The electrically-stimulated spinal reflex in pithed rats: a possible test model for evaluating blockade of central dopamine D1 and D2 receptors

Intravenous injection of the dopamine (DA) D1 receptor agonist SK&F 38393 (4.3 mumol/kg = 1.25 mg/kg), or the DA D2 receptor agonist pergolide (3.2 mumol/kg = 1.25 mg/kg) increased the electrically-stimulated spinal reflex in pithed rats by more than 600 per cent. The specific DA D1 receptor antagonist SCH 23390 potently inhibited the SK&F 38393-induced spinal reflex but not the pergolide-induced reflex. The DA D2 receptor antagonists clebopride and YM 09151-2 inhibited the pergolide-induced reflex only. Two mixed DA D1/D2 antagonists (cis(Z)-flupentixol and zuclopenthixol) inhibited the effects of both SK&F 38393 and pergolide on the spinal reflex, while the neuroleptically inactive isomer of clopenthixol (trans(E)-clopenthixol) was also inactive in this context. Various antagonists (prazosin (alpha 1), idazoxan (alpha 2), 1- propranolol (beta), bicuculline (GABA] were inactive in the test model. The 5-HT2 receptor antagonists altanserin and ketanserin also showed antagonistic effect. It is concluded that the electrically-stimulated spinal reflex in pithed rats can be used as a test model to estimate the blockade of central DA D1 and DA D2 receptors without influence from alpha 1-adrenergic, alpha 2-adrenergic, beta-adrenergic and GABA-ergic receptors. However, a serotonergic receptor antagonism does influence the specificity of the test model.     

Effects of SCH 23390 on thyrotropin-releasing hormone-induced behaviour in rabbits

The influence of the dopamine D-1 receptor antagonist, SCH 23390, on thyrotropin-releasing hormone (TRH)-induced behaviour was assessed in adult male rabbits. SCH 23390 prevented the effects of TRH (100 micrograms i.c.v.), starting at a very low dose (0.01 mg/kg i.v.). This finding seems to indicate that dopamine D-1 receptors are involved in TRH-induced behaviour.     

Dopamine D-1 but not D-2 receptor stimulation of the dorsal striatum potentiates apomorphine-induced jaw movements in rats

The effects of bilateral injections of selective D-1 and D-2 agonists and antagonists into the dorsal striata on apomorphine-induced jaw movements were studied in ketamine-anaesthetized rats after C1 spinal transection. A phototransducer attached to the lower mandible automatically detected jaw movements. YM-09151-2 (0.2 and 0.5 micrograms) and cis(Z)-flupentixol (0.5 and 1 microgram) injected into the dorsal striatum increased the frequency of jaw movements after apomorphine (0.2 mg/kg i.v.). The effects were prevented by administration of SCH23390 (1 microgram) with YM-09151-2 (0.5 microgram) or cis(Z)-flupentixol (1 microgram). Injection of SCH23390 (1 microgram) alone into the dorsal striatum failed to alter the apomorphine (0.5 mg/kg i.v.)-induced jaw movements. Local application of the selective D-1 agonists, SKF38393 (5 micrograms) and SKF75670 (10 micrograms), into the dorsal striatum potentiated the apomorphine (0.2 mg/kg i.v.)-induced jaw movements, while a D-2 agonist, quinpirole (10 micrograms), injected into the same site attenuated these movements. These data are suggestive of an oppositional D-1: D-2 receptor interaction in the dorsal striatum.     

