Possible role of dopamine D1-like and D2-like receptors in behavioural activation and "contingent" reward evaluation in sodium-replete and sodium-depleted rats licking for NaCl solutions

Based on the different effects of the dopamine D1-like and D2-like receptor antagonists SCH 23390 and raclopride on the measures of licking microstructure in rats, we suggested that the level of activation of reward-associated responses depends on dopamine D1-like receptor stimulation, and is updated, or “reboosted”, on the basis of a dopamine D2-like receptor-mediated reward evaluation. To further test this hypothesis, we examined the effects of the dopamine D2-like receptor antagonist raclopride (0, 25, 125, 250 μg/kg) and of the dopamine D1-like receptor antagonist SCH 23390 (0, 10, 20 and 40 μg/kg) on the microstructure of licking for two different NaCl solutions (0.9% and 2.7%) in rats in sodium-replete status and in the sodium-depleted status induced by the diuretic drug furosemide. Rats were exposed to each solution for 180 seconds after the first lick. Both in sodium-replete and in sodium-depleted status, SCH 23390 produced a decrease of burst number, a measure of behavioural activation, without affecting their size, a measure of reward evaluation. Raclopride reduced burst number but appeared also to exert some effects on burst size. Sodium depletion resulted in an increased intake for both NaCl solutions due to an increase in burst number and size, and in a reduced sensitivity to the effect of raclopride on lick number. These results are not in contrast with the proposed hypothesis and are consistent with previous evidence suggesting a role for dopamine D2-like receptors in the increased NaCl appetite induced by sodium depletion.     

Dopamine on D2-like receptors “reboosts” dopamine D1-like receptor-mediated behavioural activation in rats licking for sucrose

Background

The analysis of licking microstructure provides measures, such as duration and number of licking bouts, which might reveal the former an evaluation process and the latter an approach response. Dopamine D2-like receptor antagonists reduce the duration of licking bouts and mimic the effect of reducing sucrose concentration, while conflicting results are reported on the effects of dopamine D1-like receptor antagonists. The aim of this study is to examine the roles of dopamine D1-like and D2-like receptors in the activation of reward-associated responses and in reward evaluation, through the study of licking microstructure.

Methods

The effects of the dopamine D2-like receptor antagonists raclopride (0.025-0.25 mg/kg), the D1-like antagonist SCH 23390 (0.01-0.04 mg/kg) and the antipsychotic drug haloperidol (0.02-0.05 mg/kg), have been examined on the microstructure of licking for a 10% sucrose solution in rats.

Results

The results confirm that dopamine D2-like receptor antagonists reduce the duration of licking bouts and reveal that while SCH 23390 reduced licking exclusively by reducing bout number, raclopride produced on this measure an extinction mimicry effect similar to that observed in instrumental responding for different rewards.

Discussion

These results are consistent with the hypothesis that the level of activation of the responses to the reward-associated cues depends on dopamine D1-like receptor stimulation, and is updated, or “reboosted”, on the basis of a dopamine D2-like receptor-mediated evaluation process occurring during the consummatory transaction with the reward.     

Administration of the D1-like dopamine receptor antagonist SCH-23390 into the medial nucleus accumbens shell attenuates cocaine priming-induced reinstatement of drug-seeking behavior in rats

Rationale. A growing literature indicates that increased dopamine transmission in the nucleus accumbens contributes to priming-induced reinstatement of cocaine-seeking behavior. Objectives. The present experiments were designed to assess the role of D₁-like dopamine receptors in the nucleus accumbens core and shell subregions in cocaine priming-induced reinstatement of drug seeking. Methods. Rats were trained to lever press for cocaine using a fixed ratio (FR) 5 schedule of reinforcement. Drug-seeking was measured by active lever presses during daily 2-h sessions. After approximately 30 days of cocaine self-administration, the animals underwent an extinction phase during which cocaine was replaced with saline. Daily extinction sessions were conducted until responding was consistently less than 10% of the response rate maintained by cocaine self-administration. After the extinction phase, priming-induced reinstatement of cocaine-seeking behavior was assessed. Results. Cocaine dose-dependently reinstated cocaine seeking, with robust drug seeking at 10 mg/kg cocaine. Administration of the D₁-like dopamine receptor antagonist, SCH-23390 (0.1–1.0 μg), directly into the medial nucleus accumbens shell dose-dependently attenuated drug seeking induced by 10 mg/kg cocaine. Microinjection of 1.0 μg SCH-23390 into either the nucleus accumbens core or lateral septum had no influence on cocaine-seeking behavior. Conclusions. These results indicate that stimulation of D₁-like dopamine receptors in the medial nucleus accumbens shell contributes to drug-induced reinstatement of cocaine-seeking behavior.     

