Potentiation of apomorphine-induced stereotyped behaviour by acute treatment with dopamine depleting agents: a potential role for an increased stimulation of D1 dopamine receptors

Treatment of mice with reserpine (10 mg/kg, s.c.) and alpha-methylparatyrosine (400 mg/kg) led to the potentiation of stereotyped behaviour, induced by apomorphine (0.37-1.5 mg/kg, s.c.), i.e. to the appearance of licking and gnawing in addition to climbing and sniffing occurring in control mice. Similar results were obtained by combined treatment with SK&F 38393 (30 mg/kg, s.c.) and RU 24926 (15 mg/kg, i.p.). In mice treated with dopamine depleting agents, SCH 23390 (1.25-20 micrograms/kg, s.c.) and metoclopramide (0.62-20 mg/kg, i.p.) antagonized gnawing induced by 0.75 mg/kg (s.c.) apomorphine, at doses significantly larger than those required for the antagonism of climbing and sniffing. The same treatment with reserpine and alpha-methylparatyrosine produced an increased formation of cyclic AMP, induced by SK&F 38393 (10(-8)-10(-4) M), from homogenates of the striatum of the rat. Potentiation of apomorphine-induced stereotyped behaviour and increased SK&F 38393-induced formation of cyclic AMP had similar time-courses with a maximum 18 hr after treatment. These data suggest that the potentiation of apomorphine-induced stereotyped behaviour produced by acute treatment with dopamine depleting agents is at least partly due to an increased activity of the adenylate cyclase linked to D1 dopamine receptors. Finally, a small dose of amisulpride (a discriminant benzamide derivative) potentiated the stereotyped behaviour induced by the combined treatment with SK&F 38393 and RU 24926 in naive mice and, in a more marked manner, in mice treated with dopamine depleting agents; amisulpride did not produce stereotyped behaviour when combined with SK&F 38393 or RU 24926 administered alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Importance of D-2 mechanisms in the reversal of reserpine hypothermia in the mouse

The D-2 agonist LY 171555 (0.05, 0.1, 0.2 mg kg-1 s.c.) but not the D-1 agonist SK&F 38393 (5, 10, 20 mg kg-1 s.c.) reduced reserpine-induced hypothermia (RIH) in mice. This effect was antagonized by the D-2 antagonist (-)-sulpiride (50 mg kg-1 i.p.) but not by the D-1 antagonist SCH 23390 (0.1 mg kg-1 s.c.). SK&F 38393 (20 and 1 mg kg-1 s.c.) did not alter the effect of LY 171555 (0.1 and 0.2 mg kg-1) on RIH, but administration of both LY 171555 (0.2 mg kg-1 s.c.) and SK&F 38393 (1 mg kg-1 s.c.) antagonized the reserpine-induced sedation.     

Increased grooming behaviour is induced by apomorphine in mice treated with discriminant benzamide derivatives

Grooming behaviour in mice was dose dependently increased by SK&F 38393 (1.87-30 mg/kg), whereas it was dose dependently decreased by RU 24926 (2.5-10 mg/kg) or LY 171555 (0.4-1.6 mg/kg) alone or combined with SK&F 38393 or apomorphine (0.39-6 mg/kg). The inhibitory effect of 0.75 mg/kg apomorphine on grooming behaviour was not modified by SCH 23390, chlorpromazine, clozapine and thioridazine. In contrast, it was antagonized by eight other dopamine antagonists: a partial restoration to grooming scores lower or similar to those determined in control mice was obtained with flupentixol, haloperidol, metoclopramide, thioproperazine and tiapride, whereas a reversal to grooming scores higher than those determined in control mice was obtained with mice treated with (+/-)-sulpiride, amisulpride or RIV 2093. Furthermore, only SCH 23390, chlorpromazine and clozapine antagonized SK&F 38393 (1.87 mg/kg)-induced grooming behaviour, whereas the effects of flupentixol, thioridazine, metoclopramide, haloperidol and amisulpride in SK&F 38393-treated mice were parallel to those of control mice. Finally, SCH 23390 (20 micrograms/kg) antagonized the apomorphine-induced grooming in mice treated with amisulpride, (+/-)-sulpiride or tiapride. These data confirm the potential role of D-1 dopamine receptors in the expression of grooming behaviour and indicate that the dopamine receptors involved in the inhibition of grooming could be of the D-4 subtype. Our results also reveal that chlorpromazine and clozapine have D-1 antagonist properties and suggest that the modulation of apomorphine-induced grooming behaviour by dopamine antagonists in mice could be used as a test for their classification according to their activity at the different dopamine receptor subtypes.     

