Amphetamine discrimination: effects of dopamine receptor agonists

Dopamine (DA) D-1 and D-2 receptor agonists and antagonists were characterized in receptor binding and adenylate cyclase assays with respect to affinity, selectivity and efficacy. The ability of the ligands to interact with the discriminative stimulus effects of d-amphetamine (AMPH) was then assessed. The D-2 agonists, quinpirole, pergolide and CH 29-717, substituted completely for AMPH while neither partial (SKF 38393 and SKF 75670) nor full D-1 receptor agonists (SKF 89626 and SKF 81297) substituted. On the other hand, the selective D-1 and D-2 antagonists all blocked AMPH. The substitution for AMPH by pergolide was blocked by raclopride but not by SCH 23390, indicating D-2 mediation. In contrast, the motor effects of pergolide were blocked by both raclopride and SCH 23390, indicating mixed D-1/D-2 receptor involvement. These results suggest that D-1 and D-2 are equally involved in the expression of functional effects in the DAergic motor systems. Conversely, D-2 receptors may play a primary role in the DA systems involved in the AMPH cue; furthermore, the D-1 and D-2 receptors in the systems are relatively uncoupled.     

Pharmacological characterization of the discriminative stimulus properties of the dopamine D1 agonist, SKF 81297

A range of selective dopamine D1 and D2 receptor agonists and antagonists was used to characterize to the discriminative stimuli produced by d-amphetamine (0.5mg/kg) and the D1 agonists SKF 81297 (0.1mg/kg). In rats trained to discriminate d-amphetamine (0.5mg/kg) from saline, d-amphetamine produced a dose-related increase in per cent drug lever responding, and SKF 81297 did not show any d-amphetamine-like discriminative stimulus effects; neither did SKF 81297 potentiate nor antagonize the d-amphetamine discriminative stimulus. In rats trained to discriminate SKF 81297 (0.1mg/kg) from saline, SKF 81297 produced a dose-related increase in per cent drug lever responding, and SKF 38393 and SKF 83565 elicited full SKF 81297-like effects despite the fact that these compounds have widely differing efficacies for stimulating adenylate cyclase. SKF 81297 had a 25-fold greater potency than SKF 38393 in this assay. The D2 agonists, PHNO and ropinirole, did not display any SKF 81297-like discriminative stimulus effects. The SKF 81297 discriminative stimulus was completely blocked by the D1 antagonist SCH 23390 but was not blocked by the D2 antagonist BRL 34778.     

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 selective drugs for dopaminergic D1 and D2 receptors on conditioned locomotion in rats

Classically conditioned locomotor activity has been demonstrated by pairing injections of dopamine agonists or antagonists with specific environmental stimuli. The present studies investigated conditioning using drugs with varying selectivity for the dopamine D1 or D2 receptor. Experiment 1 assessed conditioning in groups of rats using the indirect acting agonist (+)-amphetamine (2.0 mg/kg), and the D1 agonist SKF 38393 (10.0 mg/kg), the D2 agonist quinpirole (2.5 mg/kg), the D1 and D2 antagonists, SCH 23390 (0.05 mg/kg) and metoclopramide (25.0 mg/kg), respectively. Paired groups received nine 2-h drug-environment (automated activity monitoring chambers) pairings whereas Unpaired groups received the stimuli explicitly unpaired. Test revealed conditioned hyperactivity with each agonist and metoclopramide whereas conditioned hypoactivity was seen with SCH 23390. Experiment 2 assessed the interaction of these agonists and antagonists on the establishment of conditioned activity. Paired groups received an agonist and antagonist during conditioning sessions. SCH 23390 blocked conditioning based on (+)-amphetamine and SKF 38393 but not quinpirole. Metoclopramide (10.0 mg/kg) blocked conditioning based on quinpirole but not SKF 38393. Metoclopramide (25.0 mg/kg) also did not block (+)-amphetamine-induced conditioning. These studies suggested that drug-induced alterations at either D1 or D2 receptors may be involved in conditioned locomotion.     

D1 and D2 dopamine receptors stimulate hypothalamo-pituitary-adrenal activity in rats.