Possible role of dopamine D1-like and D2-like receptors in behavioural activation and evaluation of response efficacy in the forced swimming test

Based on the different effects of the dopamine D1-like and D2-like receptor antagonists SCH 23390 and raclopride on the measures of licking microstructure in rats ingesting a sucrose solution, we suggested that the behavioural activation of reward-associated responses depends on dopamine D1-like receptor stimulation, and its level is updated, or “reboosted”, on the basis of a dopamine D2-like receptor-mediated evaluation process. The aim of this study was to test this hypothesis on the forced swimming test response. The effects of the dopamine D1-like and D2-like receptor antagonists SCH 23390 (0.01–0.04 mg/kg) and raclopride (0.025–0.25 mg/kg) administered before a 15-min exposure to forced swimming, and the response to a second session performed 24 h later, were examined. SCH 23390 dose-dependently reduced climbing scores in the first session and increased them in the second session, but the within-session decline of this measure was similar to that observed in the control group in both sessions. Raclopride-treated subjects showed a slightly reduced level of climbing scores at the beginning of the first session, but persisted in emitting this costly behavioural response up to the end of the session, while no effects were observed in the second session. These results, along with our results examining licking for sucrose, are consistent with the hypothesis that behavioural activation and response effort allocation are directly mediated by dopamine D1-like receptor stimulation, but the level of this activation is updated, or “reboosted”, on the basis of a dopamine D2-like receptor-mediated mechanism of response efficacy evaluation.     

SK&F 83959 and non-cyclase-coupled dopamine D1-like receptors in jaw movements via dopamine D1-like/D2-like receptor synergism

This study compared the effects of the dopamine D1-like receptor agents SK&F 83959 (3-methyl-6-chloro-7,8-dihydroxy-1-[3-methyl-phenyl]-2,3,4,5-tetrahydro- 1 H-3-benzazepine), which inhibits the stimulation of adenylyl cyclase, and A 68930 ([1R,3S]-1-aminomethyl-5,6-dihydroxy-3-phenyl-isochroman), a full efficacy agonist, in regulating jaw movements in the rat by synergism with dopamine D2-like receptor agonism. When SK&F 83959 and A 68930 were given in combination with quinpirole, there was a synergistic induction of jaw movements. Responsivity to SK&F 83959 + quinpirole was antagonised by the dopamine D1-like receptor antagonists SCH 23390 ([R]-3-methyl-7-chloro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-ben zaz epine) and BW 737C ([S]-6-chloro-1-[2,5-dimethoxy-4-propylbenzyl]-7-hydroxy-2-methyl- 1,2,3,4-tetrahydroisoquinoline); synergism was antagonised also by the dopamine D2-like receptor antagonist YM 09151-2 (cis-N-[1-benzyl-2-methyl-pyrrolidin-3-yl]-5-chloro-2-methoxy-4-++ +methyl-aminobenzamide). Responsivity to A 68930 + quinpirole was enhanced by low doses of SCH 23390, BW 737C and YM 09151-2, and antagonised by higher doses of SCH 23390 and YM 09151-2. These results implicate a novel, dopamine D1-like receptor that is coupled to a transduction system other than/additional to adenylyl cyclase, and suggest that its functional role extends to the regulation of jaw movements by synergistic interactions with dopamine D2-like receptors.     

Effects of dopamine receptor antagonists on the acquisition of ethanol-induced conditioned place preference in mice

Rationale

Studies support differential roles of dopamine receptor subfamilies in the rewarding and reinforcing properties of drugs of abuse, including ethanol. However, the roles these receptor subfamilies play in ethanol reward are not fully delineated.

Objective

To examine the roles of dopamine receptor subfamilies in the acquisition of ethanol-induced conditioned place preference (CPP), we pretreated animals systemically with antagonist drugs selective for dopamine D1-like (SCH-23390) and D2-like (raclopride) receptors prior to ethanol conditioning trials.

