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1.
The discriminative stimulus (DS) effect of apomorphine was investigated in rats trained in a two-lever, food-reinforcement procedure. Rats were given subcutaneous injections of saline or 0.1 mg/kg apomorphine HCl, 15 min before training sessions. The training dose of apomorphine was chosen to activate dopamine autoreceptors selectively. Stimulus generalization studies demonstrated that the DS effects generalized completely to other directacting dopaminergic agonists such as N-n-propylnorapomorphine (NPNA), pergolide, lergotrile, and bromocriptine. The indirect-acting dopamine agonists, (+)amphetamine, cocaine, and methylphenidate produced predominantly saline-appropriate lever responses. The DS effect of apomorphine at the training dose was incompletely antagonized by haloperidol or metoclopramide. The dopaminergic antagonists tested, however, also partially generalized to apomorphine. Both enantiomers of 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) produced apomorphine-appropriate lever choice with the (-) enantiomer being slightly more potent. The discriminative property of this (0.1 mg/kg) dose of apomorphine has characteristics consistent with selective dopamine autoreceptor activation. 相似文献
2.
This study assessed the effects of IP injections of (±) 7-hydroxy-2(N,N-di-n-propylamino)tetralin (7-OH-DPAT), a dopamine agonist that has been reported to have preferential affinity for the dopamine D3 subtype of receptor, on four behavioural procedures in the rat: 1) spontaneous locomotion, 2) electrical self-stimulation of the ventral tegmental area (VTA), using the curve-shift procedure 3) operant responding for food under a progressive-ratio (PR) schedule and 4) induction of stereotypies. The effects of (±) 7-OH-DPAT were compared to the effects of apomorphine, a non-specific DA agonist, and quinpirole, a selective D2/D3 agonist. All three dopamine agonists decreased locomotor activity at low doses (0.01–0.3 mg/kg), and only apomorphine had clear locomotor stimulant effects at the highest dose tested (3 mg/kg). The three drugs dose-dependently depressed VTA self-stimulation in a similar way, with low doses inducing a fairly parallel rightward shift of the frequency/rate curves and higher doses flattening the curves. In contrast, responding for food under the PR schedule appeared to be differentially affected by the three agonists: 7-OH-DPAT induced a biphasic effect, with a maximal decrease in lever-pressing at 0.1 mg/kg, followed by a return to baseline levels with increasing doses (0.3–3 mg/kg); quinpirole showed a tendency to decrease responding over the whole dose-range tested with a maximal effect of about 50% of baseline between 0.25 and 1 mg/kg, and apomorphine dose-dependently decreased responding, with rats ceasing to respond at 0.3 mg/kg. All three DA agonists induced stereotypies, but there was a difference in the maximal stereotypy score induced by each of the ligands: 7-OH-DPAT produced a lower maximal effect than quinpirole or apomorphine. This indicates that each of the three dopamine agonists preferentially induced different types of stereotypies. Together, these data suggest that the putative dopamine D3 agonist 7-OH-DPAT, at low doses, has depressant effects similar to those induced by low doses of the other two DA agonists. Differences in the behavioural effects of higher doses were, however, mostly observed in two procedures, PR responding and induction of stereotypies. 相似文献
3.
Previous studies have shown that discriminative stimulus control established with the 5HT1A receptor agonist, 8-OH-DPAT, generalises to other 5HT1A agonists and partial agonists but also to the 2-adrenoceptor antagonist, yohimbine. On the basis of these results it has been proposed that the 8-OH-DPAT cue may be produced by activity at more than one receptor. In the present study rats were trained to discriminate a dose of 8-OH-DPAT (0.05 mg/kg, SC) from saline. Substitution tests showed dose-dependent generalisation with the 5HT1A compounds, buspirone, ipsapirone, MDL 72832 and MDL 73005EF, the 2-adrenoceptor antagonists, yohimbine and idazoxan, and BMY 14802, which is usually described as a sigma ligand. The buspirone metabolite 1-pyrimidinyl piperazine (1-PP) which possesses mainly 2-adrenoceptor antagonist properties produced only partial generalisation which was not dose related. Receptor binding studies showed that all the compounds which substituted for 8-OH-DPAT displaced [3H]-8-OH-DPAT binding to rat hippocampal membranes. Furthermore, there were statistically significant positive correlations between drug affinity for 5HT1A sites and their ED50 values for both substitution for 8-OH-DPAT and potency to decrease response rates. These results are consistent with the view that the 8-OH-DPAT cue, like the ability of the compounds tested to decrease rates of responding, is largely mediated by activity at 5HT1A receptors. 相似文献
4.