A stimulatory role for endogenous dopamine (DA) in the regulation of hypothalamo-pituitary-adrenal activity has previously been demonstrated. In the present study, the roles of D1 and D2 subtypes of DA receptors in the regulation of activity of the hypothalamo-pituitary-adrenal axis were investigated. The intraperitoneal administration of either the D1 agonist, SKF 383393 (1-phenyl-2,3,4,5 tetrahydro-(iH)-benzazepine-7,8diol HCl, 5-20 mg/kg) or the D2 agonist quinpirole (0.05-1 mg/kg) dose-dependently elevated both adrenocorticotropic hormone (ACTH) and corticosterone (CS) in serum. Similarly, administration of either SKF 38393 or quinpirole (1-100 micrograms) into the third ventricle dose-dependently elevated ACTH in serum. The response of ACTH to intraperitoneal SKF 38393 was blocked by pretreatment with the D1 antagonist SCH 23390 (1-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5 tetrahydro-1H-3-benzazepine, 0.25 mg/kg, i.p.) but not by the D2 antagonist sulpiride (50 mg/kg, i.p.). The response of ACTH to intraperitoneal injection of quinpirole was blocked by pretreatment with sulpiride and attenuated slightly by pretreatment with SCH 23390. Further, the co-administration of sub-maximum doses of SKF 38393 and quinpirole caused additive increases in ACTH in serum. These results suggest that both D1 and D2 subtypes of DA receptors contribute to the dopaminergic regulation of function of the hypothalamo-pituitary-adrenal axis and support a role for DA neurons in the hypothalamus in this response. Further, these findings suggest that the D1 and D2 receptors, mediating the response of the hypothalamopituitary-adrenal axis are not tightly coupled.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibitory effects of partial D2 dopamine receptor agonists on the d-amphetamine discriminative cue

The ability of partial dopamine (DA) receptor agonists with low relative efficacy to inhibit the d-amphetamine discriminative cue has been determined in rats trained to discriminate 0.5mg/kg d-amphetamine from saline. The classical neuroleptic haloperidol and selective D1 antagonist SCH 23390 potently blocked the cueing properties of d-amphetamine. A complete blockade of d-amphetamine discrimination was also observed with the partial DA agonist terguride. In contrast, preclamol [(-)-3-PPP] and SDZ 208-911 produced only a partial inhibition which was characterized by an asymptotic drug effect across a wide dose range. Clear variations in the sensitivity of individual rats to the inhibitory effects of preclamol on the d-amphetamine cue were observed. Some rats were sensitive to even low doses of preclamol, while others were minimally affected across the dose range. Variations in individual response were also observed with SDZ 208-911 and terguride, but not with haloperidol or SCH 23390. The present findings are discussed in relation to the partial agonist profile of preclamol, SDZ 208-911 and terguride and to possible underlying differences in DA receptor sensitivity between individual rats.     

The role of D1 and D2 dopamine receptors in the acquisition and expression of cocaine-induced conditioned increases in locomotor behavior

Certain motoric effects of cocaine increase in intensity with repetitive administration. Conditioned drug effects are among primary determinants of such sensitization. The purpose of these experiments was to evaluate the role of D1 and D2 dopamine (DA) receptor mechanisms in the acquisition and expression of cocaine conditioning. On Day 1, rats were injected with cocaine (40mg/kg) either before (PAIRED) or after (UNPAIRED) exposure to a locomotor activity chamber. On Day 2, all animals were injected with a low dose of cocaine (10mg/kg) prior to placement in the locomotor chambers. Conditioning on Day 2 was evidenced by significantly higher activity levels in the PAIRED group relative to the UNPAIRED or saline-treated groups. Pretreatment with D1 (SCH 23390) or D2 (raclopride, sulpiride, haloperidol) DA antagonists on Day 1 prevented the development of conditioning as assessed on Day 2, indicating that both receptor subtypes are involved in acquisition. However, pretreatment with raclopride or SCH 23390 on Day 2, prior to cocaine injections, did not eliminate the differences in behavior between the conditioned and non-conditioned groups. Neither D1 (SKF 82958, SKF 38393) nor D2 (quinpirole) agonists administered alone were effective in establishing conditioning, while a combination of SKF 82958 and quinpirole was effective, suggesting that conditioning in this experimental paradigm requires the concurrent activation of both receptor subtypes. In the final study it was found that conditioned cocaine effects could be revealed only in the presence of quinpirole or apomorphine on Day 2. The D1 agonists (SKF 38393 and SKF 82958) were ineffective. This would suggest either that only quinpirole and apomorphine are effective in amplifying the conditioned effects of cocaine on Day 2 or that the cues produced by these drugs are more similar to those produced by cocaine than those produced by D1 agonists.     

