Effects of intrastriatal injections of selective dopamine D-1 and D-2 agonists and antagonists on jaw movements of rats

The effects of bilateral intrastriatal injections of the selective D-1 and D-2 antagonists, SCH23390 and sulpiride on apomorphine-induced jaw movements were studied in ketamine-anaesthetized rats after C1 spinal transection. A photo-transducer attached to the lower mandible automatically detected jaw movements. Apomorphine (0.2, 0.5 and 1.0 mg/kg i.v.) dose dependently increased jaw movements, an effect prevented by prior administration into the ventral striatum of either SCH23390 (0.1, 0.5 and 1 microgram) or sulpiride (125 ng). To be effective, SCH23390 had to be given less than 30 min before apomorphine whereas sulpiride had to be given earlier. Sulpiride injected into the dorsal striatum potentiated the effects of apomorphine, an action prevented by administering the sulpiride with SCH23390. Local application of the selective D-1 and D-2 agonists, SKF38393 (5 micrograms) and quinpirole (10 micrograms) into sites within the ventral striatum from which repeated jaw movements could be obtained by electrical stimulation, also evoked jaw movements; the effects of combining the two drugs were much greater than the effects of either drug alone.     

Role of dopamine D-1 and D-2 receptors in the ventral striatum in the turning behaviour of rats

Systemically administered methamphetamine and apomorphine evoked characteristic turning when rats were pretreated with injections of D-1 and D-2 antagonists in the ventral but not in the dorsal striatum. The frequency of turning was greater for rats pretreated with D-2 antagonists (l-sulpiride and YM-09151-2) than for rats pretreated with a D-1 antagonist (SCH 23390). The responses were apparently additive when rats were pretreated with mixed D-1/D-2 antagonists, (cis(Z)-flupentixol and SCH 23390 + l-sulpiride). These results suggest that dopamine D-1 and D-2 receptors in the ventral striatum mediate turning behaviour through separate but cooperative mechanisms.     

Synergistic effects between D-1 and D-2 dopamine antagonists on catalepsy in rats

The effect of selective D-1 and D-2 dopamine agonists on catalepsy induced by various dopamine antagonists was studied. A potent and selective D-2 antagonist, YM-09151 (YM-09151-2) at a dose of 1.2 mg/kg, SC and a selective D-1 antagonist, SCH 23390 at 1.0 mg/kg, SC induced catalepsy in rats. Mixed D-1/D-2 antagonists, haloperidol (HPD) and cis-flupentixol (FLU) also induced catalepsy at doses of 2.0 and 0.8 mg/kg, SC, respectively. A mixed D-1/D-2 agonist, apomorphine (1.0 mg/kg, SC), a selective D-2 agonist, bromocriptine (10 mg/kg, IP) and a muscarinic antagonist, scopolamine (1.0 mg/kg, SC), prevented or markedly reduced the incidence of catalepsy by the tested antagonists. In contrast, a selective D-1 agonist, SKF 38393 (4.0 mg/kg, SC) did not reduce the cataleptogenic effects of HPD, FLU and SCH 23390, but did reduce the effect of YM-09151. Moreover, co-administration of YM-09151 with SCH 23390 produced a marked increase in the incidence of catalepsy. The incidence seen after the combination of YM-09151 and SCH 23390 at low doses was significantly different from that seen after each drug alone at the doubled dose. Thus, D-1 and D-2 antagonists potentiated each other's effect in producing catalepsy. These results suggest an important role of both D-1 and D-2 receptors in the catalepsy and the existence of synergistic effects of D-1 and D-2 receptor blockade.     

