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PubMed1991

The effects of dopaminergic agonists and antagonists on the frequency-response function for hypothalamic self-stimulation in the rat.

The function of dopaminergic synapses in generating the reinforcing effect of brain stimulation was examined in 8 rats. The animals were implanted with bipolar electrodes and trained to press a bar for lateral hypothalamic stimulation. The frequency of stimulation pulses was systematically changed, and a frequency-response curve was plotted for each rat after intraperitoneal injection of a test agent. Dopamine agonists and antagonists selective to either D1 or D2 subtypes of receptors were used. The curve was shifted to a high-frequency range by either SCH 23390 (D1 antagonist) or raclopride (D2 antagonist). SKF 38393 (D1 agonist) failed to shift the curve, and quinpirole and CV 205-502 (D2 agonists) shifted the lower part of the curve to a low-frequency range. The results suggest that an activation of D2 receptors generates a reinforcing effect, and that the effect is expressed only if D1 receptors are activated to an optimal level.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1991

Attenuation of the effects of cocaine on milk consumption in rats by dopamine antagonists.

Recent research suggest the both D1 and D2 dopamine (DA) receptors play an important role in the behavioral effects of psychomotor stimulants. The present study utilized selective DA antagonists to examine the role of DA receptors in the effects of cocaine on milk intake in rats. Male Sprague-Dawley rats were given access to a milk solution (2:1 tap water:Bordens sweetened condensed milk) for 15 min each day. When milk intake was stable, dose-response functions were determined for cocaine (4.0-32 mg/kg, IP, 10 min presession) administered alone or in combination with the D1 antagonist SCH 23390 (0.12-0.5 mg/kg, IP, 30 min presession) or the D2 antagonist raclopride (0.25-1.0 mg/kg, IP, 30 min presession). As a control for the serotonin (5-HT2) antagonist effects of SCH 23390, the 5-HT2 antagonist ketanserin (4.0-16 mg/kg) was evaluated as well. To control for nonspecific drug effects on fluid consumption, the effects of cocaine alone on water intake were determined in a separate group of rats. All drugs decreased milk intake when given alone. Both SCH 23390 and raclopride attenuated the effects of at least one dose of cocaine. Ketanserin did not alter the effects of cocaine. These results suggest that stimulation of both D1 and D2, but not 5-HT2, receptors is involved in the effects of cocaine on milk intake in rats.

Animals↗
PubMed1991

Sweetness-dependent facilitation of sucrose drinking by raclopride is unrelated to calorie content.

Previous studies have reported that dopamine receptor antagonists increase the intake of solid or liquid diets containing high concentrations of sucrose. In Experiment 1, different groups of rats were trained in two-bottle tests (sweet solution vs. water), using three concentrations of either sucrose (0.7, 7 or 34%) or saccharin (0.02, 0.2 or 0.8%). Both sweeteners showed an inverted-U-shaped concentration-intake function. Raclopride increased intake of 34% sucrose, but not of 0.8% saccharin. In Experiment 2, raclopride had similar effects in three-bottle tests (all 3 concentrations available concurrently). However, whereas 34% was the most preferred sucrose solution, 0.2% saccharin was preferred to 0.8%. Thus, 0.8% saccharin differs from 34% sucrose in two ways, being not only noncaloric, but also aversive. In Experiment 3, 34% sucrose was rendered aversive by the addition of 0.08% quinine. Intake of this cocktail was not increased by raclopride. These results suggest that the difference between sucrose and saccharin in the effects of raclopride is related to the aversive properties of a concentrated solution of saccharin, rather than to its lack of calories.

Animals↗
PubMed1991

Dopamine sensitivity in rats selectively bred for increases in cholinergic function.

Because of the extensive literature demonstrating an interaction between cholinergic and dopaminergic systems, the Flinders Sensitive (FSL) and Flinders Resistant (FRL) Lines of rats, selectively bred for differences in cholinergic function, were tested for differences in dopamine sensitivity. Large differences in sensitivity to dopamine agonists were detected, but the direction depended upon the function: The FSL rats were supersensitive to the hypothermic effects of dopamine agonists, but were subsensitive to the stereotypy-inducing effects. Measurement of dopamine receptors by either standard binding techniques or autoradiography failed to demonstrate any receptor differences in the FSL and FRL rats. Behavioural studies with dopamine antagonists were less clear-cut, but suggested that the FSL rats might be more sensitive to their catalepsy-inducing effects. These findings indicate that the changes in dopamine sensitivity which accompany cholinergic supersensitivity are function-dependent, but are not associated with parallel changes in dopamine receptor concentration.