Methods

Effects of raclopride (0–1.2 mg/kg) and SCH-23390 (0–0.3 mg/kg) on the acquisition of ethanol-induced CPP were examined in DBA/2J mice (experiments 1 and 2). Based on significant effects of SCH-23390, we then determined if SCH-23390 (0.3 mg/kg) produced a place preference on its own (experiment 3). To evaluate whether SCH-23390 impaired learning, we used a conditioned place aversion (CPA) paradigm and pretreated animals with SCH-23390 (0–0.3 mg/kg) before conditioning sessions with LiCl (experiment 4).

Results

Whereas raclopride (0–1.2 mg/kg) did not affect acquisition, SCH-23390 (0.1–0.3 mg/kg) impaired the development of ethanol-induced CPP. SCH-23390 (0.3 mg/kg) did not produce place preference when tested alone and SCH-23390 (0.1–0.3 mg/kg) did not perturb the acquisition of LiCl-induced CPA.

Conclusions

Our results support a role for dopamine D1-like but not D2-like receptors in ethanol’s unconditioned rewarding effect as indexed by CPP. Blockade of D1-like receptors did not affect aversive learning in this procedure.     

Antagonism of the discriminative stimulus effects of cocaine at two training doses by dopamine D2-like receptor antagonists

RATIONALE: The relative contributions of different dopamine receptor subtypes to the discriminative stimulus effects of cocaine may be influenced by the training dose of cocaine. Substitution tests with dopamine receptor agonists have suggested that the role of dopamine D2-like receptors is diminished relative to that of D1-like receptors at a training dose of 3 mg/kg cocaine compared with a training dose of 10 mg/kg. OBJECTIVES: To test whether dopamine D2-like receptor antagonists were differentially effective at attenuating cocaine's discriminative stimulus effects at different training doses, and to test for the first time an antagonist that is selective for the dopamine D2 receptor within the D2-like receptor subfamily. METHODS: Rats were trained to press one lever after receiving cocaine and another after receiving saline (maintaining >95% drug-appropriate responding). Three dopamine D2-like receptor antagonists (haloperidol, raclopride and L-741,626) were tested in rats trained at 3 mg/kg or 10 mg/kg cocaine. At the lower training dose, the D1-like receptor antagonist SCH 39166 was also tested. RESULTS: The antagonists were not differentially effective between training groups: they all produced parallel, rightward shifts in cocaine's dose-effect function, indicating surmountable antagonism. CONCLUSIONS: The results demonstrate that D2-like receptor antagonists with different affinities for the various D2-like receptors can antagonise the discriminative stimulus effects of cocaine at two training doses. Importantly, antagonism by L-741,626 implies that stimulation of D2 receptors alone (not D3 or D4 receptors) is sufficient to mediate cocaine's discriminative stimulus effects. Finally, the claim that D1-like receptors are preferentially involved at low training doses of cocaine is only consistent with the current findings if indirect stimulation of D2 receptors by low doses of cocaine remains necessary for the expression of the D1-like receptor-mediated effect.     

The effect of dopamine receptor blockade on motor behavior in Aplysia californica

The mammalian D1- and D2-like receptor blockers SCH-23390 and raclopride were used to block receptors in Aplysia californica, and the effect on reflexes and escape behavior was examined. Four groups of 20 young adults were each injected with SCH-23390, raclopride, SCH-23390+raclopride, or seawater. The drug (0.0125 mg/g of body weight) was injected 2 mm anterior to the parapodia. After the injection of either SCH-23390 or SCH-23390+raclopride, there was a significant increase in parapodia opening (P<.001), siphon withdrawal (P<.05), and galloping following tail pinch (P<.01) compared to raclopride-injected or control animals. The data showed that blockade of receptors by SCH-23390, but not raclopride, produced significant changes in motor behavior in A. californica.     

Effect of dopamine receptor antagonists on renewal of cocaine seeking by reexposure to drug-associated contextual cues.