Four rhesus monkeys were trained to discriminate the effect of apomorphine (0.1 mg/kg IM) from that of saline injections. The discriminative stimulus (DS) effect of apomorphine generalized to the dopamine D2 receptor agonist quinpirole. The D1 dopamine receptor agonist SKF 38393 elicited responses only on the saline-appropriate lever. Stimulus generalization of the dopamine autoreceptor agonist 3-PPP exhibited stereospecificity favoring the (+) over the (-) isomer. d-Amphetamine, phencyclidine, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), and clonidine did not share the DS effect of apomorphine. The D2-selective antagonists sulpiride and metoclopramide reversed both the DS effect and the response rate reduction produced by the training dose of apomorphine. Chlorpromazine and the D1 antagonist Sch 23390 also antagonized the DS effect, but the antagonism was accompanied by a further rate reduction. Haloperidol and clozapine antagonized the DS effect incompletely. The DS effect produced by apomorphine in this study appears to be mediated predominantly by post-synaptic D2 receptor activation, with contribution also from the D1 receptor. 相似文献
5.
It was recently documented that the relatively selective dopamine D3 receptor antagonist, PNU-99194A, is capable of establishing discriminative stimulus control in rats and that the discriminative
cue associated with this compound is not similar to that produced by psychostimulants. The present experiment further characterized
the discriminative stimulus properties of PNU-99194A by examining several other dopaminergic agents for stimulus generalization
in 23 male Sprague-Dawley rats trained to discriminate 10 mg/kg PNU-99194A (SC, 15 min) from vehicle in a two-choice discrimination
procedure under an FR10 schedule of food reinforcement. Rats achieved a criterion of ten consecutive sessions with correct
lever choice after a median of 35.5 sessions (range 23–78). In substitution tests, the non-selective D2 receptor antagonist, halo- peridol (0.01– 0.1 mg/kg), and the mixed D2/D3 antagonists, amisulpiride (3.2–32 mg/kg) and sulpiride (32–200 mg/kg), failed to produce stimulus generalization, while the
D3-preferring antagonists, (–)-DS121 (1–10 mg/kg) and (+)-AJ76 (3.2–32 mg/kg), produced complete stimulus generalization. Direct
and indirect DA agonists, including apomorphine (0.01–0.32 mg/kg) and d-amphetamine (0.1–1 mg/kg), the D1 agonist SKF-38393 (10–100 mg/kg), the D2 selective agonist PNU-95666E (0.32–3.2 mg/kg) and the D3-preferring agonist pramipexole (0.032–1 mg/kg), all produced non-significant amounts of drug-appropriate responding and significantly
reduced response rate. It is concluded that PNU-99194A produces a distinctive subjective cue which is probably based on D3 receptor antagonism.
Received: 3 September 1997 / Final version: 21 January 1998 相似文献
6.