D-1 and D-2 receptor blockade have additive cataleptic effects in mice, but receptor effects may interact in opposite ways

The dopaminergic role of D-1 and D-2 receptors in catalepsy was evaluated using drugs with preferential receptor affinities. The D-1 antagonist, SCH 23390, caused distinct catalepsy in mice at 1, 2, and 10 mg/kg, IP, but not at two lower doses. The selective D-1 blocker, molindone, also caused catalepsy at 5 and 10 mg/kg; and blockade of both receptor types produced additive cataleptogenic effects. Apomorphine (4 mg/kg), which is an agonist for both receptors, potentiated SCH 23390-induced catalepsy much more than it did the catalepsy induced by molindone; the potentiation was produced by higher, not lower, doses of apomorphine. To determine if the apomorphine potentiation was mediated by D-1 or D-2 receptors, we tested selective agonists in mice that were concurrently injected with selective blockers. SCH 23390-induced catalepsy was potentiated by a large dose of the D-2 agonist, bromocriptine. The catalepsy of D-2 blockade with molindone was not potentiated by the D-1 agonist, SKF 38393, which slightly disrupted the catalepsy of D-2 blockade. We conclude that catalepsy is not a simple D-2 blockade phenomenon and that preferential antagonism of either receptor type can cause catalepsy. Catalepsy is most profound when both receptor types are blocked. Dopamine agonists, in large concentrations, are known to promote movements, and thus it is not surprising that they tend to disrupt catalepsy.(ABSTRACT TRUNCATED AT 250 WORDS)     

The St 587-induced flexor reflex in pithed rats: a model to evaluate central alpha 1-receptor blocking properties

A combination of reserpine, nialamide and the specific alpha 1-adrenoceptor agonist St 587 [2-(2-chloro-5-trifluoromethylphenylimino)-imidazolidine] induced a marked increase of the electrically stimulated flexor reflex in pithed rats. This increased reflex - which lasted for more than 3 h - could be inhibited by the alpha 1-receptor antagonist prazosin but not by the alpha 2-adrenoceptor antagonist idazoxan (RX 781094). A range of different drugs was tested, including 17 neuroleptics. Most of the neuroleptics showed marked inhibition of the St 587-induced reflex. Bromperidol, butaclamol and fluperlapine were weak inhibitors while pimozide was without effect. The results showed close correlation to alpha 1-receptor affinities in vitro (r = 0.84, P less than 0.001) while no correlation was found to either D-2 receptor affinities or to 5-HT2 receptor affinities in vitro (r = 0.43, P less than 0.2 and r = 0.41, P less than 0.05, respectively). It is concluded that inhibition of the St 587-induced flexor reflex in pithed rats is an in vivo test model for central alpha 1-receptor blocking properties.     

Permissive role of D-1 receptor stimulation by endogenous dopamine for the expression of postsynaptic D-2-mediated behavioural responses. Yawning in rats

Low doses of BHT 920, LY 171555 and (+)3PPP, three dopamine agonists selective for D-2 receptors, induced yawning in rats. This effect was reduced by the selective D-1 antagonist SCH 23390 but the antagonism did not exceed a 50% reduction from the control values. In contrast, the selective D-2 antagonist (-)sulpiride completely abolished agonist-induced yawning. A 6 h reserpine pretreatment (5 mg/kg i.p.), which depletes brain dopamine (DA) by about 95%, reduced agonist-induced yawning by an extent similar to SCH 23390; in the reserpinized rats, SCH 23390 completely lost the property of blocking agonist-induced yawning while (-)sulpiride retained it. Two 5HT receptor antagonist, ketanserin and metergoline failed to influence agonist-induced yawning. The reportedly selective D-1 agonist, SKF 38393, failed to induce yawning in normal rats as well as in rats pretreated with reserpine 6 or 16 h earlier. If one excludes that SCH 23390 and the D-2 agonists interact with the same DA-receptors, the data are consistent with the possibility that stimulation of D-1 receptors by endogenous DA plays a permissive-facilitatory role for the behavioural expression of D-2 receptor activation.     