Interactive effects of D1 and D2 agonists with scopolamine on radial-arm maze performance.

Pharmacological blockade of muscarinic cholinergic (ACh) receptors has been found to impair choice accuracy in a variety of tasks including the radial-arm maze. The cognitive impairment caused by the muscarinic antagonist scopolamine is reversed by the dopaminergic (DA) antagonist haloperidol as well as the selective D1 antagonist SCH 23390. In the current study, interactions were studied between scopolamine and selective agonists of D1 (SCH 38393) and D2 (quinpirole) receptors. Surprisingly, the D1 agonist SKF 38393 was found to significantly alleviate the scopolamine-induced choice accuracy deficit. In contrast, the D2 agonist quinpirole was not found to significantly alter the effects of scopolamine on choice accuracy but did have supra-additive effects of increasing choice latency. Both the D1 agonist SKF 38393 and the D1 antagonist SCH 23390 have been found to reverse the choice accuracy deficit caused by scopolamine and the deficit resulting from lesions of the medial projection from the basal forebrain to the cortex. Possible mechanisms for these effects are discussed.     

Ontogeny of locomotor activity and grooming in the young rat: role of dopamine D1 and D2 receptors

Locomotor activity and grooming were assessed in 11- and 17-day-old rat pups after treatment with selective dopamine (DA) D-1 and D-2 agonists (SKF 38393 and quinpirole, respectively) and antagonists (SCH 23390 and sulpiride, respectively). Quinpirole enhanced the locomotor activity of both the 11- and 17-day-olds, effects antagonized by either SCH 23390 or sulpiride. Drug-induced increases in grooming were apparent only after high doses (30.0 mg/kg i.p.) of SKF 38393 (11- and 17-day-olds) or when SKF 38393 (15.0 mg/kg i.p.) was given in conjunction with sulpiride (11-day-olds). In general, these results suggest that challenge with selective DA agonists and antagonists induces patterns of responding which are similar to those typically observed in adult rats. Moreover, these results indicate that rat pups, like adults, require a functioning DA D-1 receptor system for the expression of DA D-2-mediated activity.     

Selective protection from the inhibition by EEDQ of D1 and D2 dopamine agonist-induced rotational behavior in mice

Mice with unilateral lesions of dopamine nigrostriatal neurons produced by injecting 6-hydroxydopamine into the striatum exhibited contralateral rotational behavior to the non-selective dopamine agonist apomorphine, the D1 dopamine agonist SKF 38393, and the D2 agonist quinpirole. The non-specific dopamine antagonist EEDQ blocked the circling responses to the three agonists. Pretreatment with specific, reversible dopamine antagonists before the EEDQ injection selectively prevented this blockade. Thus, if mice were pretreated with the D1 receptor antagonist SCH 23390 before EEDQ and the animals challenged with the D1 and D2 agonists 24 hours later, the rotational response to quinpirole was still inhibited, but the response to SKF 38393 was now evident. Similarly, in mice pretreated with the D2 receptor antagonist sulpiride before EEDQ and again challenged with the D1 and D2 agonists 24 hours later, the rotational response to SKF 38393 was still inhibited but the response to quinpirole was no longer inhibited. These results indicate that in vivo blockade of either D1 or D2 subpopulations of dopamine receptors may be achieved by selective protection with a reversible dopamine antagonist given prior to the administration of an irreversibly acting dopamine antagonist such as EEDQ.     