B. A. Mattingly S. E. Fields M. S. Langfels J. K. Rowlett P. M. Robinet M. T. Bardo 《Psychopharmacology》1996,125(1):33-42
Male Wistar rats (250–350 g) were injected (SC) daily with the putative selective dopamine D3 receptor agonist, 7-OH-DPAT (0.01, 0.10, or 1.0 g/kg) or vehicle for 10 days. Fifteen minutes after each injection, the rats were tested for locomotor activity in photocell arenas for 20 min or 2 h. In two experiments, following this subchronic treatment, all rats received a challenge injection of apomorphine (1.0 mg/kg, SC), or cocaine (10 mg/kg, IP) on day 11, and were tested for locomotor activity. In a third experiment, dopamine synthesis in striatal and mesolimbic (nucleus accumbens-olfactory turbercle) tissue was assessed following acute or chronic 7-OH-DPAT treatments by measuring the accumulation of dihydroxyphenylalanine (DOPA) after treatment with a DOPA decarboxylase inhibitor. Major findings were as follows: a) acute 7-OH-DPAT treatment produced a dose-dependent decrease in locomotor activity; b) when tested for 2 h, the 1.0 mg/kg dose of 7-OH-DPAT produced a progressively greater increase in activity across the 10 test days (i.e., behavioral sensitization); c) subchronic treatment with 7-OH-DPAT did not result in cross-sensitization to either apomorphine or cocaine; d) acute treatment with the 1.0 mg/kg dose of 7-OH-DPAT significantly decreased dopamine synthesis in both striatal and mesolimbic regions; and e) chronic 7-OH-DPAT treatments did not affect basal dopamine synthesis in either brain region. Although the behavioral effects of 7-OH-DPAT were similar to the reported effects of the D2/D3 dopamine agonist quinpirole, the effects of repeated 7-OH-DPAT treatments differed from those of quinpirole in terms of cross-sensitization and basal dopamine synthesis. These results suggest that locomotor inhibition produced by low doses of 7-OH-DPAT is not related to dopamine autoreceptor stimulation, and the development of behavioral sensitization to high doses of 7-OH-DPAT is not due to the development of dopamine autoreceptor subsensitivity. 相似文献
7.
Koffarnus MN Greedy B Husbands SM Grundt P Newman AH Woods JH 《Psychopharmacology》2009,203(2):317-327
Rationale Previous research has found the stimulus effects of dopamine D2- and D3-preferring agonists difficult to distinguish in drug
discrimination studies. Antagonism studies suggest that the stimulus effects of both types of agonists may be mediated primarily
through D2 receptors.
Objectives The current study was designed to further assess the receptors mediating the stimulus effects of these agonists and to attempt
to train rats to discriminate directly between D2- and D3-preferring dopamine agonists.
Materials and methods Four groups of eight rats were trained to discriminate either 0.1 mg/kg of the D3-preferring agonist pramipexole from saline,
1.0 mg/kg of the D2-preferring agonist sumanirole from saline, 0.1 mg/kg pramipexole from either saline or 1.0 mg/kg sumanirole,
or 1.0 mg/kg sumanirole from either saline or 0.1 mg/kg pramipexole.
Results Three of eight rats in the 0.1 mg/kg pramipexole vs. 1.0 mg/kg sumanirole or saline failed to meet the training criteria,
and the discrimination in this group was tenuous. The D2-preferring antagonist L-741,626 at 1.0 mg/kg was more effective at
shifting to the right the pramipexole dose-response curve in pramipexole-trained rats, while 32 mg/kg of the selective D3
antagonist PG01037 had little effect. Quinpirole and 7-OH-DPAT fully or partially substituted for both pramipexole and sumanirole
in each group tested, while cocaine did not substitute in any group.
Conclusions Antagonist data along with the pattern of training and substitution data suggested that D2 receptor activation is primarily
responsible for the stimulus effects of both sumanirole and pramipexole with D3 receptor activation playing little or no role. 相似文献
8.