Sleep during acute dopamine D1 agonist SKF 38393 or D1 antagonist SCH 23390 administration in rats

The effect of the D1 dopamine (DA) receptor agonist SKF 38393 was compared with that produced by the D1-receptor antagonist, SCH 23390, in rats implanted with electrodes for chronic sleep recordings. SKF 38393 (0.1 to 4.0 mg/kg) significantly suppressed rapid-eye-movement sleep (REMS) after the highest dose. SCH 23390 (0.1 to 2.0 mg/kg) increased slow-wave sleep (SWS), whereas wakefulness (W) and REMS were decreased. Pretreatment with SKF 38393 (0.5 mg/kg) prevented the effects of SCH 23390 (0.25 mg/kg) on W and SWS. However, REM sleep showed a further depression. Pretreatment with SKF 38393 (2.0 mg/kg) or SCH 23390 (0.25 mg/kg) failed to modify the increase of SWS and decrease of W induced by D2 receptor agonist bromocriptine (0.5 mg/kg) in a dose that selectively stimulates DA autoreceptors. On the other hand, SCH 23390 (0.25 mg/kg) failed to prevent REMS depression induced by bromocriptine (6.0 mg/kg) in a dose that preferentially acts at postsynaptic sites. Pretreatment with SCH 23390 (0.25 mg/kg) prevented the increase of W and decrease of SWS induced by the 5-HT2 receptor agonist DOI (0.25 mg/kg). Given the "fragility" of REMS in the rat, nonspecific factors could be contributing to its depression after SKF 38389 or SCH 23390 administration. Inhibition of D1 receptors could be responsible for SCH 23390-induced increase of SWS and decrease of W. However, a blockade of 5-HT2 receptors could be partly involved in these effects. Neither SKF 38393 nor SCH 23390 exerted activity on the sleep-wake cycle, which could be considered to reflect effects at DA autoreceptors.     

EEDQ, a tool for ex vivo measurement of occupancy of D-1 and D-2 dopamine receptors

EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline) inactivates dopamine (DA) D-1 and D-2 receptors, measured by ex vivo [3H]SCH 23390 and [3H]spiperone binding in striatal homogenates. SCH 23390 (D-1 antagonist) and SK&F 38393 (D-1 agonist) protect against inactivation of D-1 receptors (ED50 values 0.075 and 53 mumol/kg, respectively). Raclopride (D-2 antagonist) and quinpirole (D-2 agonist) protect against inactivation of D-2 receptors (ED50 values 0.48 and 7.1 mumol/kg, respectively). The potencies correspond closely to those obtained by in vivo binding experiments using radioligands.     

D-1 dopamine receptor stimulation elevates plasma prolactin levels

SKF 38393, a D-1 dopamine receptor agonist, produced dose-dependent elevations in plasma prolactin concentrations. Following the administration of SCH 23390, a D-1 antagonist, plasma prolactin concentrations tended to decrease; and low doses of SCH 23390 completely prevented the SKF 38393-induced elevations in plasma prolactin. These observations suggest that D-1 receptor stimulation can promote prolactin secretion.     

Effect of chronic treatment with SCH 23390 and haloperidol on spontaneous activity of dopamine neurones in substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) in rats

The effect of chronic treatment (21 days s.c.) with SCH 23390 and haloperidol on spontaneously active DA neurones in substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) was studied in rats by means of single unit recording techniques. The specific DA D-1 receptor antagonist SCH 23390 was injected twice daily in one of the following doses: 0.06, 0.23, 0.46 or 0.90 mumol/kg. SCH 23390 decreased the number of spontaneously active neurones in SNC and VTA to the same extent. The DA D-2 receptor antagonist haloperidol was injected once daily in one of the following doses: 0.05, 0.21 or 1.7 mumol/kg and induced a decrease in the number of spontaneously active DA neurones in SNC and VTA. These results suggest that SCH 23390 has a profile similar to that of haloperidol and that SCH 23390 has clinical antipsychotic activity but also induces extrapyramidal side-effects.     

Comparative study of the EEG profile of neuroleptics selective for D-1 or D-2 dopamine receptors in the rabbit.

