Effects of dopamine D1 receptor agonists in rats trained to discriminate dihydrexidine

Rationale The full D₁ receptor agonist dihydrexidine (DHX) [(+/−)-trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine hydrochloride] is under clinical development (DAR-100) for Parkinson’s disease and schizophrenia. Despite the clinical development of DHX, very little is known about its discriminative stimulus properties in rats. To more fully characterize the discriminative stimulus properties of DHX, we trained rats to discriminate DHX (3 mg/kg, i.p.) from vehicle. Methods: Substitution tests in rats discriminating DHX (3 mg/kg, i.p.) from vehicle were performed with structurally distinct D₁ receptor agonists with both partial and full intrinsic efficacy. In addition, the peripherally restricted D₁ agonist, fenoldopam, was evaluated.Results SKF 75670A, ABT-431, dinapsoline, SKF 81297, and SKF 82958 all fully substituted in a dose-dependent manner. The rank order of potency for substitution was SKF 82958<ABT-431<SKF 75670A≤dinapsoline<SKF 81297<DHX. Fenoldopam (10 and 30 mg/kg) did not substitute and was without effect on rates of responding.Conclusions DHX produces prominent dopamine D₁ receptor agonist effects in vivo and is likely to produce subjective effects in humans similar to other D₁ receptor agonists.     

The D1 dopamine agonist SKF 38393 functions as a discriminative stimulus in rats

Rats (N=11) were trained to discriminate SKF 38393 (8.0 mg/kg, IP), a D₁ dopamine receptor agonist, from saline in a two-lever, food-reinforced (FR 30) drug discrimination paradigm. The discrimination was acquired by nine rats within an average of 77±6 (SEM) sessions. Subsequently, various doses of SKF 38393 as well as SKF 82526, a potent, selective D₁ agonist that does not readily penetrate the blood-brain barrier, were injected prior to test sessions. SKF 38393 (2–16 mg/kg) produced a dose-related increase in the percent of responses that occurred on the drug lever during test sessions. On the other hand, SKF 82526 (0.125 and 1.0 mg/kg) induced no drugappropriate responding. This experiment establishes that SKF 38393 can serve as a discriminative stimulus in rats. Furthermore, the observation that SKF 82526 did not substitute for SKF 38393 in this paradigm makes it unlikely that this effect involves a peripheral site of action. The results suggest the existence of a functional, behaviorally relevant D₁ dopamine receptor in the CNS of rats.     

Role of dopamine D-1 and D-2 receptor subtypes in mediating dopamine agonist effects on food consumption in rats

The effects of selective D-2 and D-1 dopamine (DA) receptor agonists on food consumption were investigated in free-feeding rats. A selective D-2 receptor agonist, (+)-4-propyl-9-hydroxynaphthoxazine (PHNO), increased the consumption of standard food pellets in the dose range of 7.5–120 g/kg, while SKF 38393 (5.0 mg/kg), a selective D-1 receptor agonist, decreased food pellet intake. The increase in food pellet intake produced by PHNO was blocked by haloperidol (an antagonist relatively selective for the D-2 receptor at the dose used, 0.05 mg/kg) and SCH 23390 (20 g/kg, a D-1 receptor selective antagonist). Increasing arousal by disturbance associated with repeated food weighting also increased food pellet consumption, but did not diminish PHNO-elecited feeding. However, the same range of doses of PHNO (7.5–120 g/kg) which increased food pellet intake decreased consumption of a liquid diet, and had no overall effect on a highly palatable liquid diet. The increase in consumption of solid food induced by PHNO appears to be secondary to enhancement of chewing behaviors. In contrast, the decrease in food intake induced by SKF 39393 may be due to a direct action of the drug on neural feeding mechanisms.     