The involvement of dopamine D1 and D2 receptors in the locomotor stimulation produced by (+)-amphetamine in naive and dopamine-depleted mice

The interaction between (+)-amphetamine and dopamine (DA) D1 and D2 receptors was investigated. In na?ve mice, i.e., mice with intact stores of DA, both the selective D1 antagonist SCH23390 and the selective D2 antagonist spiperone blocked the locomoter stimulation produced by (+)-amphetamine. The selective D1 agonist SKF38393 (6 mg/kg intraperitoneally) did not produce a consistent dose-dependent effect on the response to (+)-amphetamine in na?ve mice. In mice depleted of DA with reserpine 24 hr before a challenge with (+)-amphetamine, neither SCH23390 nor spiperone were completely effective in blocking (+)-amphetamine. A combination of spiperone plus SCH23390 was, however, more effective than either drug alone, although significant activity remained even after the combination. In mice pretreated with reserpine and various doses of alpha methyl-p-tyrosine (alpha MPT, intraperitoneally), the degree of stimulation produced by (+)-amphetamine was dependent on the amount and frequency of alpha MPT dosage - the higher and more frequent the dose, the more effective the blockade. In these animals, both SKF38393 and the selective D2 agonist quinpirole potentiated the stimulation induced by (+)-amphetamine when the dose of alpha MPT was not maximal. However, in those animals pretreated with reserpine plus two doses each of 400 mg/kg alpha MPT, neither SKF38393 nor quinpirole were effective in potentiating (+)-amphetamine. Nevertheless, when SKF38393 and quinpirole were administered simultaneously to these mice, marked locomotor stimulation occurred implying that the pretreatment itself had not rendered the mice incapable of locomotion.(ABSTRACT TRUNCATED AT 250 WORDS)     

The actions of (-)N-n-propylnorapomorphine and selective dopamine D1 and D2 receptor agonists to modify the release of [3H]dopamine from the rat nucleus accumbens

The ability of (-)N-n-propylnorapomorphine and selective D1 and D2 dopamine receptor agonists and antagonists to modify the release of [3H]dopamine, induced by potassium from the nucleus accumbens, was studied using an in vitro superfusion technique. (-)N-n-Propylnorapomorphine, in picomolar concentrations, inhibited the release of [3H]dopamine, the inhibition being antagonised by fluphenazine and the selective D2 receptor antagonist sulpiride; the selective D1 receptor antagonist SCH 23390 was ineffective. The selective D1 receptor agonist SKF 38393 and the selective D2 agonist quinpirole, both inhibited the potassium-induced release of [3H]dopamine; no synergistic effect was observed to a combined treatment with SKF 38393 and quinpirole. The effects of SKF 38393 and quinpirole were selectively antagonised by SCH 23390 and sulpiride, respectively, although both antagonists failed to modify the release of [3H]dopamine when administered alone. Receptor antagonists for other transmitter sites, e.g. noradrenaline, 5-hydroxytryptamine and acetylcholine, failed to modify potassium-induced release of [3H]dopamine, when administered alone or to prevent the inhibition of the release caused by (-)N-n-propylnorapomorphine. It is concluded that the action of dopamine agonists on both dopamine D1 and D2 receptors in the nucleus accumbens can reduce the release of [3H]dopamine in the in vitro system. Comparable actions in vivo may contribute to the ability of dopamine agonists to moderate locomotor responding.     

Enhancement of D2 receptor agonist-induced inhibition by D1 receptor agonist in the ventral tegmental area.

1. A microiontophoretic study was performed on chloral hydrate-anaesthetized rats to examine the role of D1 receptors in the ventral tegmental area (VTA) neurones, which are inhibited by autoreceptor and D2 receptor agonists. 2. Inhibition by microiontophoretic application of quinpirole (a D2 agonist) of antidromic spikes elicited by stimulation of the nucleus accumbens in dopaminergic neurones of the VTA, was significantly enhanced by simultaneous application of SKF 38393 (D1 agonist), although SKF 38393 alone had little effect on the neurones. 3. In addition, quinpirole-induced inhibition was antagonized by iontophoretic application of domperidone (D2 antagonist), but was not affected by SCH 23390 (D1 antagonist). 4. Furthermore, SKF 38393-induced enhancement of inhibition by quinpirole was antagonized by simultaneous application of SCH 23390. 5. These results suggest that activation of D1 receptors located on the VTA dopaminergic neurones or on non-dopaminergic nerve terminals is not essential for inducing inhibition of the dopaminergic neurones, but enhances D2 receptor-mediated inhibition directly or indirectly via inhibitory neurones.     