Stimulation of central D1 dopamine receptors reverses reserpine-induced hypothermia in mice

In mice rendered poikilothermic by a prior (18 h) subcutaneous administration of reserpine (3 mg/kg) the injection of the D1 dopamine agonist SKF 38393 in doses of 1 mg/kg or more increased dose-dependently, the body temperature. The D1 dopamine antagonist SCH 23390, administered subcutaneously, antagonized, with an ID50 of 16 micrograms/kg, the reversal by SKF 38393 of reserpine-induced hypothermia. The intracerebroventricular administration of 1 microgram per mouse of SKF 38393 was sufficient to elevate by about 7 degrees C the temperature of reserpinized mice. It is concluded that stimulation of central D1 dopamine receptors leads to a marked reversal of reserpine-induced hypothermia; this may constitute a new test to investigate interaction of drugs with these receptors. In reserpine-pretreated mice, the dopamine (DA) agonist apomorphine, which stimulates both the D1 and D2 subtypes of DA receptors, increases body temperature according to a mechanism insensitive to the specific D2 DA antagonist sulpiride (Horowski 1978) or the preferential D2 DA antagonist haloperidol (Danielson, Coutts, Keashly and Tang 1985). This observation led us to believe that D1 DA receptors could be involved in the reversal of the hypothermia induced by reserpine. To check more directly the involvement of D1 DA receptors in the reversal of the reserpine-induced hypothermia we have tested the specific D1 agonist SKF 38393 (Setler, Sarau, Zirckle and Saunders, 1978), administered peripherally or intracerebroventricularly and we have studied its interaction with the specific D1 antagonist SCH 23390 (Iorio, Barnett, Leitz, Houser and Korduba, 1983).     

Interactions of drugs acting on central dopamine receptors and cholinoceptors on yawning responses in the rat induced by apomorphine, bromocriptine or physostigmine.

1. Yawning was induced by subcutaneous (s.c.) injection of low doses of apomorphine to rats. This effect decreased with increasing doses of the drug. 2. Intraperitoneal (i.p.) pretreatment of animals with sulpiride (D2-receptor blocker) reduced the frequency of the yawns induced by apomorphine, while SCH 23390 (D1-receptor blocker, s.c.) pretreatment increased the small number of yawns which was induced by higher doses of apomorphine. Administration of SCH 23390 alone to rats also produced a low degree of yawning. 3. Apomorphine-induced yawning was decreased in animals treated with SK&F 38393 (D1-agonist, i.p.), atropine (i.p.) or theophylline (i.p.). 4. Intraperitoneal injection of bromocriptine (D2-agonist) in rats also induced dose-dependent yawning. The effect was decreased in animals pretreated with sulpiride, while SCH 23390 pretreatment did not change bromocriptine-induced yawning significantly. Pretreatment of animals with SK&F 38393, atropine or theophylline reduced the number of yawns induced by bromocriptine. 5. Physostigmine (i.p.) but not neostigmine (i.p.) also induced yawning. The effect was antagonized by atropine or theophylline but not by sulpiride. Administration of SK&F 38393 decreased yawning induced by physostigmine. This inhibitory influence of SK&F 38393 was reduced by SCH 23390 in pretreated animals. Treatment of animals with SCH 23390 or bromocriptine increased the frequency of yawns induced by physostigmine. 6. It is concluded that D2-receptor activation elicits yawning through influence on cholinergic mechanisms, whereas D1-receptor stimulation decreases yawning behaviour by a negative influence on the cholinergic system.     

Involvement of dopamine receptor subtypes in mouse thermoregulation

The effects of dopamine agonists on core body temperature (BT) were tested in mice. Apomorphine (APO) reduced BT of the mice dose dependently. The response was inhibited by the D-2 antagonist sulpiride, but not by the D-1 antagonist SCH 23390. The D-2 agonist quinpirole also decreased BT and this was prevented by sulpiride pretreatment. Administration of the D-1 agonist SKF 38393 increased BT. This hyperthermia was decreased by SCH 23390 pretreatment. In reserpinized animals, APO caused a dose-related increase in BT. The hyperthermic response of the drug was abolished in animals pretreated with a combination of sulpiride with SCH 23390, but not by single administration of sulpiride or SCH 23390. Quinpirole and SKF 38393 caused hyperthermia in reserpinized mice. The response was decreased in animals pretreated with sulpiride or SCH 23390, respectively. BT of the intact mice was decreased, while that of reserpinized animals was increased by SCH 23390 but not by sulpiride pretreatment. It is concluded that the presynaptic dopamine neurons are involved in hypothermia, while both post-synaptic D-1 and D-2 dopamine receptors may mediated the hyperthermia induced by dopaminergic agents.     