The neuroleptics SCH 23390 and raclopride, which interact selectively with either D-1 or D-2 dopamine receptor, were studied for their effects on electroencephalographic (EEG) activity in the rabbit. Haloperidol (0.3 and 1 mg/kg intravenously, i.v.), which was used for comparison, induced synchronization of the cortical EEG activity. Spectral EEG analysis showed increase of power in the whole frequency range (0.1-38.5 Hz) and in all frequency bands in the cortex, whereas a slight decrease of slow and fast theta activity (3.7-7.2 and 7.2-12.2 Hz) was observed in the hippocampus. Animals appeared sedated and arousal response to somatosensory stimuli was markedly inhibited. SCH 23390 (0.03 and 0.3 mg/kg i.v.) induced periods of cortical synchronization and changes of spectral power qualitatively similar to those accompanying haloperidol administration. The drug slightly reduced the duration of arousal elicited by stimuli. Raclopride (1 and 3 mg/kg i.v.) induced weak EEG changes and little effect on arousal response to stimulation. There was an increase of slow wave activity which was particularly evident in the hippocampus. The data indicate that, although to a lesser degree, the D-1 receptor antagonist SCH 23390 induced EEG effects similar to those of haloperidol, whereas blockade of D-2 receptors by raclopride resulted in different patterns of EEG activity.     

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.     

Further studies of the mechanism behind scopolamine-induced reversal of antistereotypic and cataleptogenic effects of neuroleptics in rats

Scopolamine is known to attenuate the amphetamine antagonistic and cataleptogenic effect of selective DA D-2 antagonists. To study further the influence of other receptor systems three approaches were taken: concomitant treatment with receptor blockers (scopolamine, prazosin and ketanserin) and a selective D-2 antagonist YM 09151-2, testing of a neuroleptic droperidol, with mixed D-2, alpha 1 and 5-HT2 antagonistic properties and testing a selective D-1 antagonist SCH 23390. Scopolamine markedly attenuated both effects of YM 09151-2 and droperidol. In contrast neither prazosin nor ketanserin influenced the effects of YM 09151-2. Furthermore, prazosin did not influence the interaction between scopolamine and YM 09151-2 in the tests of stereotypy and catalepsy. Scopolamine did not change the amphetamine antagonistic potency of SCH 23390, but decreased moderately its cataleptogenic potency. It is concluded that 5-HT2 and alpha 1-adrenergic receptor blockade are of minor importance in order to determine the sensitivity of a DA D-2 antagonist to the reversal induced by scopolamine. Thus, our earlier hypothesis, that DA D-1 receptor blockade is the main mechanism stabilizing these neuroleptic effects against scopolamine reversal, are further supported by the present experiments.     

Stimulation of dopamine D-2 but not D-1 receptors reduces immobility time of rats in the forced swimming test: implication for antidepressant activity

The involvement of dopamine D-1 and D-2 receptor mechanisms was investigated in the forced swimming test with rats. d,1-Sulpiride, a D-2 receptor antagonist, reported to reduce desipramine-induced anti-immobility, did not alter the brain levels of desipramine. In addition, the anti-immobility effect of desipramine was not antagonized by SCH 23390, a D-1 receptor antagonist. Amineptine (20 mg/kg i.p., 60 min before testing), a dopamine uptake blocker, and LY171555 (0.2 mg/kg i.p., 60 min before testing), a dopaminergic D-2 stimulant reduced immobility time in the forced swimming test, but benserazide + 1-DOPA (200 mg/kg p.o., 45 min before testing), which increases dopamine release, or SKF 38393A (20 mg/kg s.c., 60 min before testing), a D-1 agent, did not. The anti-immobility effect but not the stereotypy was increased following chronic (21 days) LY171555 (0.1 and 0.2 mg/kg i.p.) treatment. The effect of acute or repeated (7 days) LY171555 (0.2 mg/kg i.p.) treatment was antagonized by 1-sulpiride (50 mg/kg i.p., 90 min before testing), a D-2 receptor antagonist. Neither SKF 38393A (20 mg/kg s.c., 60 min before testing) nor SCH 23390 (0.05 mg/kg s.c., 30 min before testing) modified the acute anti-immobility effect of LY171555 (0.2 mg/kg i.p.) SCH 23390 (0.025 and 0.05 mg/kg) increased the immobility time at doses which decreased motor activity. The increase in immobility time brought about by SCH 23390 was not antagonized by SKF 38393A (20 mg/kg). The findings indicate that activation of dopamine D-2 receptors could reduce immobility time.     