Dopamine D-1 receptor agonists combined with the selective D-2 agonist quinpirole facilitate the expression of oral stereotyped behaviour in rats

The behaviour of rats was studied after combined treatment with the selective DA D-2 agonist quinpirole and three selective D-1 agonists (SK & F 38393, SK & F 75670 and Lu 24-040). The effects on behaviour were compared with those on receptor binding and adenylate cyclase (AC). While the D-1 agonists alone did not induce stereotyped behaviour, quinpirole induced dose-dependent hyperactivity (locomotion, sniffing, head movements and rearing), whereas licking/biting was absent or seen only occasionally. Combined treatment with quinpirole and a D-1 agonist was followed by dose-dependent licking and occasional biting behaviour. The D-1 agonists had similar efficacies, but SK & F 75670 and Lu 24-040 were more potent than SK & F 38393. The maximal effects of SK & F 38393 plus quinpirole were effectively blocked by either a D-1 antagonist (SCH 23390) or a D-2 antagonist (YM 09151-2) confirming the close relation between D-1 and D-2 receptor sites in the brain. Good correspondence was found between affinities to D-1 receptors [( 3H]SCH 23390 binding) in vitro and the EC50 values for stimulation of AC activity. However, the maximal effects on DA-sensitive AC activity were less for SK & F 75670 and Lu 24-040 than for SK & F 38393. Thus, the results indicate that efficacies in the adenylate cyclase assay are dissociated from those on behaviour. Furthermore, the data indicate that in normal rats D-1 receptors are functionally relevant since D-1 agonists facilitate the expression of oral stereotyped behaviour after combination with a D-2 agonist.     

Hypothermia in mice: D2 dopamine receptor mediation and absence of spare receptors

The nonselective dopamine (DA) receptor agonists R(-)apomorphine (APO) and R(-)-N-n-propylnorapomorphine (NPA) elicited dose- and time-dependent hypothermia in mice with ED50 values of 300 and 18 micrograms/kg, respectively. The selective D2 agonist quinpirole (LY 171555) also elicited dose-dependent hypothermia, whereas the selective D1 agonist SKF 38393 had no effect. The selective D1 and D2 antagonists SCH 23390 (1 mg/kg) and sulpiride (200 mg/kg), respectively, did not significantly alter body temperature. The hypothermic effect of a maximal dose of NPA (0.2 mg/kg) was not blocked by SCH 23390 (1 mg/kg) but was significantly attenuated (p less than 0.001) by pretreatment with sulpiride (200 mg/kg). Pretreatment with sulpiride (200 mg/kg) produced a parallel, 40-fold shift to the right of the dose-response curve for NPA. Partial, irreversible DA receptor inactivation by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) (2 mg/kg) reduced the maximal hypothermic effect of NPA (to 49% of control) without altering its ED50. Analysis of the data indicated a linear relationship between DA receptor occupancy and hypothermic response. The results demonstrate that DA agonist-induced hypothermia in mice is mediated by D2 receptors and that there is no receptor reserved for this response.     