We recently found that in rats trained to self-administer a heroin-cocaine mixture, exposure to the drug self-administration environment, after extinction of the drug-reinforced behavior in a different context, leads to renewal of drug seeking. Here we further explored the role of contextual stimuli in drug seeking by characterizing the effect of drug-associated environmental stimuli on renewal of cocaine seeking. We also investigated whether activation of dopamine receptors contributes to context-induced renewal of cocaine seeking by testing the effects of selective D1-like (SCH 23390) and D2-like (raclopride) receptor antagonists. Rats were trained for 10 days to self-administer cocaine by pressing a lever. Next, lever pressing was extinguished in the presence of the discrete cues associated with cocaine infusions for 10 days in a context that was distinctively different from the drug-taking context. On the test days, rats were pretreated with SCH 23390 (0, 5 or 10 microg/kg) or raclopride (0, 50 or 100 microg/kg) and non-reinforced lever-pressing behavior was determined either in the extinction context (Control group) or the cocaine-associated context (Renewal group). Consistent with our previous report, cocaine seeking was renewed when rats were exposed to the drug-associated context after extinction in a different context. Furthermore, pretreatment with the D1-like or the D2-like receptor antagonists attenuated context-induced renewal of cocaine seeking. These data suggest that activation of dopamine receptors is involved in reinstatement of cocaine seeking induced by exposure to the drug self-administration context.     

The role of D2-like dopamine receptors in the locomotor stimulant effects of cocaine in mice

RATIONALE: Previous studies indicate antagonism of cocaine-stimulated locomotor activity by dopamine D2-like receptor antagonists, but only at doses of the antagonists, that by themselves attenuate locomotor activity, raising questions of the specificity of the interaction and whether it might be due solely to a summation of opposing effects. OBJECTIVES: The interactions of cocaine and several D2-like dopamine antagonists and non-dopamine "physiological antagonists" were compared across a full range of doses in order to fully characterize the interaction and assess the specificity of the effects of dopamine antagonists and cocaine. METHODS: Swiss-Webster mice were treated with either vehicle, a D2-like antagonist (haloperidol, spiperone, raclopride, spiperone, (+) or (-) eticlopride), or a "physiological" antagonist (chlordiazepoxide, clonidine, or R(-) N6-(2-phenylisopropyl)adenosine) and cocaine (5-80 mg/kg) prior to a 30-min locomotor activity test. RESULTS: All test drugs decreased locomotor activity when given alone. All test drugs attenuated cocaine-induced locomotion and decreased peak responding to cocaine. In general, the D2-like antagonists also decreased maximal responding to cocaine and decreased the slope of the ascending limb of the cocaine dose-effect curve, effects not obtained with physiological antagonists. CONCLUSIONS: Blockade of D2-like receptors resulted in an interaction with cocaine that was fundamentally different from that produced through non-dopaminergic mechanisms and appears to be more than a summation of opposing effects. The present data suggest that D2-like receptors are involved in the mechanisms underlying the induction of locomotor activity by cocaine.     

The role of dopamine receptors in ventrolateral orbital cortex-evoked antinociception in a rat formalin test model

The present study examined the roles of dopamine and D(1)- and D(2)-like dopamine receptors in ventrolateral orbital cortex (VLO)-evoked antinociception in rats with persistent inflammatory pain. Following formalin injection into the rat unilateral hindpaw pad, the effects of dopamine receptor agonist and antagonist microinjections into the VLO on nociceptive behavior were observed. Results demonstrated that VLO microinjection of the non-selective dopamine receptor agonist apomorphine (R(-)-apomorphine hydrochloride, 1.0, 2.5 and 5.0μg) depressed later-phase nociceptive behavior induced by formalin injection; this effect was attenuated by the D(2)-like dopamine receptor antagonist S(-)-raclopride(+)-tartrate salt (raclopride, 3.0μg), but not by the D(1)-like dopamine receptor antagonist R(+)-SCH-23390 hydrochloride (SCH-23390, 1.0μg). Apomorphine-induced antinociception was mimicked by microinjection of the D(2)-like dopamine receptor agonist (-)-quinpirole hydrochloride (2.0 and 5.0μg) into the same VLO site, and this effect was antagonized by raclopride (3.0μg). In addition, microinjection of the D(1)-like dopamine receptor agonist R(+)-SKF-38393 hydrochloride (5.0μg) had no effect on formalin-induced nociceptive behavior during the later phase. However, the D(1)-like dopamine receptor antagonist SCH-23390 (2.5, 5.0 and 10μg) depressed nociceptive behavior in a dose-dependent manner. These results suggested that dopamine mediated VLO-induced antinociception via different mechanisms in the persistent inflammatory pain model; D(2)-like receptors mediated dopamine-induced antinociception, while D(1)-like dopamine receptors exhibited tonic facilitatory action on nociceptive behavior, thereby blocking D(1)-like dopamine receptors could induce antinociception.     

