suggests that novel object recognition is optimal at intermediate levels of D2 receptor activity.
Topics: Animals; Dopamine Antagonists; Dopamine Plasma Membrane Transport Proteins; Dose-Response Relationship, Drug; Haloperidol; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Recognition, Psychology; Statistics, Nonparametric
PubMed: 27059337
DOI: 10.1016/j.bbr.2016.04.009 -
Pharmacology, Biochemistry, and Behavior Oct 20008-[3-(4-Fluorophenoxy) propyl]-1-phenyl-1,3,8-triazaspiro[4, 5]decan-4-one (AMI-193) was developed as a 5-HT(2A)-selective antagonist with in vivo activity suitable for...
8-[3-(4-Fluorophenoxy) propyl]-1-phenyl-1,3,8-triazaspiro[4, 5]decan-4-one (AMI-193) was developed as a 5-HT(2A)-selective antagonist with in vivo activity suitable for behavioral studies. However, AMI-193 is a potent dopamine D(2)-receptor antagonist with low nanomolar affinity. Accordingly, D(2)-actions may contribute to its behavioral pharmacology. In the present study, the effects of AMI-193 on operant behavior were characterized in squirrel monkeys. In subjects trained under a fixed-interval (FI) schedule of stimulus termination, AMI-193 (0.003-0.01 mg/kg) dose-dependently decreased response rate. When administered in combination with cocaine (0.03-3. 0 mg/kg) or the selective dopamine uptake inhibitor, GBR 12909 (0. 03-3.0 mg/kg), the rate-decreasing effects of AMI-193 were reversed by both dopamine indirect agonists. In drug-discrimination experiments, AMI-193 (0.003 and 0.01 mg/kg) attenuated the discriminative-stimulus effects of cocaine. AMI-193 (0.003 and 0.01 mg/kg) also reduced response rate under a second-order schedule of i. v. self-administration of cocaine (0.1 mg/infusion). The profile of behavioral effects and drug interactions observed in the present study, in conjunction with the relatively high affinity of AMI-193 for dopamine D(2) receptors, suggests that its D(2)-antagonist effects play a prominent role in the behavioral pharmacology of AMI-193.
Topics: Animals; Aza Compounds; Behavior, Animal; Cocaine; Discrimination Learning; Discrimination, Psychological; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Drug Administration Schedule; Male; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Saimiri; Serotonin Antagonists; Spiro Compounds
PubMed: 11124389
DOI: 10.1016/s0091-3057(00)00321-x -
Pharmacology, Biochemistry, and Behavior May 2016Despite the high prevalence of methamphetamine (METH) use, no FDA-approved pharmacological treatment is currently available for individuals with a METH addiction....
Despite the high prevalence of methamphetamine (METH) use, no FDA-approved pharmacological treatment is currently available for individuals with a METH addiction. Levo-tetrahydropalmatine (l-THP) is an alkaloid substance derived from corydalis and stephania that has been used in traditional Asian medicine for its analgesic, sedative and hypnotic properties. Previous pharmacological studies of l-THP indicated that it not only binds to D1 and D2 receptors but also has a low affinity for D3 receptors and may function as an antagonist. The unique pharmacological profile of l-THP suggests that it may have potential therapeutic effects on drug addiction; however, the effects of l-THP in individuals with METH addictions are largely unknown. In this study, we investigated the effects of l-THP on METH self-administration and METH-induced reinstatement. In our experiments, l-THP (1.25, 2.50 and 5.00 mg/kg, i.p.) decreased METH self-administration under the fixed-ratio 1 schedule. l-THP (2.50 and 5.00 mg/kg, i.p) also prevented the METH-induced reinstatement of METH-seeking behaviors. Interestingly, l-THP (1.25 and 2.50mg/kg, i.p) did not affect locomotor activity following METH injection (1mg/kg) suggesting that the observed effects of l-THP (2.50mg/kg) on METH-induced reinstatement were not due to motor impairments. Thus, l-THP (a natural, mixed dopamine (DA) receptor antagonist) attenuates METH self-administration and METH-induced reinstatement.