Animals↗
PubMed1992

Raclopride decreases sucrose intake of rat pups in independent ingestion tests.

To investigate the role of dopaminergic activity at D2 receptors in the mediation of the positive reinforcing effect of sucrose on ingestion in preweanling rats, we tested the effects of the D2 antagonist, raclopride, on the intake of 10% sucrose of rats on postnatal days (PN) 7, 14, and 21. Intake was measured during independent ingestion tests in which pups licked sucrose from the floor of a beaker and during oral catheter tests in which sucrose was continuously infused through an anterior, sublingual, oral catheter. Rats were tested once to eliminate the possibility that repeated test experience would affect the response to raclopride. Pretreatment with raclopride resulted in decreased intake in independent ingestion (II) tests, but not in oral catheter (OC) tests on PN 7, 14, and 21. The inhibition of intake was not due to a generalized motor deficit because raclopride did not affect latency to eat, time-sampled activity scores, or latency to withdraw the hindlimb from a raised position. These results demonstrate that dopaminergic activity at D2 receptors is necessary for the positive reinforcing effect of sucrose that maintains ingestion in the II test but not in the OC test.

Animals↗
PubMed1993

Effects of atypical antipsychotic agents on social behavior in rodents.

There are numerous preclinical screening procedures that are predictive of clinical efficacy for the positive symptoms of schizophrenia but no assays for the negative symptoms such as social withdrawal. In the social interaction test in rats, the atypical antipsychotic drug clozapine (10.0 mg/kg) and two putative atypical agents risperidone (0.0625 mg/kg) and HP 873 (0.5 and 1.0 mg/kg) significantly increased social interaction behaviors between pairs of unfamiliar but not familiar rats. The benzodiazepine diazepam (1.25-5.0 mg/kg) increased social behaviors in both paradigms. Haloperidol, chlorpromazine, raclopride, and SCH23390 decreased social behaviors in these assays. In vitro receptor binding studies revealed that only clozapine, risperidone, and HP 873 displayed dopamine to serotonin affinity ratios for both D2/5-hydroxytryptamine2(5-HT2)/ and D1/5-HT1A of greater than or equal to 12.9 and 1.0, respectively. The present study suggests that antipsychotic agents that may be effective in social withdrawal can be identified in this modified social interaction paradigm. Further, our data suggests that a compound's effectiveness for the treatment of social withdrawal is at least in part due to its relative affinity for binding to dopamine D1 and serotonin 5-HT1A receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1993

D1 and D2 dopamine receptor-mediated mechanisms and behavioral supersensitivity.

The contribution of D1 and D2 dopamine (DA) receptor mechanisms to the behavioral supersensitivity and receptor upregulation induced by chronic DA antagonist administration were compared. Rats received either the selective D1 DA receptor antagonist SCH23390, the selective D2 DA receptor antagonist raclopride, their combination, or haloperidol, a predominantly D2 antagonist, for 21 days. Equivalent cataleptogenic doses of all drugs and drug combinations were employed. Tolerance to the cataleptic response was observed only in the haloperidol-treated group. Apomorphine-induced stereotypies were significantly enhanced in SCH23390-, raclopride-, and haloperidol-treated rats. In contrast, coadministration of both SCH23390 and raclopride had no effect on apomorphine-induced stereotypy. These findings suggest that neuroleptics blocking in equal proportion D1 and D2 receptor sites might be less likely to induce tardive dyskinesia and drug tolerance than those acting selectively on one or the other of these receptor subtypes.

Animals↗
PubMed1993

SCH23390, but not raclopride, decreases intake of intraorally infused 10% sucrose in adult rats.

When 10% sucrose is infused intraorally on postnatal days (PN) 7, 14, and 21, raclopride, a D2 dopaminergic antagonist, does not affect intake at any age and SCH23390, a D1 antagonist, does not affect intake on PN 7 but a large dose decreases intake on PN 14 and 21. To determine if this differential effect of the antagonists on PN 14 and 21 remains after further postnatal development, we studied adult rats in this intraoral intake test. Female (n = 77) and male (n = 81) adult rats, approximately 43 or 96 days old, were deprived for 4 h before intraoral infusion of 10% sucrose. Each rat was tested once and this was its first experience with sucrose. SCH23390 (133 or 267 micrograms/kg), raclopride (357 or 714 micrograms/kg), or saline vehicle was given IP at -15 min. The larger dose of SCH23390 significantly decreased intake of rats that were approximately 43 and 96 days old, but neither dose of raclopride changed intake at either age. These results suggest that D1, but not D2, receptors are necessary components of the central neural network that processes the unconditioned gustatory stimulus of 10% sucrose into mouthing and swallowing movements that maintain ingestion in late preweanling and adult rats under these conditions.