Ventral striatal vs. accumbal (shell) mechanisms and non-cyclase-coupled dopamine D(1)-like receptors in jaw movements.

This study compared the effects of intracerebral injections of the dopamine D(1)-like receptor agents 3-methyl-6-chloro-7,8-dihydroxy-1-[3-methylphenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine (SK&F 83959) and [R]-3-methyl-7-chloro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH 23390) into the ventrolateral striatum or the shell of the nucleus accumbens on the synergistic induction of jaw movements by intravenous (i.v.) co-administration of [R]-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SK&F 38393) or SK&F 83959 with the dopamine D(2)-like receptor agonist, quinpirole. In the ventrolateral striatum, SCH 23390 and SK&F 83959 each blocked jaw movements induced by i.v. SK&F 38393 with quinpirole, while only SCH 23390 blocked i.v. SK&F 83959 with quinpirole. SCH 23390 was less effective in the accumbens shell than in the ventrolateral striatum, and SK&F 83959 was ineffective to block i.v. SK&F 38393 with quinpirole, while neither SCH 23390 nor SK&F 83959 blocked i.v. SK&F 83959 with quinpirole. As SK&F 83959 inhibits the stimulation of adenylyl cyclase via dopamine D(1A) receptors but acts as an agonist at a putative dopamine D(1)-like receptor site not linked to cyclase, an important role is indicated for non-cyclase-coupled dopamine D(1)-like receptor sites as well as dopamine D(1A) receptors in the regulation of jaw movements via dopamine D(1)-like/D(2)-like receptor synergism, particularly in the ventrolateral striatum.     

Dopaminergic Involvement in Improving Effects of Dynorphin A-(1-13) on Galanin-Induced Impairment of Passive Avoidance Learning in Mice

The present study was designed to clarify whether dopaminergic systems are involved in the effects of dynorphin A-(1-13), an endogenous κ-opioid receptor agonist, on the galanin-induced impairment of passive avoidance learning in mice. Galanin (0·3 μg, i.c.v.) shortened step-down latency of passive avoidance learning, while the dopamine D₁ receptor agonist SKF 38393 (3 and 10 mg/kg, s.c.), the dopamine D₂ receptor agonist RU 24213 (0·3 and 1 mg/kg, s.c.), the dopamine D₁ receptor antagonist SCH 23390 (0·01 and 0·03 mg/kg, i.p.) or the dopamine D₂ receptor antagonist S(−)-sulpiride (10 and 30 mg/kg, i.p.) failed to influence it. Dynorphin A-(1-13) (3 μg, i.c.v.) and SKF 38393 (10 mg/kg, s.c.) markedly improved the galanin (0·3 μg, i.c.v.)-induced shortening of step-down latency. However, RU 24213 (0·3 and 1 mg/kg, s.c.), SCH 23390 (0·01 and 0·03 mg/kg, i.p.) or S(−)-sulpiride (10 and 30 mg/kg, i.p.) did not affect the galanin (0·3 μg, i.c.v.)-induced shortening of step-down latency. In contrast, SCH 23390 (0·3 mg/kg, i.p.) significantly reversed the improving effects of dynorphin A-(1-13) (3 μg, i.c.v.) on the galanin (0·3 μg, i.c.v.)-induced dysfunction of passive avoidance learning, although SKF 38393 (1 and 3 mg/kg, s.c.), RU 24213 (0·3 and 1 mg/kg, s.c.) or S(−)-sulpiride (10 and 30 mg/kg, i.p.) did not influence the effects of dynorphin A-(1-13) (3 μg, i.c.v.). These results suggest that dynorphin A-(1-13) improves the galanin-induced amnesia resulting from indirect stimulation of dopamine D₁ receptors. © 1997 John Wiley & Sons, Ltd.     

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.     