Cocaine self-administration was compared with responding maintained by the dopamine D3 agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) in rhesus monkeys. In the first experiment, monkeys (n=3) with an extensive cocaine history responded under a fixed-interval (FI) 5-min schedule of IV cocaine (0.03 mg/kg per injection) presentation, during daily 4-h sessions. When responding was stable, dose-response curves were determined for cocaine (0.01-0.3 mg/kg per injection) and 7-OH-DPAT (0,001–0.1 mg/kg per injection); each dose was available for at least five consecutive sessions. When substituted for the baseline dose of cocaine, other doses of cocaine and 7-OH-DPAT maintained rates higher than responding maintained by saline injections, in all monkeys. 7-OH-DPAT maintained response rates equal to or higher than rates of cocainemaintained responding in all monkeys. In a second experiment, acquisition of 7-OH-DPAT self-administration was evaluated in a group of cocaine-navie monkeys (n=3). Various doses of 7-OH-DPAT (0.003–0.03 mg/kg during daily 4-h sessions. After 10–13 sessions, 7-OH-DPAT self-administration could not be trained in any cocaine-naive monkey. When cocaine was made available to these monkeys, responding was reliably maintained within one to four sessions and the schedule was gradually increased to FI 5-min. After stable responding under an FI 5-min schedule of 0.03 mg/kg per injection cocaine presentation, 7-OH-DPAT (0.01 mg/kg per injection) was again made available to two of the monkeys, and maintained responding at rates higher than saline. To determine better whether a history of responding maintained by another reinforcer would result in high rates of 7-OH-DPAT self-administration, two cocaine-naive monkeys were trained to respond under an FI 5-min schedule of food presentation. Substituting 7-OH-DOAT (0.003–0.03 mg/kg per injection) for food resulted in very low rates of responding. Taken together, these results suggest that despite comparable reinforcing effects in cocaine-substitution studies, 7-OH-DPAT and cocaine differ in their rate of acquisition, perhaps indicating a lower abuse liability for 7-OH-DPAT. 相似文献
9.
The primary objective of this study was to determine whether the development of behavioral sensitization to the putative
dopamine D3 receptor agonist 7-OH-DPAT could be prevented by either selective D1-type or D2-type dopamine receptor antagonists. In three experiments, male Wistar rats (250–350 g) were given seven to nine injections
(at 48-h intervals) of 7-OH-DPAT (1.0 mg/kg, SC) or vehicle in combination with the D2-type dopamine antagonist eticlopride (0.3 mg/kg, SC), the D1-type dopamine antagonist SCH 23390 (0.1 or 0.2 mg/kg, SC), or vehicle. After the injections, the rats were tested for locomotor
activity in photocell arenas for 2 h. In the first two experiments, after seven injections, all rats were tested for activity
following vehicle injections to test for possible conditioning effects. In each experiment, after the last pre-exposure session,
all rats were given a challenge injection of 7-OH-DPAT (1.0 mg/kg, SC) and tested for activity. Major findings were as follows:
a) 7-OH-DPAT treatments produced a progressively greater increase in locomotor activity with repeated treatment; b) concurrent
treatment with eticlopride or SCH 23390 (0.1 and 0.2 mg/kg) blocked the acute locomotor-activating effects of 7-OH-DPAT across
days; c) eticlopride, but not SCH 23390, completely blocked the development of behavioral sensitization to 7-OH-DPAT. Although
the low dose of SCH 23390 (0.1 mg/kg) produced a partial attenuation of sensitization, the higher dose (0.2 mg/kg) of SCH
23390 appeared to augment, rather than block, sensitization to 7-OH-DPAT; d) rats previously treated with SCH 23390 (0.2 mg/kg,
but not 0.1 mg/kg) without 7-OH-DPAT displayed a hyperactive response to the 7-OH-DPAT challenge injection; and e) after vehicle
injections, rats previously given 7-OH-DPAT, SCH 23390, or eticlopride either alone or in combination were more active than
vehicle control rats. These findings suggest that the neurochemical mechanisms mediating the development of behavioral sensitization
to 7-OH-DPAT may differ from those of other dopamine D2-type agonists such as quinpirole or bromocriptine. Moreover, these results demonstrate that hyperactivity responses following
vehicle injections in drug-pretreated animals do not necessarily reflect conditioning mechanisms.
Received: 28 May 1997/Final version: 2 April 1998 相似文献
10.
The present investigation examined the effects of several dopaminergic compounds in pigeons trained to discriminate either
a 0.1 (low) or 5.6 (high) mg/kg dose of the mu opioid butorphanol from saline. Various dopamine (DA) re-uptake inhibitors,
releasers, a D1 agonist, a D2 agonist and a D3 agonist engendered partial substitution (50–79% butorphanol responding) for the butorphanol stimulus in the low-dose group.