Administration, Oral↗
PubMed1993

Effects of dopaminergic drugs on working and reference memory in rats.

Changes in dopaminergic function have been associated with alterations in motor and cognitive function in man and in animals. This study was designed to assess the effects of dopaminergic drugs on these aspects of conditioned behavior in animals. Male Long-Evans rats were trained to perform an appetitive operant task that allowed daily quantification of working memory (accuracy of spatial delayed nonmatching-to-position), reference memory (accuracy of visual discrimination) and motor function [choice lever-press latency and nosepoke interresponse time (IRT) during delay]. The indirect dopamine agonist d-amphetamine (0.3-1.0 mg/kg) reduced nonmatching accuracy without significantly affecting discrimination accuracy, response latency, or nosepoke IRT. The D2/D3 agonist quinpirole (0.01-0.056 mg/kg) also decreased nonmatching accuracy without changing discrimination accuracy, but increased choice response latency and nosepoke IRT as well. The D1 agonist SKF 38393 (1.0-3.0 mg/kg) and the D1 antagonist SCH 23390 (0.01-0.03 mg/kg) only affected nosepoke IRT, at doses below those causing response failure. The D2 antagonist raclopride (0.056-0.177 mg/kg) exerted no significant effects at doses that did not suppress responding completely. The selective reduction of nonmatching accuracy by d-amphetamine and quinpirole indicates a mnemonic impairment specific to working memory (relative to reference memory). These results suggest further 1) that stimulation of D2/D3, but not D1, receptors may account for the d-amphetamine-induced deficit in working memory; 2) that stimulation of D2/D3 receptors alone by quinpirole may also impair spatial working memory, but only in conjunction with motor slowing; and 3) that antagonism of either receptor type (by SCH 23390 or raclopride) does not significantly affect memory at doses causing motor slowing and response failure.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1993

Time sampling observation procedure for studying drug effects: interaction between d-amphetamine and selective dopamine receptor antagonists in the rat.

A rapid time sampling observation procedure combined with two forms of automatic activity assessment is described. The methods are illustrated by examination of the behavioral effects of d-amphetamine, administered to rats either alone or in combination with antagonists selective for D1 or D2 dopamine (DA) receptors. Low doses of d-amphetamine (0.5-4.0 mg/kg) increased photocell counts, rearing, ambulation, and various forms of sniffing. Similar effects were observed in the first 30 min following administration of 8.0 mg/kg d-amphetamine. However, animals exhibited licking, intense sniffing down, and repetitive head and limb movements in the following 30 min; minimal ambulation, rearing, and sniffing up were observed. The "traditional" total photocell count measure did not differentiate between these time-dependent changes in locomotion. On the other hand, latch counts-where subjects had to move between the beams to register a count-adequately demonstrated this change in locomotion. The selective D1 receptor antagonist SCH23390 and selective D2 antagonist raclopride dose dependently inhibited the behavioral changes produced by 1.5 mg/kg d-amphetamine. Higher doses of SCH23390, but not raclopride, produced a behavioral pattern indistinguishable from that observed in control sessions. Both DA antagonists equipotently blocked the intense sniffing down and repetitive head/body movements produced by 8.0 mg/kg d-amphetamine. A narrow intermediate range of doses of SCH23390 reduced the incidences of these behaviors and produced levels of locomotion and sniffing straight that were significantly higher than those observed in control session. This form of behavioral activation was not observed with raclopride. Therefore, this observation procedure revealed subtle differences between the inhibitory effects of SCH23390 and raclopride on d-amphetamine-induced behavioral changes.

Animals↗
PubMed1993

Reward and reinforcement produced by drinking water: role of opioids and dopamine receptor subtypes.