Effects of the putative dopamine D3 receptor agonist 7-OH-DPAT in rhesus monkeys trained to discriminate cocaine from saline

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     

Conditioning of pre- and post-synaptic behavioural responses to the dopamine receptor agonist apomorphine in rats

We investigated whether pharmacological effects of the dopamine agonist apomorphine can be conditioned by establishing an association of apomorphine administration with exteroceptive cues. Apomorphine was repeatedly administered and subsequently, the rat was put into a test cage and exposed to an acoustic and an olfactory stimulus (conditioned rats). Control animals (pseudoconditioned rats) were treated with the same pharmacological schedule of apomorphine not temporally associated with the stimuli. On the test day, both groups were injected with saline and exposed to the stimuli described.The stereotyped behaviour produced by large doses of apomorphine (0.5 or 2.0 mg/kg SC), namely sniffing, licking and gnawing, could be conditioned in a pronounced way. During the conditioning period, a change in the stereotypies was observed with regard to the time-course (earlier occurrence) and to the character of the stereotypies (from sniffing to licking and gnawing), when 0.5 mg/kg apomorphine was used, but not with the dose of 2.0 mg/kg. The conditioned responses showed a relatively uniform distribution during the observation period with some increase towards the end of the observation period. Some signs produced by a low dose of apomorphine (0.07 mg/kg SC), namely hypomotility and ptosis, but not yawning, could also be conditioned, although in a less pronounced way. An intermediate dose of apomorphine (0.18 mg/kg SC) produced both signs observed after large doses and those observed after a small dose, occurring alternatingly. Both types of signs could be conditioned using this dosage. Conditioning did not alter striatal or mesolimbic dopamine turnover.These results suggest that only behavioural signs due to an activation of postsynaptic dopamine receptors, but also some symptoms produced by an activation of dopamine autoreceptors can be conditioned.     

Discriminative stimulus effects of apomorphine and 7-OH-DPAT: a potential role for dopamine D3 receptors

Previous studies have reported that the non-selective dopamine agonist, apomorphine, can serve effectively as a discriminative stimulus in experimental animals, and evidence has been presented that this effect is mediated by dopamine D₂ receptors. More recently, it has been found that another dopamine agonist, 7-OH-DPAT, which has some selectivity for D₃ receptors, also produces a discriminative cue in rats. The present study set out to make a direct comparison of the discriminative stimulus effects of these two compounds. Rats were trained to discriminate either apomorphine (0.05 mg/kg, SC) or 7-OH-DPAT (0.1 mg/kg, IP) from saline. Both discriminations were acquired but extended training was necessary. Cross generalisation occurred between the two compounds and both cues generalised to the dopamine agonists, quinpirole, quinelorane, PD 128207, and bromocriptine. When the potencies of these compounds to produce the apomorphine or 7-OH-DPAT cues were correlated with their potencies to produce D₂ or D₃ functional responses in vitro (mitogenesis in transfected cells–results taken from the literature) stronger correlations with D₃ than with D₂ responses were observed. Both the cueing and the response rate-decreasing effects of apomorphine and 7-OH-DPAT were antagonised by the autoreceptor selective dopamine antagonist amisulpride, and sulpiride also antagonised the cues but without affecting response rates. In contrast, haloperidol blocked the cues but potentiated the response rate decreases. These results suggest that, at the doses used, apomorphine and 7-OH-DPAT produce similar discriminative stimuli, which may be mediated by presynaptically located dopamine D₃ receptors. Received: 5 October 1996 / Final version: 15 November 1996     

Studies on the discriminative stimulus properties of apomorphine in rhesus monkeys

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.     

Effects of stimulation and blockade of dopamine receptor subtypes on the discriminative stimulus properties of cocaine

The involvement of dopamine (DA) receptor subtypes in the behavioral effects of CNS stimulants was studied in rats trained to discriminate occaine from saline. In substitution tests, the stimulus effects of 10mg/kg of this substance generalized tod-amphetamine (0.25–1.0 mg/kg) and the selective D₂ against LY-171555 (0.05–0.25 mg/kg); but not to the D₁ agonist SKF-38393 (5.0–15.0 mg/kg); in combination tests, the D₁ antagonist Sch-23390 (0.0625–0.5 mg/kg) significantly blocked, and the D₂ antagonist spiperone (0.25–0.5 mg/kg) partially blocked the cocaine cue. These data suggest that the involvement of DA systems in the behavioral effects of cocaine is more complex than either D₁ or D₂ receptor activation; for example, the stimulus properties of this substance might involve both D₁ and D₂ receptor activation.Some of these results were presented at the meeting of the Society for Neuroscience, Toronto, 1988     