Effects of dopamine D1 and D2 agonists and antagonists injected into the nucleus accumbens and globus pallidus on jaw movements of rats

The effects of bilateral injections of selective D1 and D2 agonists and antagonists into the anteromedial part of the nucleus accumbens and the globus pallidus on apomorphine-induced jaw movements were studied in ketamine-anaesthetized rats after C1 spinal transection. Both SCH 23390 (0.1 and 1 micrograms) and 1-sulpiride (5 and 25 ng) injected into the nucleus accumbens suppressed the display of jaw movements after apomorphine (0.5 mg/kg i.v.). Injection of 1-sulpiride (5 and 25 ng) into the globus pallidus also blocked the effect of apomorphine, whereas SCH 23390 (1 microgram) injected into the same site was ineffective in this respect. Simultaneous application of the selective D1 and D2 agonists, SKF (1 or 5 micrograms) + quinpirole (10 micrograms), into the nucleus accumbens strongly potentiated the effect induced by local administration of each drug alone; a comparable, but smaller, effect was seen after simultaneous injections of these agents into the globus pallidus. These results show that dopaminergic mechanisms within the nucleus accumbens are involved in apomorphine-induced jaw movements, and that the expression of these movements requires concurrent activation of D1 and D2 receptors.     

Differential effects of dopamine D-1 and D-2 receptor agonists on EEG activity and behaviour in the rabbit

SKF 38393, a selective agonist for dopamine D-1 receptors, LY 171555, a selective agonist for D-2 receptors and apomorphine, an agonist for both receptor sites, all induced activation of the electrical activity of the brain (EEG) in the rabbit. While SKF 38393 induced EEG changes without concomitant signs of stereotyped behaviour, the injection of both LY 171555 and apomorphine also elicited marked behavioural effects, mostly stereotyped mouth and head movements. The EEG effects of SKF 38393 were prevented by SCH 23390 (0.003 mg/kg i.v.), but not by (-)-sulpiride (6.2-25 mg/kg i.v.). Haloperidol attenuated the effects induced by SKF 38393 only at a dose (1 mg/kg) that induced EEG changes of its own. Similarly, effects of apomorphine on both EEG and behaviour were prevented by SCH 23390 and to a lesser extent by haloperidol, but not influenced by (-)-sulpiride. Different patterns of interactions were observed when D-2 receptors were selectively stimulated by LY 171555. Behavioural effects induced by LY 171555 were fully inhibited by both (-)-sulpiride (6.2-12.5 mg/kg i.v.) and haloperidol (0.1-0.3 mg/kg i.v.). The drug SCH 23390 attenuated some behavioural components at 0.3 mg/kg (i.v.), a dose at least 100-fold that effective on the EEG effects induced by SKF 38393. However, all these antagonists exerted weak or no effects on EEG activation induced by LY 171555 and did not restore the control patterns at any doses examined.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of dopamine D-1 and D-2 receptor selective drugs on dopamine release and metabolism in rat striatum in vivo

Summary The effect of the dopamine (DA) D-1 agonist SKF 38393, the D-2 agonist LY 171555 and the mixed D-1/D-2 agonist apomorphine on striatal DA release and metabolism was tested in vivo using an intracerebral dialysis method in halothane-anaesthetized rats. The specificity of responses to these agonists was tested using the selective DA antagonists SCH 23390 (D-1) and sulpiride (D-2).Both LY 171555, 0.01 mg/kg, and SKF 38393, 10 mg/kg, reduced levels of DA in striatal perfusates. Neither SCH 23390, 0.5 and 5 mg/kg, nor sulpiride, 10 mg/kg, affected levels of DA in striatal perfusates, but 250 mg/kg sulpiride caused a DA increase. The decrease of DA levels induced by LY 171555 (0.01 mg/kg) was prevented by pretreatment with sulpiride (10 mg/kg) but not SCH 23390 (0.5 mg/kg). In comparison, pretreatment with SCH 23390 (0.5 mg/kg) completely inhibited the reduction of DA induced by SKF 38393 (10 mg/kg) while sulpiride (10 mg/kg) was without effect. Apomorphine (0.05 mg/kg) also decreased DA in striatal perfusates and this action was partially inhibited by both SCH 23390 (0.5 mg/kg) and sulpiride (10 mg/kg).Levels of the DA metabolite DOPAC in striatal perfusates also significantly decreased following LY 171555 (0.01 mg/kg) and apomorphine (0.05 mg/kg) but not SKF 38393 (10 mg/kg). The antagonist SCH 23390, in a dose, 0.5 mg/kg, that alone did not increase levels of DOPAC, inhibited the reduction of DOPAC induced by both LY 171555 and apomorphine. Sulpiride, 10 mg/kg, caused a marked increase in striatal DOPAC and this was not affected by a subsequent injection of LY 171555, SKF 38393 or apomorphine.We conclude from these data that DA release in rat striatum is autoregulated by independent D-1 and D-2 receptor-linked mechanisms. In contrast, the level of DA metabolism is controlled by a D-2 receptor-coupled mechanism which can be influenced by the D-1 receptor. This study provides further evidence that DA release and DA synthesis/metabolism are able to change independent of each other.     