Administration of SCH 23390 into the medial prefrontal cortex blocks the expression of MDMA-induced behavioral sensitization in rats: an effect mediated by 5-HT2C receptor stimulation and not by D1 receptor blockade.

Akin to what has been reported for cocaine, systemic administration of the dopamine D1 receptor antagonist, SCH 23390 ((R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride), blocks the expression but not the induction of 3,4-methylenedioxymethamphetamine (MDMA)-induced behavioral sensitization. Since the medial prefrontal cortex (mPFC) appears to regulate the expression of sensitization to cocaine, this study examined whether microinjection of SCH 23390 into the mPFC would alter the expression of MDMA sensitization. Saline or MDMA was administered for 5 consecutive days. After 12 days of withdrawal, rats received a bilateral intra-mPFC microinjection of SCH 23390 or saline followed by an intraperitoneal (i.p.) challenge dose of MDMA. While SCH 23390 enhanced locomotion in MDMA-na?ve rats, it completely suppressed the expression of sensitization in MDMA-pretreated animals. Since, SCH 23390 has a fairly good affinity for 5-HT(2C) receptors, we went further to study the role of mPFC D1 and 5-HT(2C) receptors in this, apparently, paradoxical effect shown by SCH 23390. Thus, the microinjection of both SKF 81297 (R-(+)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide) and MK 212 (6-chloro-2-(1-piperazinyl)pyrazine hydrochloride), a D1 and 5-HT(2C) receptor agonist, respectively, blocked MDMA sensitization. By contrast, the 5-HT(2C) receptor antagonist, RS 102221 (8-[5-(2,4-dimethoxy-5-(4-trifluoromethylphenylsulfonamido)phenyl-5-oxopentyl]-1,3,8-triazaspiro[4,5]decane-2,4-dione hydrochloride), had no effect in MDMA-na?ve or MDMA-sensitized animals, but reversed the effects of SCH 23390 in MDMA-pretreated rats. These results demonstrate that suppression of MDMA-induced sensitization by SCH 23390 is mediated by 5-HT(2C) receptor stimulation in the mPFC and not by the blockade of mPFC D1 receptors. Furthermore, these data indicate that stimulation of 5-HT(2C) receptors by SCH 23390 is not a minor issue and should be considered when interpreting future data.     

Effects of the putative D-1 antagonist SCH 23390 on stereotyped behaviour induced by the D-2 agonist RU24213

The effects of the putative selective dopamine D-1 antagonist benzazepine SCH 23390 and of the selective dopamine D-2 antagonist Ro22-2586 on stereotypy induced by the selective D-2 agonist RU24213 were compared. RU24213 (0.5–15 mg/kg) dose-dependently induced stereotyped behaviour characterised by continuous downward sniffing and locomotion. These responses were antagonised, as expected, by 40–200 g/kg Ro22-2586, but surprisingly blocked by 40–200 g/kg SCH 23390. The selectivities of these compounds for dopamine receptor subtypes were verified in terms of their relative abilities to displace the in vitro binding of ³H-piflutixol to striatal D-1 receptors and of ³H-spiperone to D-2 receptors. As SCH 23390 fails to influence D-2 mediated prolactin secretion or emesis in vivo, there appears to be no significant formation of an active metabolite of SCH 23390 with D-2 antagonist activity. Because SCH 23390 has some affinity for 5-hydroxytryptamine receptors, any effect on the serotonergic behavioural syndrome induced by 10 mg/kg 5-methoxy-N,N-dimethyltryptamine was also studied. The serotonergic responses of hind limb abduction, reciprocal forepaw treading and Straub tail were unaltered after 40–200 g/kg SCH 23390, indicating no significant 5-HT blockade or non-specific depressant action at these doses which might influence the expression of stereotypy. Thus, these data are consistent with blockade of tonic D-1 dopaminergic activity that may influence the expression of behaviours initiated byD-2 dopaminergic stimulation.     