Effects of SR 48692, a selective non-peptide neurotensin receptor antagonist,on two dopamine-dependent behavioural responses in mice and rats

One major mechanism underlying the central action of neurotensin is an interaction with the function of dopamine (DA)-containing neurons. In addition, direct or indirect DA agonists have been reported to promote neurotensin release. We have found that SR 48692, a non-peptide neurotensin receptor antagonist (0.04 – 0.64 mg/kg orally), antagonizes (50–65%) yawning induced by apomorphine (0.07 mg/kg SC) or bromocriptine (2 mg/kg IP) in rats, and turning behaviour induced by intrastriatal injection of apomorphine (0.25 µg), (+) SKF 38393 (0.1 µg), bromocriptine (0.01 ng) or (+) amphetamine (10 µg) in mice. Other apomorphine-induced effects in mice and rats such as climbing, hypothermia, hypo- and hyper-locomotion, penile erections and stereotypies were not significantly modified by SR 48692. Taken together, these data suggest that neurotensin may play a permissive role in the expression of some but not all behavioural responses to DA receptor stimulation.     

Repeated ECS enhances dopamine D-1 but not D-2 agonist-induced behavioural responses in rats

The present study examined the effect of acute and repeated administration of electroconvulsive shock (ECS) on behaviours induced by various dopamine agonists in rats. Components of behavioural arousal induced by the dopamine D-1 agonist SKF 38393, the dopamine D-2 agonist RU 24213 and the mixed D-1/D-2 agonist apomorphine were assessed using a behavioural check-list method. Also, the overall behavioural syndrome produced by these drugs was measured using rating scales. Rats receiving repeated (5 times over 10 days) but not a single ECS showed enhanced grooming and sniffing in response to SKF 38393 (7.5 mg/kg) when compared to controls. Repetitive sniffing induced by apomorphine (0.5 mg/kg) was also enhanced by repeated ECS. Neither repeated nor a single ECS significantly changed behaviours induced by RU 24213 (0.75 mg/kg), although a downward trend was evident. The behaviour rating scale measurements also demonstrated that repeated administration to ECS increased behavioural responsiveness to SKF 38393 and apomorphine but not RU 24213. These results suggest that the increase of dopamine-mediated behaviour in rats seen after chronic ECS relates to an increase in central dopamine D-1 receptor function.     

Evidence for dopamine D(1) receptor involvement in the stimulus selection task: overshadowing in the rat

RATIONALE: A number of lines of evidence suggest that dopamine might play a role in stimulus selection, the process whereby specific cues are selected to guide action. OBJECTIVES: In order further to define the potential role for dopamine in stimulus selection, the present series of studies examined whether dopaminergic drugs modulate overshadowing, a paradigm that involves stimulus selection in rats. Overshadowing is where preferential learning occurs to one (usually the more salient) element of a stimulus compound. METHODS: Overshadowing was measured in rats using a thirst motivated conditioned emotional response paradigm (CER). Two simultaneously presented stimuli (light and tone) were paired with an aversive unconditioned stimulus (mild footshock); overshadowing is observed when learning to the less salient stimulus is weaker than learning to the same stimulus when it is conditioned alone. RESULTS: d-Amphetamine sulphate (1 mg/kg, IP) was found selectively to disrupt overshadowing, without affecting the CER in control animals. The dopamine (DA) D(2) receptor antagonists, haloperidol (0.2 mg/kg, IP) or raclopride (0.5 mg/kg, IP), failed to reverse amphetamine-induced disruption of overshadowing. In contrast, the selective DA D(1) antagonist SCH 23390 (0.05 mg/kg, IP) reversed amphetamine-induced disruption of overshadowing. The partial DA D(1) agonist SKF 38393 (5 mg/kg, IP) was found to abolish overshadowing when given alone. CONCLUSION: These data indicate a modulatory role for the DA D(1) receptor in the expression of stimulus selection and suggest that the DA D(1) receptor might play a role in salience allocation aspects of learning.     