The anti-influenza drug oseltamivir evokes hypothermia in mice through dopamine D2 receptor activation via central actions

Oseltamivir has a hypothermic effect in mice when injected intraperitoneally (i.p.) and intracerebroventricularly (i.c.v.). Here we show that the hypothermia evoked by i.c.v.-oseltamivir is inhibited by non-selective dopamine receptor antagonists (sulpiride and haloperidol) and the D₂-selective antagonist L-741,626, but not by D₁/D₅-selective and D₃-selective antagonists (SCH-23390 and SB-277011-A, respectively). The hypothermic effect of i.p.-administered oseltamivir was not inhibited by sulpiride, haloperidol, L-741,626 and SCH-23390. In addition, neither sulpiride, haloperidol nor SCH-23390 blocked hypothermia evoked by i.c.v.-administered oseltamivir carboxylate (a hydrolyzed metabolite of oseltamivir). These results suggest that oseltamivir in the brain induces hypothermia through activation of dopamine D₂ receptors.     

The role of prefrontal cortex D1-like and D2-like receptors in cocaine-seeking behavior in rats

Rationale Evidence from preclinical and clinical studies indicates an important role for the mesocorticolimbic dopamine system in cocaine craving and relapse.Objectives To investigate the relative involvement of prefrontal cortex D1-like and D2-like dopamine receptors in cocaine-primed, drug-seeking behavior.Methods Rats were trained to press a lever to self-administer cocaine (i.v., 0.25 mg per infusion) in daily 2-h sessions. Responding was reinforced, contingent on a modified fixed-ratio 5 schedule. Reinstatement tests began after lever-pressing behavior was extinguished in the absence of cocaine and conditioned cues (light and tone). Before each reinstatement test, rats received bilateral microinfusions of different doses of selective D1-like and D2-like antagonists, SCH 23390, and eticlopride, respectively, followed by intraperitoneal administration of 10 mg/kg cocaine; 3 min later the session started. Responding in the reinstatement test was reinforced only by the conditioned cues contingent on a fixed-ratio 5 schedule.Results Both drugs dose dependently decreased cocaine-primed reinstatement without affecting operant behavior maintained by food. Eticlopride, but not SCH 23390, increased cocaine self-administration and decreased food-primed reinstatement at the dose found to decrease cocaine-primed reinstatement.Conclusions These data suggest that, although both D1-like and D2-like receptors in the prefrontal cortex are involved in cocaine-primed drug-seeking behavior, they may modulate different aspects of this process.     

A role for dopamine D1-like receptors in acute food deprivation-induced reinstatement of heroin seeking in rats

Dopamine has a critical role in drug reinforcement and the reinstatement of drug seeking due to priming or exposure to drug-associated cues. In contrast, the role of dopamine in stress-induced reinstatement is not clear. We have previously demonstrated that acute food deprivation, a clinically relevant stressor, reinstates heroin seeking in rats via a leptin-dependent mechanism. Recent reports have suggested a modulating role for leptin on dopamine transmission and drug-related behaviours. Thus, here we investigated the role of dopamine in acute food deprivation-induced reinstatement of heroin seeking. Rats were trained to self-administer heroin (0.05 mg/kg per infusion) for 10 d. Following training, heroin seeking was extinguished and rats were tested for 48-h food deprivation-induced reinstatement while pretreated with the dopamine D1-, D2-, or D3-like receptor antagonists: SCH 23390 (0.0, 5.0 or 10.0 microg/kg), raclopride (0.0, 50.0 or 100.0 microg/kg) or NGB 2904 (0.0, 0.1 or 5.0 mg/kg), respectively. The dopamine D1-like receptor antagonist, SCH 23390, but neither of the other antagonists, showed a dose-dependent attenuation of food deprivation-induced reinstatement. Our results suggest that acute food deprivation-induced reinstatement may be mediated, at least in part, by activation of the dopamine D1-like receptor.     