D-1 type of dopamine autoreceptors are not involved in the regulation of dopamine synthesis in the striatum

To clarify if dopamine (DA) synthesis is regulated by D-1 DA receptors located on dopaminergic nerve terminals in the striatum, we investigated effects of D-1 DA receptor agonist and antagonist on striatal 3,4-dihydroxyphenylalanine (DOPA) accumulation induced by gamma-butyrolactone in mice treated with an amino acid decarboxylase inhibitor. SKF 38393, a D-1 agonist, did not affect DOPA accumulation, whereas apomorphine that stimulates both D-1 and D-2 receptors inhibited the accumulation. SCH 23390, a D-1 antagonist, did not antagonize apomorphine-induced inhibition of DOPA accumulation, while YM-09151-2, a D-2 antagonist, reversed it. These results suggest that D-1 type of DA autoreceptors is not involved in the inhibition of in vivo DA synthesis.     

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.     

SCH 23390--a selective dopamine D-1 receptor antagonist with putative 5-HT1 receptor agonistic activity

The selective dopamine D-1 receptor antagonist SCH 23390 has been tested in vitro in the rat fundus model and in vivo in the electrically stimulated flexor reflex model. In the fundus model, SCH 23390 showed a potent agonistic activity compared to that of different 5-HT receptor agonists. Pindolol, 1-propranolol and pirenperone showed no or only weak inhibition of the SCH 23390-induced contractions in the fundus strip whereas methysergide was a potent inhibitor. The 5-HT3 receptor antagonist ICS 205-930 did not induce an inhibitory effect. In the electrically stimulated flexor reflex model in pithed rats, SCH 23390 induced a marked increase of the reflex. This increase was slightly inhibited by a mixed dopamine (DA) D-1/D-2 antagonist cis(Z)-flupentixol and by a specific DA D-2 antagonist YM 09151-2. Different reference antagonists: bicuculline (GABAergic), propranolol (beta-adrenergic), scopolamine (muscarinic), yohimbine (alpha 2-adrenergic), prazosin (alpha 1-adrenergic) were all without an antagonist effect on the SCH 23390-induced increase of the flexor reflex. Ketanserin, a selective 5-HT2 receptor antagonist, showed a weak and short-lasting inhibition of the SCH 23390 effect in high doses, whereas ritanserin showed only 35% inhibition of the SCH 23390-induced flexor reflex at a dose of 1.3 mumol/kg i.v. The mixed 5-HT1/5-HT2 antagonists methiothepin and metergoline showed a marked inhibitory effect at 2.6 mumol/kg i.v. and 3.1 mumol/kg i.v., respectively (1.3 mg/kg i.v.). These findings suggest that SCH 23390 might possess 5-HT1 receptor agonist activity.     