Discriminative stimulus effects of a low dose of apomorphine in the rat

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.     

Role of specific dopamine receptor subtypes in amphetamine discrimination

Biochemical, electrophysiological, and behavioral experiments suggest that the dopamine D-1 and D-2 receptor subtypes functionally interact. In rats trained to discriminate 1.0 mg/kg d-amphetamine, substitution with the D-2 agonist quinpirole (0.1–2.0 mg/kg) produces amphetaminelever responding, whereas the D-1 agonist SKF 38393 (0.3–10.0 mg/kg) elicits only saline-appropriate responding. Combining either quinpirole (0.05–0.5 mg/kg) or SKF 38393 (0.5–10.0 mg/kg) with 0.3 mg/kg d-amphetamine results in dose-dependent increases in amphetamine-lever responding. Conversely, the D-1 antagonist SCH 23390 (0.02–0.1 mg/kg) antagonizes the discrimination produced by 0.7 mg/kg d-amphetamine. Additional combination studies examined the effect of DA receptor drugs on discrimination when quinpirole is substituted in d-amphetamine trained rats. SKF 38393 (0.5–7.0 mg/kg) fails to increase the amphetamine-appropriate lever response produced by either 0.05 or 0.2 mg/kg quinpirole. Similarly, SCH 23390 (0.01–0.1 mg/kg) fails to antagonize the amphetamine-lever responding produced by either 0.2 or 0.5 mg/kg quinpirole. Haloperidol (0.02–0.2 mg/kg) does antagonize the amphetamine-appropriate response produced by quinpirole substitution. The d-amphetamine discrimination studies indicate that stimulating D-2 receptors alone or D-1 receptors in the presence of d-amphetamine yields d-amphetamine-lever responding, and suggests that D-1/D-2 receptors can functionally interact to alter discrimination behavior. Quinpirole substitution, on the other hand, shows an insensitivity to D-1 receptor manipulations.     

Extinction and reacquisition of differential responding in rats trained to discriminate between chlordiazepoxide and saline

In order to assess the resistance of drug discriminative responding to prolonged reinforcement omission, rats were trained to discriminate between either 6.0 mg/kg PO or 30.0 mg/kg PO. CDP and saline, using a food reinforced (VI40-FR10) operant procedure. Dose generalization tests were conducted for both groups. Sessions were then run without reinforcement while drug (D) and saline (S) administrations were continued (extinction phase). After a maximum of 30 sessions without reinforcement, or when the rats emitted less than ten responses on either lever during three successive sessions (extinction criterion), reinforcement was reinstated. Finally, additional dose generalization tests with CDP were run. The discriminative responding controlled by the D and S administrations was not affected significantly by prolonged reinforcement omission in either group. For both groups, response rates were decreased and latencies to initiate responding were increased during the extinction phase. Response rate reduction occurred more rapidly for the drug condition in the high training dose group. This group also reached the extinction criterion sooner than the low training dose group. The reacquisition process occurred very rapidly. Response rates increased substantially after the first reinforcement had been obtained. After ten reacquisition sessions, response rates and latencies had reached values similar to those observed before extinction was initiated. Data revealed no differences between groups and the course of reacquisition did not differ between the S and D conditions. The generalization tests executed before the extinction phase and after the reacquisition phase yielded similar results and were in agreement with earlier findings. The major conclusion was that the resistance to extinction of the discriminative accuracy was substantial.     