Responses to selective D-1 and D-2 agonists after repeated treatment with selective D-1 and D-2 antagonists

This study was aimed at achieving a better understanding of the functional role of D-1 and D-2 receptors in some dopamine-mediated behaviors. Hypermotility, grooming behavior and stereotyped behavior were induced, respectively, by LY 171555 (D-2 agonist), SKF 38393 (D-1 agonist) and apomorphine (mixed agonist). Acute pretreatment either with the D-1 selective antagonist SCH 23390 (0.02 mg/kg) or with the D-2 receptor blocker YM 09151-2 (0.02 mg/kg, IP) blocked all these behaviors, suggesting the existence of functional interactions between D-1 and D-2 receptors. Striatal membranes prepared from rats receiving repeated administrations with SCH 23390 (0.05 mg/kg, twice daily for 21 days) showed an increase in the number of D-1 but not of D-2 receptors. On the contrary the repeated treatments with YM 09151-2 increased only the Bmax values of D-2 receptors. While the D-1 supersensitive rats showed only enhancement of apomorphine-induced stereotyped behavior, the D-2 supersensitive rats exhibited an increase of both apomorphine-elicited stereotypy and LY 171555-elicited hypermotility. SKF 38393-induced grooming was unaffected by any pretreatments. Moreover when D-2 supersensitive rats were acutely pretreated with SCH 23390, the enhancement of apomorphine-induced stereotyped behavior was abolished. It is concluded that the behavioral expression of D-1 receptor supersensitivity requires the simultaneous activation of D-1 and D-2 receptors.     

Unilateral inactivation of dopamine receptors after intrastriatal injection of N-ethoxy-carbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ): a novel rotational model to investigate dopamine receptor interactions

The interaction between D1 and D2 dopamine (DA) receptors was investigated in a novel rotational model. Rats were unilaterally injected into the striatum with the irreversible DA receptor blocker N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). This treatment induced a marked decrease in the density of D1 (-48%) and D2 (-45%) DA receptors available for binding to 3H-SCH 23390 and 3H-spiperone, respectively. Under these experimental conditions, the effect of DA receptor agonists were predominant on the intact side and resulted in rotations ipsilateral to the injected side. The effects of different agonists and antagonists for D1 and D2 DA receptors were evaluated 24 hr after EEDQ administration. The D2 agonist LY 171555 induced ipsilateral rotations in a dose-dependent manner (0.1-10.0 mg/kg, IP) in rats treated intrastriatally with EEDQ. In contrast, the D1 agonist SKF 38393 (1-20 mg/kg, IP) was unable to elicit circling behavior per se. However, SKF 38393 increased the number of rotations caused by LY 171555. The circling behavior induced by LY 171555 was blocked by the D2 antagonists (-)sulpiride and raclopride and by the D1 antagonist SCH 23390. Moreover, the inhibition of circling behavior induced by SCH 23390 was reversed by SKF 38393 in a dose-dependent manner. LY 171555 (1 mg/kg, IP) was unable to induce rotations in EEDQ-treated rats following DA depletion by alpha-methyl-p-tyrosine, whilst the combined administration of LY 171555 (1 mg/kg, IP) and SKF 38393 (10 mg/kg, IP) elicited intense circling behavior in DA depleted rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neurophysiological evidence that D-1 dopamine receptor blockade attenuates postsynaptic but not autoreceptor-mediated effects of dopamine agonists

The putatively selective D-1 dopamine receptor antagonist SCH 23390 was used to study the role of the D-1 dopamine receptor in mediating the pre- and postsynaptic effects of dopamine agonists in the basal ganglia. SCH 23390 (1 mg/kg) had no significant effect on the tonic activity of substantia nigra dopamine neurons in 47% of the 19 cells studied, while the firing rates of 53% of the cells were increased. SCH 23390 did not shift the dose response of these cells to apomorphine, whereas the selective D-2 antagonist, YM-09151-2 completely blocked apomorphine's inhibitory effects on nigral dopamine cell activity. These results suggest that SCH 23390 does not interact with the D-2 dopamine autoreceptors, but does excite a subpopulation of dopamine neurons presumably through postsynaptic actions. In contrast to its inability to modify the effects of apomorphine on dopamine autoreceptors, SCH 23390 partially to fully reversed the effects of apomorphine on globus pallidus and substantia nigra pars reticulata cell activity and significantly attenuated the effects of apomorphine, pergolide, quinpirole (LY 171555) and d-amphetamine on firing rates of globus pallidus neurons. The D-1 antagonist alone had no significant effect on tonic globus pallidus neuronal activity. SCH 23390 was more potent than haloperidol in its ability to attenuate the effects of apomorphine on pallidal activity, but unlike haloperidol, was unable to totally inhibit these effects, suggesting that the two antagonists block the excitatory effects of apomorphine on pallidal cell firing rates by different mechanisms. The serotonin2 receptor antagonist, ketanserin, had no effect on pallidal or dopamine cell activity, indicating that the effects of SCH 23390 were not mediated through interactions with serotonin2 receptors. These results suggest that D-1 receptor blockade attenuates the postsynaptic, but not autoreceptor-mediated effects of dopamine agonists.     