Dopamine receptor regulation of ethanol intake and extracellular dopamine levels in the ventral pallidum of alcohol preferring (P) rats

Sufficient evidence exists for the inclusion of the ventral pallidum (VP) into the category of a dopaminoceptive brain region. The effects of inhibiting dopamine D(1)- or D(2)-like receptors in the VP on (a) ethanol intake and (b) extracellular levels of dopamine, were investigated in the alcohol-preferring (P) rat. The D(1)-like antagonist, SCH-23390, and the D(2)-like antagonist, sulpiride (0.25-2 microg/0.5 microl) were bilaterally injected into the VP and ethanol (15%, v/v) intake was assessed in a 1 h limited access paradigm. The results indicate that microinjections of sulpiride significantly increased ethanol consumption (65% increase at the 2.0 microg dose). Whereas the D(1) antagonists SCH-23390 tended to decrease ethanol intake, the effect was not statistically significant. In a separate group of rats, reverse microdialysis of sulpiride and SCH-23390 (10-200 microM) were conducted in the VP of P rats. Local perfusion of only the 200 microM sulpiride dose significantly increased the extracellular levels of dopamine (maximal increase: 250% of baseline). On the other hand, local perfusion of SCH-23390 (10-200 microM) dose dependently increased the extracellular levels of dopamine 180-640% of baseline. Overall, the results of this study suggest that (a) tonic activation of D(2) postsynaptic receptors in VP imposes a limit on ethanol intake in the P rat; (b) there are few D(2) autoreceptors functioning in the VP; (c) there is tonic D(1)-like receptor mediated inhibitory feedback regulation of VP-dopamine release.     

Inhibition of mu opioid-induced motor activity in the ventral pallidum by D1 receptor blockade

Microinjection of the mu opioid, [D-Ala(2), N-Me-Phe(4), Gly-ol(5)]-enkephalin (DAMGO) into the ventral pallidum (VP) elicits a motor stimulant response. The coadministration of dopamine (DA) antagonists with DAMGO into the VP was used to determine the role of DA transmission in the motor response. The mixed D1/D2 antagonist, fluphenazine, was found to produce a partial reduction in DAMGO-induced motor activity. To evaluate the role of DA receptor subtypes, the D1 and D2 selective antagonists, SCH-23390 and raclopride, respectively, were coadministered with DAMGO into the VP. SCH-23390 was found to produce a dose-dependent reduction in both horizontal and vertical motor activity with a minimum effective dose of 0.3nmol/side. However, only a partial reduction in horizontal activity occurred with a dose of SCH-23390 as high as 6.0nmol/side. Raclopride was without effect at any dose examined, and an equimolar mixture of SCH-23390 and raclopride did not alter the minimum effective dose nor the maximum reduction in motor activity produced by SCH-23390 alone. It is concluded that stimulation of D1 receptors is permissive to the motor stimulant effect elicited by DAMGO in the VP.     

Dopamine on D2-like receptors is involved in reward evaluation in water-deprived rats licking for NaCl and water

The analysis of licking microstructure provides measures, size and number of licking bouts, which might reveal, respectively, reward evaluation and behavioural activation. Based on the ability of the dopamine D2-like receptor antagonist raclopride to reduce bout size and to induce an “extinction mimicry effect” on bout number, we suggested that the level of activation of reward-associated responses is updated, or “reboosted”, on the basis of a dopamine D2-like receptor-mediated evaluation process occurring during the consummatory transaction with the reward. Here we investigate the effects of the dopamine D2-like receptor antagonist raclopride (0, 25, 125, and 250 µg/kg) on the microstructure of licking for water and sodium chloride solutions (0.075 M, 0.15 M, and 0.3 M) in 12 h water-deprived rats. In each session, rats were exposed to brief contact tests (1 min) for each solution. Bout size, but not bout number, was decreased at the highest NaCl concentration. Raclopride reduced lick number owing to reduced bout size, while bout number was either not affected or even increased depending on the dose. These results are in agreement with the previous observations on sucrose licking, and suggest the involvement of dopamine D2-like receptors in an evaluation process occurring during the consummatory transaction with the reward.     

The rewarding effect of aggression is reduced by nucleus accumbens dopamine receptor antagonism in mice