In the high-dose group, with a few exceptions, these compounds produced predominately saline responding. In the low-dose group,
the opioid antagonist naloxone antagonized the stimulus effects produced by butorphanol, but failed to attenuate the butorphanol-like
discriminative stimulus effects produced by the DA re-uptake inhibitors mazindol and cocaine. The D1 antagonist (+)-SCH 23390 and the D2 antagonist raclopride failed to attenuate the stimulus effects produced by either the low or high training dose of butorphanol.
Doses of mazindol and cocaine that engendered between 16% and 70% butorphanol responding failed to alter the butorphanol dose-effect
curve in either the low- or high-dose group, indicating a less than additive interaction. In the high-dose group, the D3 agonist (±)-7-hydroxy-dipropylaminotetralin [(±)-7-OH-DPAT] attenuated butorphanol’s stimulus effects in a dose-dependent
manner along with the butorphanol-like stimulus effects produced by nalbuphine and morphine. The present findings indicate
that direct and indirect DA agonists share similar stimulus effects with a low but not high training dose of butorphanol,
and in the high-training dose group, activation of the D3 receptor by (±)-7-OH-DPAT results in the attenuation of the discriminative stimulus effects of mu opioids.
Received: 19 May 1997 / Final version: 30 September 1997 相似文献
11.
These studies were designed to evaluate the effects of the putative dopamine D3 receptor agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetraline (7-OH-DPAT), alone and in combination with cocaine, in four rhesus monkeys trained to discriminate cocaine (0.4 mg/kg, IM) from saline under a fixed-ratio 30 schedule of food presentation. Under these conditions, cumulative doses of cocaine (0.013–1.3 mg/kg) produced a dose-dependent and complete generalization to the training dose of cocaine in all monkeys, while producing only minimal effects on response rates. The discriminative stimulus effects of cocaine were antagonized by the non-selective dopamine receptor antagonist flupenthixol (0.018 mg/kg, IM) in all four monkeys. The effects of 7-OH-DPAT (0.01–1.8 mg/kg) were inconsistent across monkeys. In two of the four monkeys (monkeys L990 and L958), 7-OH-DPAT consistently and completely generalized to cocaine and decreased response rates in a dose-dependent manner. Both the cocaine-like discriminative stimulus effects and rate-decreasing effects of 7-OH-DPAT were antagonized by flupenthixol in these two monkeys. Pretreatment with low doses of 7-OH-DPAT (0.01–0.032 mg/kg) had no effect on the cocaine dose-effect curve in monkeys L990 and L958; however, higher doses of 7-OH-DPAT (0.032–0.32 mg/kg) shifted the cocaine dose-effect curve to the left. In the other two monkeys (monkeys 150F and 89B036), 7-OH-DPAT produced a dose-dependent decrease in response rates but did not consistently generalize to cocaine. Flupenthixol did not antagonize the rate-decreasing effects of 7-OH-DPAT in these two monkeys, and pretreatment with 7-OH-DPAT (0.1–0.32 mg/kg) produced a decrease in response rates but had no effect on the cocaine dose-effect curve. Time-course experiments revealed that 7-OH-DPAT (0.32 mg/kg) displayed a slower onset and a longer duration of effect than the training dose of cocaine. Finally, the D3/D2 dopamine agonist quinpirole completely generalized to cocaine in three monkeys, and partially in the fourth monkey. Quinpirole showed the highest potency in those monkeys in which 7-OH-DPAT consistently generalized to cocaine. The results of the present study suggest that, in rhesus monkeys, 7-OH-DPAT produces cocaine-like effects and may modulate the discriminative stimulus effects of cocaine in some monkeys.This paper is dedicated to the memory of Xavier Lamas, who died on 26 August 1995 on Mount Everest 相似文献
12.