The conditioned place preference procedure was used to evaluate the reinforcing properties of drinking in water-deprived rats. Subjects were allowed to drink for 8 min and were then transferred to place preference cages. In Experiment 1, the effects of naloxone and pimozide on drinking-induced place preference were analyzed. Animals treated with naloxone, 16 mg/kg, before the conditioning sessions showed a place aversion instead of the place preference found in saline-treated animals. Naloxone also reduced drinking. It was proposed that naloxone induced a state of frustrative nonreward. Pimozide, 1 mg/kg, blocked place preference and somewhat reduced drinking. In Experiment 2, doses of 1 and 4 mg/kg naloxone were used. Both doses blocked place preference. A dose of 4 mg/kg had a marginal effect on drinking, while 1 mg/kg lacked effect on this behavior. Thus, naloxone may block the establishment of place preference without modifying drinking. The effects of the dopamine D1 antagonist SCH23390 and the D2 antagonist raclopride were studied in Experiment 3. SCH23390 blocked place preference and reduced drinking at doses of 0.25 and 0.125 mg/kg. A dose of 0.06 mg/kg did not affect drinking but inhibited place preference. Raclopride, 0.25 mg/kg, had the same effects as SCH23390 at the same dose while 0.125 mg/kg blocked place preference without affecting drinking. It appears that the effects of a D1 and a D2 antagonist are similar. Because the effects of these latter drugs also are similar to those obtained with naloxone, it is suggested that both dopamine and opioids are important for water-induced reinforcement. Possible interactions between these two neurotransmitter systems are discussed.

Animals↗
PubMedDate not supplied

Effects of the dopamine D3 receptor ligand 7-OH-DPAT on male rat ejaculatory behavior.

As previously shown, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) produces a marked and highly characteristic facilitation of male rat ejaculatory behavior, and this effect is not sensitive to dopamine (DA) receptor antagonists of the D1 or D2 receptor families. The structural congener 7-OH-DPAT, primarily characterized as a DA D3 receptor selective ligand, produced a facilitation of male rat ejaculatory behavior, as evidenced by a dose-dependent decrease in the number of intromissions preceding ejaculation and in time to ejaculation. These effects could be antagonized by pretreatment with the DA D2/D3 receptor antagonist, raclopride. Thus, 7-OH-DPAT-induced effects on male rat ejaculatory behavior can be pharmacologically differentiated from effects produced by 8-OH-DPAT.

Animals↗
PubMed1995

Dihydrexidine, a full D1 dopamine receptor agonist, induces rotational asymmetry in hemiparkinsonian monkeys.

Dihydrexidine (trans-10,11-dihydroxy5,6,6a,7,8,12b hexanhyydrobenso- [alpha]phenanthridine) is a full dopamine D1 agonist. In rhesus macaque monkeys rendered hemiparkinsonian by unilateral intracarotid infusions of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), dihydrexidine (0.15-0.9 mg/kg) elicited dose-dependent contralateral rotation. The effects of dihydrexidine were blocked by pretreatment with the D1 antagonist SCH 23390 (0.03 mg/kg), but not by the D2 antagonist raclopride (0.025 mg/kg). These results suggest a functional role for D1 receptors in stimulating motor behavior in a primate model of Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1995

Dopaminergic drugs in the medial preoptic area and nucleus accumbens: effects on motor activity, sexual motivation, and sexual performance.

In two experiments, dopamine agonists and/or antagonists were injected into the medial preoptic area (MPOA) or the nucleus accumbens (NAcc) of male rats. The animals were then tested in an X-mase with four goal boxes, which contained a receptive female, a male, or were empty. In Experiment 1, the D1 antagonist SCH-23390 and the D2 antagonist raclopride in the MPOA decreased the percentage of trials on which the female's chamber was chosen, a measure of sexual motivation. Raclopride also decreased the number of animals that copulated after choosing the female's chamber. The 10-micrograms dose of the D3/D2 agonist quinelorane increased the latency to reach the female's chamber, slowed the onset of copulation, and decreased the number of intromissions preceding an ejaculation. In Experiment 2, 1- and 5-micrograms doses of quinelorane and of the mixed D1/D2 agonist apomorphine were injected bilaterally into the NAcc. Both doses of quinelorane increased the number of times that the subject did not select a chamber within 60 s. No drug in the NAcc affected specifically sexual motivation or performance. The results are consistent with differential influence of the MPOA and the NAcc on motor activity, sexual motivation, and sexual performance.

Animals↗
PubMed1994

Contrasting effects of dopaminergic blockade on MDMA and d-amphetamine conditioned taste aversions.