Rationale Dopamine (DA) receptors within the nucleus accumbens (NAc) are implicated in the rewarding properties of stimuli. Aggressive behavior can be reinforcing but the involvement of NAc DA in the reinforcing effects of aggression has yet to be demonstrated. Objective To microinject DA receptor antagonists into the NAc to dissociate their effects on reinforcement from their effects on aggressive behavior and general movement. Materials and methods Male Swiss Webster mice were implanted with guide cannulae aimed for the NAc and tested for aggressive behavior in a resident–intruder procedure. Aggressive mice were then conditioned on a variable-ratio 5 (VR-5) schedule with presentation of the intruder as the reinforcing event. The D1- and D2-like receptor antagonists SCH-23390 and sulpiride were microinfused (12–50 ng) before the mice responded on the VR-5 schedule and attacked the intruder. Open-field activity was also determined following the highest doses of these drugs. Results SCH-23390 and sulpiride dose-dependently reduced VR responding but did not affect open-field activity. The 50-ng SCH-23390 dose suppressed response rates by 40% and biting behaviors by 10%; other aggressive behaviors were not affected. The 25 and 50 ng sulpiride doses almost completely inhibited VR responding; the 50-ng dose suppressed biting by 50%. Conclusions These results suggest that both D1- and D2-like receptors in the ventral striatum are involved in the rewarding properties of aggression, but that D1-like receptors may be related to the motivation to earn reinforcement as opposed to aggressive behavior.     

The role of dopaminergic transmission through D1-like and D2-like receptors in amphetamine-induced rat ultrasonic vocalizations

Rationale

Systemic amphetamine (AMPH) administration increases the rate of 50-kHz ultrasonic vocalizations (USVs) in adult rats and preferentially enhances the ‘trill’ subtype; these effects of AMPH critically depend on noradrenergic transmission, but the possible contributions of dopamine are unclear.

Objective

To assess the role of dopamine in 50-kHz USVs emitted drug-free and following systemic AMPH administration.

Methods

Adult male Long–Evans rats pre-selected for high AMPH-induced calling rates were tested with AMPH (1 mg/kg, intraperitoneal (IP)) and saline following pretreatment with the following dopamine receptor antagonists: SCH 23390 (0.005–0.02 mg/kg, subcutaneous (SC)), SCH 39166 (0.03–0.3 mg/kg, SC), haloperidol (0.1, 0.2 mg/kg, IP), sulpiride (20–80 mg/kg, SC), raclopride (0.1–0.5 mg/kg, SC), clozapine (4 mg/kg, SC), risperidone (0.5 mg/kg, SC), and pimozide (1 mg/kg, IP). The dopamine and noradrenaline reuptake inhibitors (GBR 12909 and nisoxetine, respectively) were also tested, alone and in combination.

Results

SCH 23390, SCH 39166, haloperidol, and raclopride dose-dependently inhibited vocalizations under AMPH and suppressed the proportion of trill calls. Sulpiride, however, had no discernable effect on call rate or profile, even at a high dose that reduced locomotor activity. Single doses of clozapine, risperidone, and pimozide all markedly decreased calling under saline and AMPH. Finally, GBR 12909 and nisoxetine failed to promote 50-kHz USVs detectably or alter the subtype profile, when tested alone or in combination.

Conclusions

The rate of 50-kHz USVs and the call subtype profile following systemic AMPH administration depends on dopaminergic neurotransmission through D1-like and D2-like receptors. However, inhibiting dopamine and/or noradrenaline reuptake appears insufficient to induce calling.     

SCH 23390: the first selective dopamine D1-like receptor antagonist

SCH 23390, the halobenzazepine (R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5- tetrahydro-1H-3-benzazepine, is a highly potent and selective dopamine D1-like receptor antagonist with a K(i) of 0.2 and 0.3 nM for the D1 and D5 dopamine receptor subtypes, respectively. In vitro, it also binds with high affinity to the 5-HT2 and 5-HT1C serotonin receptor subtypes. However, the doses required to induce a similar response in vivo are greater than 10-fold higher than those required to induce a D1-mediated response. Previous in vivo pharmacological studies with SCH 23390 have shown it to abolish generalized seizures evoked by the chemoconvulsants: pilocarpine and soman. These studies provide evidence of the potential importance of D1-like dopaminergic receptor mechanisms in facilitating the initiation and spread of seizures. The inference from a majority of studies is that the activation of dopamine D1 receptors facilitates seizure activity, whereas activation of D2 receptors may inhibit the development of seizures. SCH 23390 has also been used in studies of other neurological disorders in which the dopamine system has been implicated, such as psychosis and Parkinson's disease. Apart from the study of neurological disorders, SCH 23390 has been extensively used as a tool in the topographical determination of brain D1 receptors in rodents, nonhuman primates, and humans. In summary, SCH 23390 has been a major tool in gaining a better understanding of the role of the dopamine system, more specifically the D1 receptor, in neurological function and dysfunction.