Recent experiments from this laboratory demonstrated synergistic locomotor depressant effects of AMPA/kainate receptor blockade and D(2/3) dopamine (DA) receptor stimulation. This study explored functional interactions between DA and glutamate (Glu) systems using the NMDA receptor antagonist MK-801 and the DA receptor agonists 7-OH-DPAT and apomorphine. Using photocell locomotor activity boxes, systemic effects of MK-801 in combination with 7-OH-DPAT (0.03 mgkg(-1) SC, n=8) or a pre-synaptically effective dose of apomorphine (0.05 mgkg(-1) SC, n=6) were measured in male Sprague-Dawley rats. Effects of bilateral applications of MK-801 and 7-OH-DPAT into the nucleus accumbens (NAS) shell subregion were also investigated (n=7). When given alone, MK-801 (0.13 mgkg(-1) or 0.66 microg intra-NAS shell) increased horizontal locomotor activity, while 7-OH-DPAT (0.03 mgkg(-1)) or apomorphine (0.05 mgkg(-1)) decreased this measure. Co-administration of 7-OH-DPAT (systemically or into the NAS shell) completely blocked MK-801 induced hyperactivity. In contrast, MK-801 and apomorphine demonstrated additive effects. Stimulation of D(3) DA receptors may therefore block the hyperactivity induced by NMDA receptor antagonism, and the NAS shell is an important site for this interaction. The differential effects of the DA agonists on hyperactivity induced by NMDA receptor blockade support the proposal that 7-OH-DPAT may induce hypoactivity by stimulation of postsynaptic D(3) DA receptors. 相似文献
13.
Effects of selective dopamine receptor agonists in rats trained to discriminate apomorphine from saline 总被引:1,自引:0,他引:1
Rats (N = 12) were trained to discriminate apomorphine (0.25 mg/kg, IP) from saline in a two-lever, food-reinforced (FR 30) drug discrimination paradigm. When the discrimination was acquired, various doses of apomorphine as well as several other dopamine receptor agonists were injected before test sessions. Apomorphine (0.03-0.25 mg/kg, IP) produced a dose-related increase in the percent of responses that occurred on the drug lever during test sessions. The selective DA2 receptor agonist piribedil (0.25-8.0 mg/kg, IP) produced a dose-related increase in drug lever responding that was similar to that seen with apomorphine. On the other hand, administration of the selective DA1 receptor agonist SKF 38393 (1.0-32 mg/kg, IP) resulted in principally saline lever responding, even at doses that substantially reduced the rate of responding. Administration of dopamine (1.0-8.0 mg/kg, IP), which does not readily cross the blood-brain barrier, also resulted in principally saline lever responding. These results suggest that the discriminative stimulus properties of apomorphine are based on its action at a receptor that is similar to the DA2 receptor that has been characterized in the periphery and that this receptor is centrally located. 相似文献
14.
Patrick M. Callahan Richard De La Garza II Kathryn A. Cunningham 《Psychopharmacology》1994,115(1-2):110-114
Dopamine (DA) D1 and D2 receptors are involved in mediating the behavioral effects of cocaine, including its discriminative stimulus properties. The purpose of the present study was to investigate the role of the nucleus accumbens and, in particular, accum bens DA D1 receptors in modulating the stimulus effects of cocaine. Thus, rats were trained to discriminate cocaine (10 mg/kg, IP) from saline using a two-lever, water-reinforced FR 20 drug discrimination task. In substitution tests, systemic (IP) administration of cocaine (0.625–20 mg/kg) produced a dose-related increase in cocaine-appropriate responding. Microinjections of cocaine (2.5–40 µg) into the nucleus accumbens also engendered dose-dependent and complete substitutions (> 80% drug-lever responding) for the systemic training dose of cocaine, whereas intra-accumbens artificial cerebrospinal fluid (1 µl/side) produced primarily saline-appropriate responding. In antagonism tests, pretreatment with the DA D1 antagonist SCH 23390 (3–12 µg/kg) completely antagonized (<20% drug-lever responding) a dose of cocaine (5 mg/kg) that produced greater than 90% cocaine-lever responding when given alone. Additionally, intra-accumbens injections of SCH 23390 (0.025–0.4 µg) prior to systemic cocaine (5 mg/kg) also significantly blocked the cocaine stimulus. The present results confirm the importance of the nucleus accumbens in mediating the discriminative stimulus properties of cocaine and suggest a primary role of accumbens DA D1 receptors in modulating this behavior.Some of these data were presented at the annual FASEB Experimental Biology meeting in New Orleans (1993) 相似文献
15.