A series of experiments examined the role of dopamine in the conditioned taste aversion (CTA) produced by 3,4-methylenedioxymethamphetamine (MDMA) and d-amphetamine in rats. The CTA induced by MDMA (1.0 mg/kg) was unaffected by the D1 dopamine receptor antagonist SCH23390 (0.3 or 0.6 mg/kg), the D2 receptor antagonist raclopride (0.3 or 0.6 mg/kg), SCH23390 and raclopride combined (both 0.3 or 0.6 mg/kg), or the D1/D2 receptor antagonist haloperidol (0.4 mg/kg). In contrast, the CTA produced by d-amphetamine (0.5 mg/kg) was attenuated by SCH23390 and raclopride combined (both 0.3 mg/kg) as well as haloperidol (0.4 mg/kg), but not by SCH23390 (0.3 or 0.6 mg/kg) or raclopride (0.3 or 0.6 mg/kg) alone. These results suggest that dopamine plays different roles in MDMA and amphetamine CTAs, and that the D1 and D2 receptors independently mediate the aversive effect of amphetamine in CTA.

3,4-Methylenedioxyamphetamine↗
PubMed1994

D1 and D2 dopamine receptor antagonists block caffeine-induced stimulation of locomotor activity in rats.

The mechanism of action for the behavioral stimulant effects of caffeine has been extensively studied, but results have been ambiguous and inconsistent. The present study examined the role of dopamine in caffeine-induced stimulation of locomotor activity in rats. d-Amphetamine was also tested for comparison. Locomotor activity of male Sprague-Dawley rats (300-350 g) was measured using two-channel electronic activity monitors. Activity counts were recorded for 30 min following a 30-min pretreatment with either caffeine (3.0-100 mg/kg, IP) or d-amphetamine (0.1-3.0 mg/kg, IP) alone and in combination with the D1 dopamine antagonist SCH23390 (0.01 and 0.003 mg/kg, SC) or the D2 dopamine antagonists sulpiride (30 mg/kg, SC) or eticlopride (0.03 mg/kg, SC). Caffeine and d-amphetamine dose dependently increased locomotor activity. This effect of both caffeine and d-amphetamine was blocked by SCH23390 as well as by eticlopride. Sulpiride blocked the stimulatory effects of caffeine but not d-amphetamine. These results suggest that the locomotor stimulant effect of caffeine, like that of d-amphetamine, is mediated through dopaminergic systems; both D1 and D2 receptors appear to be involved.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1994

Evidence for specific interactions between 5-HT1A and dopamine D2 receptor mechanisms in the mediation of extrapyramidal motor functions in the rat.

Administration of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.1 mg kg-1 SC) completely antagonised the catalepsy produced by the dopamine (DA) D2 receptor antagonist raclopride (16 mg kg-1 SC). This effect by 8-OH-DPAT was in turn completely antagonised by treatment with the new 5-HT1A receptor antagonist (S)-5-fluoro-8-hydroxy-2-(di-n-propylamino)tetralin [(S)-UH-301] (3.5 mg kg-1 SC), but not by the mixed 5-HT1 receptor/beta-adrenoceptor antagonist (-)pindolol (2.0 mg kg-1 SC). The failure by (-)pindolol to antagonise the effects of 8-OH-DPAT on raclopride-induced catalepsy could be due to its beta-receptor-blocking properties, since by themselves both (-)pindolol and the selective beta-adrenoceptor antagonist betaxolol (4 mg kg-1 SC) at least partially antagonised the raclopride-induced catalepsy. The present results provide further support for specific interactions between 5-HT1A and DA D2 receptor mechanisms in the mediation of extrapyramidal motor functions in the rat.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1994

Behavioral profile of raclopride in agonistic encounters between male mice.

Raclopride is a substituted benzamide with high selectivity as an antagonist of central dopaminergic D2 receptors and potential antipsychotic effects. In comparison with a classic DA receptor blocking agent like haloperidol, raclopride displays an atypical profile in preclinical tests for extrapyramidal side effects. Antiaggressive properties of raclopride on agonistic behavior have not yet been fully explored. In this work the effects of raclopride (0.1, 0.3, or 0.6 mg/kg) on aggressive and motor behaviors in male mice were studied. Aggression tests were performed 30 min after injections. Encounters were videotaped and behavior was evaluated, measuring the time spent in 11 broad categories of behavior. The results show a clear antiaggressive effect of raclopride, with very little motor impairment and some increase in exploratory behavior. This behavioral profile is very similar to the one observed with other atypical neuroleptics and differs somewhat from that found in the classic compounds.

Agonistic Behavior↗