Interaction of the beta adrenergic receptor antagonist bucindolol with serotonergic receptors

Bucindolol is a nonselective beta-adrenergic receptor antagonist that has additional vasodilating properties. Because some beta-adrenergic receptor antagonists such as cyanopindolol are used as 5-HT1A/5-HT1B receptor antagonists, we tested the hypothesis that bucindolol can interact with 5-HT receptors. Both in vitro and in vivo methods were used to examine the interaction of bucindolol with 5-HT receptors relevant to the cardiovascular system-the 5-HT1A, 5-HT1D, 5-HT2A, and 5-HT2B receptors-and with alpha1-adrenergic receptors. In binding studies, bucindolol displayed high affinity for the 5-HT1A receptor (Ki, 11 nM), modest affinity for the 5-HT2A receptor (Ki, 382 nM), and no measurable affinity for the 5-HT1D receptor; binding affinity for the 5-HT2B receptor was not studied. Bucindolol also displayed significant binding affinity (Ki, 69 nM) for the alpha1-adrenergic receptors. Alpha1-Adrenergic receptor antagonist activity was confirmed by the ability of bucindolol (1 mg/kg) to act as a competitive antagonist against 0.01-30 microg/kg phenylephrine-induced pressor responses in conscious rats. In conscious permanently instrumented rats, bucindolol (0.1-3.0 mg/kg, i.v.) did not cause bradycardia similar to that elicited by the 5-HT1A-receptor agonist 8-OH-DPAT (3-300 microg/kg, i.v.), nor did bucindolol (1 mg/kg) block the 8-OH-DPAT-induced bradycardia. Bucindolol (10(-9)-10(-5) M) did not cause relaxation in the PGF2alpha-contracted, endothelium-intact porcine coronary artery, nor did bucindolol (10(-5) M) block 5-HT-induced coronary artery relaxation, indicating that bucindolol does not have significant interactions at the 5-HT1D receptor. Bucindolol also displayed no agonist activity at the 5-HT2A and 5-HT2B receptor (endothelium-denuded rat thoracic aorta and rat stomach fundus, respectively), but did act as a weak 5-HT2A-receptor antagonist (-log K(B) [M] = 5.4+/-0.1) and 5-HT2B-receptor antagonist (-log K(B) [M] = 7.8+/-0.1). Thus, these data suggest that bucindolol lacks the ability to activate the 5-HT1A, 5-HT1D, 5-HT2A, and 5-HT2B receptor, but can block alpha1-adrenergic receptors and act as a weak 5-HT2A- and 5-HT2B-receptor antagonist. The relevance of these serotoninergic effects as it pertains to the mechanism of bucindolol-induced vasodilation is unknown.     

Effect of prolonged treatment with neuroleptics on dopamine D-1 and D-2 receptor density in corpus striatum of mice

The effects of long-term treatment with neuroleptics on D-1 and D-2 receptor parameters in corpus striatum were studied in mice. Mice were treated daily for 12 days with the selective D-1 antagonist, the benzazepine SCH 23390, the mixed D-1/D-2 antagonist zuclopenthixol or the selective D-2 antagonist haloperidol. Three days after withdrawal Bmax and KD for 3H-SCH 23390 binding to D-1 receptors and 3H-spiperone binding to D-2 receptors were determined. The study showed that the density of D-2 receptors increased after haloperidol whereas no changes were seen after SCH 23390 or zuclopenthixol. No changes in D-1 receptor density were seen after either treatment. The results are in full agreement with published behavioural results where haloperidol induces tolerance whereas SCH 23390 or zuclopenthixol do not. Some changes in KD values were seen. The cause and meaning of these changes await further investigation.     