Mice treated with low doses of apomorphine tend to adopt a vertical position along the walls of their cage. Optimal conditions have been defined to obtain a reliable dose-response relationship.This peculiar behavior appears to be elicited by stimulation of dopamine receptors in the striatum: it is suppressed after coagulation of this structure while it is facilitated when these receptors are made hypersensitive by previous treatments with 6-hydroxydopamine or haloperidol; on the other hand, it is not modified by coagulation of the nucleus accumbens.The relative efficacy of various agonists and antagonists of dopamine receptors have been determined on this test.It appears that this stereotyped behavior might represent a convenient mean to assess the stimulation of striatal dopamine receptors in mice. 相似文献
16.
Rationale Drug-discrimination studies have proven instructive in the characterization of psychotropic agents, a procedure applied herein
to the novel antiparkinson agent, S32504. This highly selective agonist at dopamine D3 and (less potently) D2 receptors displays potent antiparkinson, neuroprotective and antidepressant properties (Millan et al., J Pharmacol Exp Ther
309:936–950, 2004a; Millan et al., J Pharmacol Exp Ther 309:903–920, 2004b; Millan et al., J Pharmacol Exp Ther 309:921–935, 2004c).
Objectives To generate a discriminative stimulus (DS) with S32504 and undertake substitution/antagonism studies with diverse antiparkinson
and antipsychotic agents.
Materials and methods Using a two-lever, fixed-ratio 10 schedule, rats were trained to recognize S32504 (0.04 mg/kg, s.c.) from saline.
Results S32504 displayed dose-dependent and stereospecific substitution in comparison to its less active racemic form, (±) S31411,
and to its inactive (−) distomer, S32601. Apomorphine, and the selective D3/D2 receptor agonists, ropinirole, PD128,907, 7-OH-DPAT and CGS15855A, fully (=80%) substituted for S32504, whereas D4 and D1/D5 receptor agonists were ineffective. The selective D3 vs D2 receptor partial agonist, BP897, did not substitute for S32504 and the selective D3 receptor antagonists, S33084, SB277,011, GR218,231, PNU99194A and S14297, did not block its DS properties. By contrast, S32504
lever selection was blocked by the preferential D2 vs D3 receptor antagonists, L741,626 and S23199, and by the D2/D3 antagonists, raclopride and haloperidol. The D2/D3 receptor partial agonists and antipsychotics, aripiprazole, bifeprunox, N-desmethylclozapine and preclamol did not substitute for S32504: indeed, they dose-dependently attenuated its DS properties.
Conclusion The antiparkinson agent, S32504, displays DS properties principally mediated by high-efficacy activation of D2 receptors Antipsychotics known to act as partial agonists at D2/D3 receptors attenuate DS properties of S32504, actions reflecting their low efficacy at these sites. 相似文献
17.
Rats were trained to discriminate arecoline (1.74 mg/kg) from saline in a milk-reinforced (variable interval 12 s) two-lever operant paradigm. The discriminative stimulus (DS) effects of arecoline were antagonized by atropine sulfate, but not by atropine methylnitrate or mecamylamine. In contrast to the effects on discrimination, atropine did not antagonize the response rate suppressant effects of arecoline. The DS effect of arecoline completely generalized to oxotremorine, partially generalized to pilocarpine, and did not generalize to nicotine. These data demonstrate that the DS effect of arecoline depends on central muscarinic receptors. 相似文献
18.
S. L. Andersen Nathalie L. Dumont Martin H. Teicher 《Naunyn-Schmiedeberg's archives of pharmacology》1997,356(2):173-181
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.