Striatal and nigral D1 mechanisms involved in the antiparkinsonian effects of SKF 82958 (APB): studies of tremulous jaw movements in rats

  Rationale: Previous work has demonstrated that cholinomimetic-induced tremulous jaw movements in rats have temporal and pharmacological characteristics similar to parkinsonian tremor. Objective: This rodent model was used to characterize the putative antiparkinsonian effects of the full D₁ dopamine receptor agonist, SKF 82958. Methods: Jaw movement activity was induced by the muscarine agonist pilocarpine (4.0 mg/kg IP), and a series of experiments studied the pharmacological characteristics of the reversal of pilocarpine-induced jaw movements by SKF 82958. Results: SKF 82958 (0.5–2.0 mg/kg IP) reduced the tremulous jaw movements induced by pilocarpine. The suppressive effects of SKF 82958 on jaw movements were dose-dependently reversed by systemic pretreatment with the selective D₁ dopamine receptor antagonist SCH 23390 (0.025–0.2 mg/kg IP); SCH 23390 was about 16 times more potent than the D₂ antagonist raclopride at reversing the effects of SKF 82958. Intracranial injection of SCH 23390 (0.5–2.0 μg/side) into the ventrolateral striatum, the rodent homologue of the human ventral putamen, dose-dependently reversed the reduction of pilocarpine-induced jaw movements produced by SKF 82958. Intracranial injection of SCH 23390 (0.5–2.0 μg/side) into the substantia nigra pars reticulata also dose-dependently reversed the reduction by SKF 82958 of pilocarpine-induced jaw movements. Injections of SCH 23390 (2.0 μg/side) into control sites dorsal to the striatum or substantia nigra had no effects on the action of SKF 82958. Intranigral (SNr) injections of the GABA-A antagonist bicuculline blocked the suppressive effect of systemically administered SKF 82958 on jaw movement activity. Conclusions: These data suggest that the antiparkinsonian actions of SKF 82958 may be due to stimulation of D₁ receptors in the ventrolateral striatum and substantia nigra pars reticulata. In addition, these results indicate that GABA mechanisms in the substantia nigra pars reticulata may be important for the antiparkinsonian effects of D₁ agonists. Received: 9 June 1998 / Final version: 10 October 1998     

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.     

Cholinergic/dopaminergic interaction in the rat striatum assessed from drug-induced repetitive oral movements.

The role of striatal dopaminergic/cholinergic interactions in the regulation of oral behaviour in rats was studied using methods which resolve distinct patterns of jaw movements, allowing a more accurate quantitative and qualitative analysis. Both dopamine and acetylcholine receptor agonists given either systemically or into the ventral striatum induced repetitive oral movements. However, the cholinergic movements differed from dopaminergic movements as to pattern of activity. Oral movements induced by apomorphine (0.2 mg/kg i.v.) were potentiated by carbachol (0.1 microgram/0.2 microliters) injected into the dorsal striatum, while inhibition was observed when carbachol was injected into the ventral striatum. Pilocarpine (4 mg/kg)-induced oral movements were reduced by injecting flupentixol (10 micrograms/0.2 microliters), but not a combination of SKF 38393 (3 micrograms)+quinpirole (10 micrograms/0.2 microliter), into either the dorsal or the ventral striatum. Oral movements induced by the injection of carbachol (1 microgram/0.2 microliter) into the ventral striatum were enhanced by previous injection of this combination of dopamine receptor agonists into the same site and were inhibited by flupentixol. These results suggest that cholinergic and dopaminergic oral movements are separate behaviors and that the striatal dopamine/acetylcholine interaction in their regulation is neither simply antagonistic or synergistic, nor reciprocal.     

Sedation and sleep induced by high doses of apomorphine after blockade of D-1 receptors by SCH 23390

The effect of SCH 23390, a selective blocker of D-1 receptors, on apomorphine-induced behavioural and EEG changes was studied in rats. In control rats, a low dose of apomorphine (50 micrograms/kg s.c.) produced sedation associated with EEG synchronization. A high dose of apomorphine (1 mg/kg s.c.) produced stereotypy associated with EEG desynchronization. At the dose of 1 mg/kg i.p., SCH 23390 decreased motor activity but failed to alter the EEG pattern. The administration of either the low or high dose of apomorphine to SCH 23390-treated rats elicited a marked sedative response associated with EEG synchronization. The EEG synchronization produced by apomorphine (50 micrograms/kg) in SCH 23390-treated rats was prevented by (-)-sulpiride (25 mg/kg i.p.), a D-2 receptor blocker. It is concluded that by preventing the excitatory response to apomorphine SCH 23390 discloses the existence of a population of D-2 receptors mediating sedation and sleep.     