Dual activation by lisuride of central serotonin 5-HT(1A) and dopamine D(2) receptor sites: drug discrimination and receptor binding studies

To investigate central serotonergic (5-HT) and dopaminergic (DA) actions of lisuride, the discriminative properties of lisuride (0.05mg/kg, i.p.) in rats were investigated, in addition to the radioligand binding of the compound to 5-HT and DA receptor subtypes. Lisuride was found to possess high affinities for 5-HT(1A) receptor sites (Ki=0.5nM) and D(2) receptor sites (Ki=2.0nM). The autoradiographic binding pattern of 4nM [(3)H]lisuride in rat brain showed high densities of sites displaceable by the 5-HT(1A) agonist 8-OH-DPAT in hippocampus, lateral septal nucleus and amygdala, as well as those displaceable by the D(2) antagonist sulpiride in striatum, nucleus accumbens and olfactory tubercle. In drug discrimination tests, the mixed, D(1)/D(2) agonist apomorphine, the partial D(2) receptor agonists (-)-3-PPP and terguride and the 5-HT(1A) agonist 8-OH-DPAT substituted for lisuride. The D(1) agonist SKF38393, the D(1) antagonist SCH23390, the D(2) antagonist sulpiride, the 5HT(1B) agonist m-CPP and the 5-HT(2) agonist DOI were not generalized to the lisuride cue. In antagonism tests, the D(2) antagonist haloperidol and the 5-HT antagonist methysergide both induced partial but significant antagonism to the lisuride cue, but the D(1) antagonist SCH23390 did not. These results indicate that discriminative stimulus properties of lisuride are mediated by the dual activation of 5-HT(1A) and D(2) receptor sites in brain.     

Acute effects of D-1 and D-2 dopamine receptor agonist and antagonist drugs on basal ganglia [Met5]- and [Leu5]-enkephalin and neurotensin content in the rat.

The effects of acute systemic injection of the D-1 agonist SKF 38393 (2.5-20 mg/kg) or the D-1 antagonist SCH 23390 (0.25-2.0 mg/kg), and of the D-2 agonist quinpirole (0.12-1.0 mg/kg) or the D-2 antagonist sulpiride (25-100 mg/kg) on the neuropeptide content of rat basal ganglia were investigated. In striatum, the [Met5]- and [Leu5]-enkephalin content was unaffected by administration of SKF 38393 or SCH 23390. Quinpirole had no effect on [Met5]- and [Leu5]-enkephalin levels but sulpiride produced an increase in both [Met5]- and [Leu5]-enkephalin content. In the nucleus accumbens, SKF 38393 decreased and SCH 23390 increased [Met5]- and [Leu5]enkephalin levels. Quinpirole decreased [Met5]- and [Leu5]-enkephalin levels, while sulpiride decreased [Leu5]-enkephalin levels alone. The content of [Leu5]- but not [Met5]-enkephalin levels in the substantia nigra was increased by administration of SKF 38393, and decreased by SCH 23390. Quinpirole and sulpiride were without effect on the [Met5]- or [Leu5]-enkephalin content of substantia nigra. Neurotensin levels in striatum were increased by administration of SKF 38393 and decreased by SCH 23390. Similarly, quinpirole decreased the neurotensin content while sulpiride caused an increase. In the nucleus accumbens, the neurotensin content was not affected by administration of SKF 38393 but increased by SCH 23390. Neither quinpirole nor sulpiride altered neurotensin levels in the nucleus accumbens. Neurotensin levels in substantia nigra were unaffected by the administration of SKF 38393 and SCH 23390, or by quinpirole and sulpiride. These results indicate that acute administration of D-1 and D-2 agonist and antagonist drugs can alter the levels of [Met5]- and [Leu5]-enkephalin and neurotensin in basal ganglia. However, there are marked differences between brain regions in the regulation of peptide levels by acute D-1 and D-2 receptor occupation.