Received: 20 December 1996 / Accepted: 7 April 1997 相似文献
19.
Shinichiro Nakajima Philip Gerretsen Hiroyoshi Takeuchi Fernando Caravaggio Tiffany Chow Bernard Le Foll Benoit Mulsant Bruce Pollock Ariel Graff-Guerrero 《European neuropsychopharmacology》2013,23(8):799-813
Currently available treatments have limited pro-cognitive effects for neuropsychiatric disorders, such as schizophrenia, Parkinson's disease and Alzheimer's disease. The primary objective of this work is to review the literature on the role of dopamine D3 receptors in cognition, and propose dopamine D3 receptor antagonists as possible cognitive enhancers for neuropsychiatric disorders. A literature search was performed to identify animal and human studies on D3 receptors and cognition using PubMed, MEDLINE and EMBASE. The search terms included “dopamine D3 receptor” and “cognition”. The literature search identified 164 articles. The results revealed: (1) D3 receptors are associated with cognitive functioning in both healthy individuals and those with neuropsychiatric disorders; (2) D3 receptor blockade appears to enhance while D3 receptor agonism seems to impair cognitive function, including memory, attention, learning, processing speed, social recognition and executive function independent of age; and (3) D3 receptor antagonists may exert their pro-cognitive effect by enhancing the release of acetylcholine in the prefrontal cortex, disinhibiting the activity of dopamine neurons projecting to the nucleus accumbens or prefrontal cortex, or activating CREB signaling in the hippocampus. These findings suggest that D3 receptor blockade may enhance cognitive performance in healthy individuals and treat cognitive dysfunction in individuals with a neuropsychiatric disorder. Clinical trials are needed to confirm these effects. 相似文献
20.
Vootele Vikar Andres Soosaar Vallo Volke Sulev Kks Michel Bourin Pekka T. Mnnist Eero Vasar 《European neuropsychopharmacology》1999,9(6):318-514
Apomorphine-induced behavioural sensitization was studied in male Wistar rats. The acute administration of apomorphine (0.5 mg/kg s.c.), a dopamine agonist, did not affect the locomotor activity of rats, but it caused stereotyped behaviour characterized by repeated gnawing, licking and sniffing. A significant increase in the locomotor activity became evident after repeated treatments with apomorphine (0.5 mg/kg twice daily for 14 days). However, there were marked individual differences in the sensitization of rats to apomorphine. One third of animals did not react with increased locomotor activity even after the 2-week administration of apomorphine, whereas the other one third needed only a few injections to display increased behavioural response to apomorphine. The behavioural response of the remaining one third of rats was between weak and strong responders. Simultaneously, the stereotyped behaviour occurred earlier and its intensity tended to be lower after repeated treatment with apomorphine. Nevertheless, the established changes of stereotyped behaviour did not correlate with the increase of locomotor activity. The administration of amphetamine (2.5 mg/kg, s.c.), an indirect dopamine agonist, but not a non-competitive NMDA antagonist dizocilpine (0.25 mg/kg i.p.), tended to cause a similar response profile with apomorphine in sensitized rats. The ED50 values of the dopamine antagonists blocking apomorphine-induced increase in the locomotor activity were the following: 0.09 mg/kg for raclopride (dopamine D2 antagonist), 0.023 mg/kg for SCH 23390 (dopamine D1 antagonist), 6.42 mg/kg for clozapine (dopamine D4 antagonist). This supports the involvement of D1 and D2 receptors in the expression of apomorphine-induced behavioural sensitization. The concomitant administration of dizocilpine (0.5 mg/kg), SCH 23390 (0.05 mg/kg), raclopride (0.1 mg/kg) and clozapine (20 mg/kg) with apomorphine (0.5 mg/kg twice daily for 2 weeks) antagonized the development of behavioural sensitization to apomorphine. Accordingly, at least three different molecular targets, namely dopamine D1 and D2, and NMDA receptors, are involved in the development of apomorphine-induced behavioural sensitization. 相似文献