Effect of the D1 receptor agonist SKF 38393 on some behavioural effects of apomorphine in rats

Summary The dopamine receptor agonist apomorphine in experiments on rats in low doses (0.025–0.2 mg/kg, s.c.) induced yawning which reflected a selective activation of presynaptic dopamine receptors. In high doses (0.25–1.0 mg/kg) apomorphine induced stereotyped sniffing and yawning in consequence of postsynaptic D 2 receptor activation. Dopamine D 1 receptor agonist SKF 38393 inhibited yawning induced by low doses of apomorphine. The inhibitory effect of SKF 38393 on apomorphine-induced yawning was attenuated by pretreatment with specific D I receptor antagonist SCH 23390 [2-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1 H-3-benzazepine-7-ol]. On the other hand however, SKF 38393 potentiated sniffing induced by the high doses of apomorphine without affecting gnawing. These data indicate that D 1 receptor activation modulates both pre- and postsynaptic effects of apomorphine in opposite directions.     

Differential effects of apomorphine in 6-hydroxydopamine-treated and aged rats

Effects of dopamine depletion and old age were tested on the ability of rats to discriminate the interoceptive cue produced by IP administered apomorphine. In Experiment 1, rats were administered IC injections of 6-hydroxydopamine or its vehicle at 5 days of age. Administration of this dopamine neurotoxin resulted in significant depletion of whole-brain dopamine to 27.2% of controls as indicated when the brains of littermate rats, killed at 35 days of age, were analyzed by high-pressure liquid chromatography. Although this dopamine depletion was significant, toxintreated rats learned to discriminate 0.16 mg/kg apomorphine from saline at the same rate as control rats. However, the dose-response curve for apomorphine discrimination after doses of 0.04–0.24 mg/kg suggested hypersensitivity to the dopamine agonist in toxin-treated rats. In Experiment 2, senescent rats were similarly trained to discriminate apomorphine in the two-lever food-motivated operant task. Dose-response testing indicated hypersensitivity similar to that found in 6-OHDA-treated rats. This increased behavioral responsiveness of aged rats to dopamine agonists is discussed in relation to receptor supersensitivity, metabolic rates, and blood-brain barrier permeability.     

Individual differences in behavior following amphetamine,GBR-12909, or apomorphine but not SKF-38393 or quinpirole

Subjects that respond more to a novel environment show a greater locomotor response to drugs of abuse such as cocaine and amphetamine. The current study was performed to examine differences between high (HR) and low (LR) responding rats to a novel environment following administration of amphetamine, a selective dopamine uptake blocker (GBR-12909), a nonselective dopamine agonist (apomorphine), and selective dopamine D₁ and D₂/D₃ agonists. A behavioral checklist and a rating scale were used to determine the behavioral arousal caused by administration of amphetamine (0, 0.5, 2.0, and 8.0 mg/kg), GBR-12909 (0, 1.25, 5.0, and 20.0 mg/kg), apomorphine (0, 0.1, 0.3, and 1 mg/kg), SKF 38393 (0, 2.5, 10, and 40 mg/kg), or quinpirole (0, 0.05, 0.5, and 5.0 mg/kg). The five drugs produced behavioral activation profiles distinct from each other. Following amphetamine administration, both HR and LR subjects showed dose dependent increases in behavioral arousal. The behaviors primarily affected were sniffing, locomotor activity, rearing, and oral activity. HR rats showed a greater overall behavioral response to amphetamine administration compared with LR rats and there were differences in specific behaviors between the two groups. Following GBR-12909 administration, all subjects showed dose dependent increases in sniffing, locomotor activity, and rearing. Differences between HR and LR were observed in sniffing, locomotor activity, and rearing behaviors. HR and LR both showed dose dependent increases in behavior following apomorphine administration. HR showed greater behavioral activation after apomorphine than LR. SKF 38393 produced pronounced increases in the amount of sniffing, grooming, and intense grooming, in addition to increasing the overall behavioral rating of all subjects, while quinpirole produced increases in sniffing, locomotor activity, and oral movements. However, the behavioral effects of SKF 38393 and quinpirole did not differ between HR and LR. These results suggest that activation of the dopamine system but probably not only one type of dopamine receptor is sufficient to produce behavioral differences between high and low responding subjects.     