Topics: Animals; Berberine Alkaloids; Dopamine Antagonists; Locomotion; Male; Methamphetamine; Rats; Rats, Sprague-Dawley; Self Administration
PubMed: 26806555
DOI: 10.1016/j.pbb.2016.01.010 -
Journal of Animal Science Nov 1994Effects on rat brain D2 dopamine receptors by endophyte-infected tall fescue seed consumption and antagonist injection were characterized. Forty-eight male Wistar rats...
Effects on rat brain D2 dopamine receptors by endophyte-infected tall fescue seed consumption and antagonist injection were characterized. Forty-eight male Wistar rats (225 g) in three separate trials were exposed to either 22 or 32 degrees C. Diets, to maintain similar concentrations of ergovaline, contained 10% (Trial 1) or 15% (Trials 2 and 3) endophyte-infected (E+; 325 average ppb of ergovaline) or uninfected (E-; 0 ppb of ergovaline) tall fescue seed. Rats were injected i.p. daily with either placebo (PL) or an experimental D2 dopamine antagonist (DA, .0375 mg/kg BW). No effects (P > .10) on diet DM intake by E+ ingestion or DA injection were detected at 22 degrees C. However, ingestion of E+ reduced (P < .01) and injection of DA improved (P < .05) DM intake of rats housed in 32 degrees C (11.1 vs 15.4 g of DM/d for E+ vs E-, respectively). Whole brain D2 dopamine receptor density (Bmax) and mRNA were reduced (P < .05) by E+ and increased (P < .05) by DA in Trial 1. No treatment effects (P > .10) on cerebral cortex alpha 1- and alpha 2-adrenergic or striatal D2 dopamine receptor Bmax were measured in Trials 2 and 3. In summary, dietary E+ reduced whole brain D2 dopamine mRNA and Bmax, whereas injection of DA increased D2 dopamine mRNA. Thus, long-term regulation of monoamine receptors seems to be affected by E+ ingestion or DA injection.
Topics: Animals; Blotting, Northern; Brain Chemistry; Dopamine Antagonists; Ergotamines; Male; Plant Poisoning; Poaceae; RNA, Messenger; Rats; Rats, Wistar; Receptors, Dopamine D2; Seeds; Vasoconstrictor Agents
PubMed: 7730184
DOI: 10.2527/1994.72112905x -
European Journal of Pharmacology Dec 1994S 14506 (1-[-(4-fluorobenzoylamino)ethyl]-4-(7-methoxynaphthyl)piper azine hydrochloride), 8-OH-DPAT ((+/-)-8-hydroxydipropylaminotetralin hydrobromide), clozapine and...
S 14506 (1-[-(4-fluorobenzoylamino)ethyl]-4-(7-methoxynaphthyl)piper azine hydrochloride), 8-OH-DPAT ((+/-)-8-hydroxydipropylaminotetralin hydrobromide), clozapine and raclopride were compared in some behavioural models able to characterize dopamine antagonist properties. In mice treated with apomorphine (0.75 mg/kg, s.c.), stereotyped climbing and sniffing were dose dependently antagonized by S 14506, by clozapine and by raclopride, but were virtually not modified by 8-OH-DPAT. Stereotyped climbing and sniffing induced by (+)-amphetamine (1.25 mg/kg, s.c.) in mice treated with L-DOPA (L-3,4-dihydroxyphenylalanine 75 mg/kg, associated with benserazide, i.p.) were also dose dependently antagonized by S 14506 and by raclopride, but were only partially antagonized by clozapine and unaffected by 8-OH-DPAT. Grooming behaviour induced by SK&F 38393 ((+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride, 1.87 mg/kg, s.c.) in mice was inhibited by low doses of S 14506 and of clozapine, and by relatively high doses of 8-OH-DPAT and of raclopride. The decreased grooming behaviour observed in apomorphine-treated mice was partly antagonized by high dose of raclopride but was significantly potentiated by S 14506, 8-OH-DPAT and clozapine. Raclopride produced the same effect in mice treated with (+)-amphetamine and L-DOPA. In rats treated with apomorphine (0.6 mg/kg, s.c.), sniffing was dose dependently antagonized by S 14506, by raclopride and by clozapine, but not by 8-OH-DPAT. Again, whereas increasing doses of raclopride allowed grooming to reappear in apomorphine (0.6 mg/kg)-treated rats, S 14506, 8-OH-DPAT and clozapine did not. Raclopride induced catalepsy in rats, whereas like clozapine, S 14506 was virtually ineffective. All the tested compounds inhibited in vitro [3H]raclopride binding in rat striatum (raclopride > S 14506 > clozapine > 8-OH-DPAT), whereas only clozapine inhibited [3H]SCH 23390 binding. Finally, S 14506 inhibited the in vivo binding of [3H]raclopride in striatum and olfactory bulbs, but did not affect the striatal in vivo binding of [3H]SCH 23390. From these data, it appears that like raclopride, S 14506 displays dopamine antagonist properties by blocking dopamine D2 receptors. However, the psychopharmacological profile of S 14506 is closer to that of clozapine than to that of raclopride, probably as a result of its actions at 5-HT receptors.
Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Behavior, Animal; Benzamides; Benzazepines; Catalepsy; Clozapine; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Grooming; Male; Mice; Piperazines; Raclopride; Rats; Rats, Wistar; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2; Salicylamides; Stereotyped Behavior
PubMed: 7698199
DOI: 10.1016/0014-2999(94)90277-1 -
Birth Defects Research Mar 2019
Topics: Dopamine Antagonists; Molindone; Reproduction
PubMed: 30632696
DOI: 10.1002/bdr2.1447 -
Psychopharmacology May 1999Blockade of D1/D2 dopamine receptors produce an antiaggressive action commonly associated with an impairment of other motor behaviors. The D3 receptor seems to present...
RATIONALE
Blockade of D1/D2 dopamine receptors produce an antiaggressive action commonly associated with an impairment of other motor behaviors. The D3 receptor seems to present opposite actions to the D1 and D2, since the blockade of this receptor produces stimulation of motor activity which has been associated with an increase in dopamine neurotransmission.
OBJECTIVE
In this work, the action of the dopamine D3 antagonist U-99194a maleate on locomotor activity and in a social interaction test in male mice was evaluated.
METHODS
Animals isolated during 30 days were treated with U-99194a maleate (20-40 mg/kg) or saline and locomotor activity was measured 20 min after drug administration. The behavioral interaction test was performed afterwards, between the experimental isolated animal and a standard opponent.
RESULTS
The higher dose used produces a significant decrease in spontaneous motor activity and presents an antiaggressive action without impairment of other behaviors, such as nonsocial exploration or immobility. At all doses tested, U-99194a maleate significantly increases social investigation.
CONCLUSIONS
Our results give support to the hypothesis that the D3 receptor could play a role in emotional behaviors.
Topics: Aggression; Analysis of Variance; Animals; Behavior, Animal; Dopamine Antagonists; Indans; Male; Mice
PubMed: 10379629
DOI: 10.1007/s002130050981 -
Theriogenology Nov 2015Estradiol decreases the pulse frequency of LH during the nonbreeding season through dopaminergic neurons that results in anestrus in the ewe. Long-term administration of...
Estradiol decreases the pulse frequency of LH during the nonbreeding season through dopaminergic neurons that results in anestrus in the ewe. Long-term administration of sulpiride, a dopamine antagonist, induced ovulation in seasonally anestrus mares. Accordingly, we tested whether sulpiride would induce ovulatory estrus in seasonally anestrus Malpura ewes. A total of 12 Malpura ewes were divided into sulpiride (at 0.6 mg/kg b.i.d.) or control groups. Anestrus was defined on the basis of the absence of heat signs for 2 months through twice-a-day heat detection during the nonbreeding season (October-November) and progesterone level of less than 1 ng/mL. Rates of estrus induction, ovulation, multiple ovulations, and lambing in the sulpiride-treated ewes were 83.3%, 100%, 16.6%, and 66.7%, respectively. The mean interval from treatment to estrus was 5.25 ± 1.49 days. Progesterone levels were elevated after ovulation significantly on Days 5 and 7 after estrus as compared to Day 0 after sulpiride treatment (P < 0.05). In contrast, none of the control group ewes showed either estrus or ovulation. There was a significant association between sulpiride treatment and estrus induction rate as well as ovulation rate (P < 0.05). It is concluded that the result provides proof of concept that the dopamine antagonist can induce ovulation in seasonally anestrus ewes.
Topics: Anestrus; Animals; Dopamine Antagonists; Female; Ovulation Induction; Progesterone; Sheep; Sulpiride
PubMed: 26275500
DOI: 10.1016/j.theriogenology.2015.07.020