Alpha 1 (but not alpha 2)-adrenoceptor agonists in combination with the dopamine D2 agonist quinpirole produce locomotor stimulation in dopamine-depleted mice

Mice were premedicated with reserpine and alpha-methyl-p-tyrosine to deplete stores of dopamine (DA) (and other neurotransmitters) and to stop DA (and noradrenaline (NA] synthesis. In DA-depleted mice, the mixed alpha 1/alpha 2 agonist clonidine potentiated locomotor stimulation induced by a low dose of apomorphine as measured in automated activity cages. Clonidine and the slightly alpha 1-selective agonist ST587, but not ST91, an alpha-agonist which does not readily cross the blood brain barrier, produced marked stimulation when combined with the selective D2 agonist quinpirole. The D1 -selective agonist SKF38393 also produced marked excitation when combined with quinpirole. All the selective agonists, bar quinpirole which in some cases produced a significant locomotor stimulation, were relatively inactive when given alone. A "blind" observational analysis of the animals challenged with clonidine plus quinpirole indicated an increase in sniffing, rearing and shaking behaviour. In contrast, observation of the animals challenged with SKF38393 plus quinpirole indicated increased sniffing, rearing and biting and, in one case, increased grooming behaviour. Clonidine did not produce excitation (in automated cages) when combined with the selective D1 agonist SKF38393. The excitation produced by clonidine plus quinpirole was blocked by the selective D2 antagonist raclopride but not by the selective D1 antagonist SCH23390. The stimulation was also blocked by the alpha 1 antagonist prazosin but not by the alpha 2 antagonists idazoxan or yohimbine. Biochemical analysis in the striata of mice challenged with clonidine plus quinpirole did not provide any obvious biochemical basis for the behavioural interaction. It is concluded that alpha 1 receptor agonists in combination with D2 DA agonists can produce marked stimulation in DA depleted mice.     

Dissociation of the striatal D-2 dopamine receptor from adenylyl cyclase following 6-hydroxydopamine-induced denervation.

Intracellular cyclic AMP accumulation following exposure to dopamine (DA) agonists and and antagonists was measured in striatal slices from rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal pathway and which showed contralateral circling to apomorphine. Both DA (10-320 microM) and the D-1 agonist SKF 38393 (0.1-32 microM) increased cyclic AMP accumulation in striatal slices from the lesioned and intact hemispheres. The EC50 for DA to increase cyclic AMP accumulation in slices was greater in the 6-OHDA-lesioned striata compared to the intact striatum, but the EC50 for SKF 38393 was not affected. The D-1 antagonist SCH 23390 (10 microM) completely inhibited the ability of DA and SKF 38393 to increase cyclic AMP accumulation in striatal slices from both denervated and intact sides of the brain. In slices from the intact hemisphere the increase in DA-induced cyclic AMP accumulation was enhanced by the D-2 antagonist (+/-)-sulpiride (50 microM) but (+/-)-sulpiride had no effect on the DA response in slices from the lesioned side. Similarly, the ability of SKF 38393 to enhance cyclic AMP accumulation was blocked by the D-2 agonist quinpirole (10 microM) in striatal slices from the intact hemisphere but not in tissue from the lesioned side. The density of striatal D-1 and D-2 receptors assessed by [3H]SCH 23390 and [3H]spiperone binding did not differ between the hemispheres although there was an increase in the affinity of D-1 receptors for [3H]SCH 23390 in the lesioned striatum. After striatal deafferentiation there appears to be an uncoupling of the "inhibitory" D-2 receptor from the D-1 receptor-associated adenylyl cyclase.