Effects of dopamine D1 receptor full agonists in rats trained to discriminate SKF 38393

Although the dopaminergic pharmacology of the D1 receptor full agonists, dinapsoline, dihydrexidine and the prodrug ABT-431 have been studied, no information is available on the ability of these agonists to substitute for the D1 agonist SKF 38393 in rats trained to discriminate this compound from vehicle. The present study was designed to characterize the potential D1 discriminative stimulus effects of these compounds. The selective dopamine D1-receptor agonists dihydrexidine [(+/-)-trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a] phenanthridine hydrochloride], ABT-431 [(-)-trans-9,10-diacetyloxy-2-propyl-4,5,5a,6,7,11b-hexahydro-3-thia-5-azacyclopent-1-ena[c]phenanthrene hydrochloride], the diacetyl prodrug derivative of A-86929, and dinapsoline [9-dihydroxy-2,3,7,11b-tetrahydro-1H-naph[1,2,3-de]isoquinoline] were studied in rats trained to discriminate racemic SKF 38393 [(+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol], a selective D1 receptor partial agonist from vehicle. All of the agonists substituted fully for the discriminative stimulus effects of SKF 38393. The rank order of potency for substitution was ABT-431 > dinapsoline > dihydrexidine > SKF 38393. The D1 receptor antagonist, SCH 23390, blocked the discriminative stimulus effects of SKF 38393. The D3/D2-receptor agonist PD 128,907 [S(+)-(4aR,10bR)-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]-benzopyrano[4,3-b]-1,4-oxazin-9-ol] did not substitute up to doses that produced profound rate-suppressant effects. Thus, consistent with their D1 receptor pharmacology, the full D1-receptor agonists substituted completely for the discriminative stimulus of SKF 38393.     

Anatomical differentiation within the nucleus accumbens of the locomotor stimulatory actions of selective dopamine agonists andd-amphetamine

The effects of local injections of dopamine receptor agonists into various areas within the nucleus accumbens or the medial caudate-putamen on the generation of locomotor activity were examined. Combinations of 0.32 µg/side of the dopamine receptor agonists SKF 38393 (D₁) and quinpirole (D₂) produced increases in locomotor activity that varied according to the rostral-caudal placement of the cannulae within the nucleus accumbens. The greatest levels of locomotion were generated by injections into a region in the caudal-central nucleus accumbens, with lower levels of activity elicited by injections into more rostral or caudal regions. A similar pattern of responses was produced by administration of the indirect dopamine agonistd-amphetamine. These results indicate that there is marked heterogeneity in the response of discrete sub-regions of the nucleus accumbens to dopamine receptor stimulation and that this heterogeneity is functionally expressed in the mediation of the locomotor effects of dopaminergic agonists.     

Evidence for heterogeneous rotational responsiveness to apomorphine, 3-PPP and SKF 38393 in 6-hydroxydopamine-denervated rats

Several novel dopamine (DA) agonists (SKF 38393, 3-PPP, TL-99) have been reported to induce rotational behavior (RB) in rats unilaterally denervated of the nigro-striatal pathway by 6-hydroxydopamine. Other reports have indicated no RB, however, and these drugs do not cause other behavioral manifestations of postsynaptic DA agonism. In the present experiments, two groups of 6-hydroxydopamine-denervated rats were distinguished by their relative responsiveness to apomorphine-induced RB. A highly sensitive group showed maximal RB in response to doses as low as 0.03 mg/kg, while a less sensitive group exhibited comparable RB only in response to 15- to 20-fold higher doses. The high sensitivity group exhibited RB in response to SKF 38393, 3-PPP and pergolide, but the low sensitivity group did not show appreciable RB after these drugs, even at doses 50 to 100-fold higher. Haloperidol markedly attenuated apomorphine-induced RB in the low sensitivity subgroup, but only reduced by approximately one-half the number of turns induced by apomorphine or SKF 38393 in the high sensitivity group. The atypical antipsychotics, clozapine and RMI 81582, and the muscle relaxant, methocarbamol, reduced RB in all groups, but only at doses that caused performance impairment in a rotorod test. These results appear to reflect qualitative differences in responsiveness to different DA agonists. Behavioral preselection of 6-hydroxydopamine-denervated animals is necessary to achieve consistent pharmacological results with the 6-hydroxydopamine RB model.