Motor activity following the administration of selective D-1 and D-2 dopaminergic drugs to normal common marmosets

In normal common marmosets administration of the D-1/D-2 agonist apomorphine or the selective D-2 agonist quinpirole caused a dose-dependent increase in motor activity and induced stereotyped behaviour. Both the selective D-2 antagonist raclopride and the selective D-1 antagonist SCH 23390 inhibited normal locomotor activity and induced catalepsy. Quinpirole- and apomorphine-induced motor activity were potently inhibited by pretreatment with raclopride. The effects of quinpirole, but not apomorphine, were weakly inhibited by SCH 23390. The selective D-1 partial agonist SKF 38393 decreased motor activity and did not induce grooming, oral movements or other behaviours. SKF 38393 inhibited motor activity induced by the administration of quinpirole but did not alter apomorphine-induced motor behaviour. Locomotor activity in normal common marmosets appears to be mediated mainly via D-2 systems. In contrast to rodents, administration of SKF 38393 does not induce behavioural activation and there does not appear to be a facilitating effect of D-1 systems on D-2 function in the normal common marmoset. However, the ability of both SKF 38393 and SCH 23390 to inhibit quinpirole locomotor activity suggests some interaction between D-1 and D-2 systems to occur in this species.     

Behavioural stimulation is induced by separate dopamine D-1 and D-2 receptor sites in reserpine-pretreated but not in normal rats

The dopamine (DA) D-1 agonist SK&F 38393 as well as the D-2 agonist pergolide and the mixed D-1/D-2 agonist apomorphine induced strong hypermotility and oral stereotypy in rats pretreated with a daily dose of reserpine for 2 and in particular for 4 days (3 and 5 injections, respectively). SK&F 38393 had no behavioural stimulant effect in saline-pretreated rats, whereas pergolide and apomorphine produced stimulation, although only after higher doses. Agonists at 5-HT and muscarinic receptors and at alpha 1-adrenoceptors were ineffective in reserpine-pretreated rats whereas the alpha 2-adrenoceptor agonist, clonidine, and the muscarinic antagonist, scopolamine, produced weak locomotor stimulation. The hypermotility induced by SK&F 38393 in reserpinized rats was blocked by pretreatment with the DA D-1 antagonists, SCH 23390 and SK&F 83566c, whereas the DA D-2 antagonists, YM 09151-2, clebopride and spiroperidol were weak or ineffective. In contrast pergolide-induced hypermotility was blocked by low doses of the D-2 antagonists but was weakly or not influenced by the D-1 antagonists. Selectivity ratios between drug potencies in the two models ranged from 65 to more than 600. The mixed D-1/D-2 antagonists, cis(Z)-flupentixol and cis(Z)-clopenthixol, blocked the effect of both SK&F 38393 and pergolide. The alpha 1-adrenoceptor antagonist, prazosin, and the 5-HT2 receptor antagonist, ketanserin, did not modify the effect of SK&F 38393 or pergolide. Stereotyped behaviour induced by a high pergolide dose in normal rats was, in contrast to the effect in reserpinized rats, blocked by low doses of either SCH 23390 or spiroperidol. Finally, the hypermotility induced by apomorphine in reserpinized rats was markedly antagonized by both SCH 23390 and spiroperidol. The results suggest a close relation between D-1 and D-2 receptor sites in normal rats. After prolonged reserpine treatment, the D-1 agonist acquires full DA agonist efficacy. Furthermore, behavioural stimulation under these conditions is mediated by two separate D-1 and D-2 receptor sites which can be manipulated independently by antagonists. The mechanism by which this phenomenon occurs is unknown but the adaptational changes show close similarities to those observed after 6-hydroxyDA-induced denervation.     

SCH 23390 antagonizes apomorphine- and ergot-induced hypothermia

The reportedly specific D-1 dopamine (DA) receptor antagonist SCH 23390 significantly reduced the hypothermia elicited by various DA receptor agonists like apomorphine, pergolide and lisuride. When tested against equihypothermic doses of each agonist, SCH 23390 significantly reduced the hypothermia elicited by apomorphine (0.2 mg/kg s.c.) and by pergolide (0.1 mg/kg i.p.) at doses of 0.025 mg/kg s.c. Doses of 0.050 mg/kg s.c. of SCH 23390 were necessary to reduce the hypothermia elicited by 0.012 mg/kg s.c. of lisuride. Pretreatment with the specific D-2 antagonist (-)sulpiride (50 mg/kg i.p.) completely prevented the hypothermia elicited by lisuride (0.012 mg/kg i.p.), pergolide (0.1 mg/kg i.p.) and apomorphine (0.2 mg/kg s.c.) and shifted to the right the dose-response curve for agonist-induced hypothermia. A study of the interaction between 0.05 mg/kg s.c. of SCH 23390 with various doses of the agonists showed that the effectiveness of SCH 23390 in antagonizing the hypothermia was maximal towards apomorphine and least towards lisuride for which significant antagonism was observed only against the lowest dose tested (0.012 mg/kg s.c.). The reportedly specific D-1 receptor agonist SKF 38393 given in doses up to 20 mg/kg i.p. or intracerebroventricularly up to 100 micrograms failed to influence body temperature while it evoked intense grooming and stimulated motility.     

Topography of dopamine D-1 and D-2 receptor-mediated rotation after intrastriatal injections of dopamine-related drugs in normosensitive rats

Naive rats were challenged systematically with apomorphine after receiving unilateral dorsal or ventral intracaudate injections of the dopamine D-1 receptor antagonist, SCH23390, or the D-2 receptor antagonist, sulpiride. Sulpiride injections into both the dorsal and ventral striatum induced a robust ipsilateral rotation, while SCH23390 elicited a weaker ipsilateral rotation only on injection into the ventral striatum. Both drugs were ineffective in saline-treated rats, although sulpiride injections into the ventral striatum after systemic saline elicited a small ipsilateral preference. The results from this rotational model mediated by normosensitive receptors indicate that only dopamine D-1 receptors in the ventral striatum mediate rotation while D-2 receptors in both striatal regions mediate rotation. A functional dichotomy between these two neostriatal regions is thus proposed.     

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.     

Cholecystokinin octapeptide and caerulein injection into the dorsomedial nucleus accumbens potentiate apomorphine-induced jaw movements in rats.

The effects of bilateral intra-accumbal and intrastriatal injections of CCK-8 sulphate and its analogue, caerulein, on apomorphine-induced jaw movements were studied in ketamine-anaesthetized rats after C1 spinal transection. Jaw movements were detected by a photo-transducer attached to the mandible. CCK-8 (5, 10 and 20 ng) and its analogue, caerulein (1 and 5 ng), injected into the dorsomedial nucleus accumbens increased the frequency of apomorphine (0.2 mg/kg i.v.)-induced jaw movements. The potentiation was prevented by administration of a CCK-A receptor antagonist, lorglumide (5 ng), together with CCK-8 (20 ng) or caerulein (5 ng). Injection of lorglumide alone into the dorsomedial nucleus accumbens did not alter apomorphine (0.5 mg/kg i.v.)-induced jaw movements. Injections of CCK-8 (20 ng) and caerulein (5 ng) into adjacent sites (the ventrolateral nucleus accumbens, dorsal striatum and ventral striatum) did not affect the responses elicited by apomorphine (0.2 mg/kg i.v.). These results demonstrate that CCK-8 modulates responses elicited by a dopamine receptor agonist, apomorphine, in a region of the brain where CCK-8 is known to co-exist with dopamine.     

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.