Similarity of clozapine and SCH 23390 in reserpinized rats suggests a common mechanism of action

Clozapine at doses up to 100 mg/kg p.o. did not antagonize apomorphine-induced stereotypy in vehicle pre-treated rats. However, if the animals were injected with reserpine (30 mg/kg i.p.) 24 h prior to the test, then clozapine (3-100 mg/kg p.o.) produced a dose-related blockade of apomorphine-induced stereotypy. The blockade of apomorphine-induced stereotypy in reserpinized rats by clozapine was attenuated by the D-2 selective agonist LY 171555 but not the D-1 selective agonist SKF 38393. This profile of agonist reversal of antagonist blockade of apomorphine-induced stereotypy seen with clozapine was identical to that seen with the selective D-1 antagonist SCH 23390. Presumably, the D-2 agonist was active because D-1 receptor systems were inhibited (either at the receptor or at some other post-synaptic site) by clozapine or SCH 23390; this allowed a partial restoration of apomorphine-induced stereotypy via the D-2 system. Therefore, these data indicate that clozapine and SCH 23390 share a common mechanism of action via D-1 receptor systems.     

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.     

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.     

The effects of dopamine D-1 and D-2 receptor agonists on body temperature in male mice

The effect of dopamine D-1 and D-2 receptor stimulation on body temperature has been investigated in male mice. The selective D-2 receptor agonists, quinpirole and LY 163502, and the mixed D-1/D-2 agonist, apomorphine, induced a dose-dependent hypothermia, whereas the selective D-1 receptor agonists, SK&F 81297, SK&F 38393 and SK&F 75670, induced hyperthermia. The hyperthermic responses of these agents were of a similar magnitude although the relative efficacies determined in vitro with the adenylate cyclase assay were different. The peripherally acting D-1 agonist, fenoldopam, did not influence body temperature, indicating that the hyperthermia is mediated, centrally. Studies with combinations of quinpirole and SK&F 38393 showed that the effect of one of the substances could be counteracted by the other. Furthermore, antagonist studies showed that the hypothermia induced by quinpirole could be inhibited by the D-2-selective antagonist, YM 09151-2, and by the mixed D-1/D-2 antagonist, cis(Z)-flupentixol, but not by the D-1-selective antagonist, SCH 23390. Similar results were found for apomorphine-induced hypothermia. SK&F 38393-induced hyperthermia could be antagonized by all three antagonists. These results suggest that the two receptor subtypes act differentially on body temperature, and that they influence a common out-put system, but in opposite directions. These findings are opposite to those of behavioural studies, where a synergistic function of D-1 and D-2 receptors has been demonstrated in the regulation of motor function.     

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.     

The effects of selective dopamine receptor agonists and antagonists on body temperature in rats

Body temperature was measured at repeated time intervals following the administration of various dopamine agonists and antagonists. The D-1 and D-2 receptor agonist, apomorphine, produced dose-dependent hypothermia. This effect was inhibited by the D-2 receptor antagonist, spiroperidol. Stimulation of D-2 receptor by LY171555 produced dose-dependent hypothermia, which was attenuated by pretreatment with spiroperidol and not altered by the D-1 receptor antagonist SCH23390. The D-1 receptor agonist, SK&F38393 had no effect on body temperature. SCH23390 administered alone produced initial hyperthermia and subsequent hypothermia. When administered with apomorphine, SCH23390 both attenuated and potentiated the hypothermic response, depending on the dose and time of administration of each drug. The results suggest that dopamine receptor agonists induce hypothermia by stimulation of the D-2 receptor subtype.     

Effects of dopamine receptor agonists on passive avoidance learning in mice: interaction of dopamine D1 and D2 receptors.

The present study examined the effects of dopamine D1 and D2 receptor agonists on the acquisition stage of passive avoidance learning and on locomotor activity in mice. The D2 agonist, RU 24213 (1-10 mg/kg s.c.), and the non-selective agonist, apomorphine (0.3-3 mg/kg s.c.), but not the D1 agonist, SKF 38393 (1-10 mg/kg s.c.), impaired learning and activated locomotion. RU 24213 (1 mg/kg s.c.) was more effective in impairing learning than in activating locomotion. The concurrent administration of SKF 38393 (10 mg/kg i.p.) and RU 24213 (1 and 3 mg/kg s.c.) produced a synergistic effect in both behavioral situations. The D1 antagonist, SCH 23390 (0.025 mg/kg i.p.), slightly inhibited the effects of apomorphine and of the combination of SKF 38393 and RU 24213 on learning but not on locomotion. The D2 antagonist, (-)-sulpiride (40 mg/kg i.p.), completely blocked these effects in both situations. These results suggest that dopamine receptor agonists impair passive avoidance learning through the D2 receptor, and that D1 and D2 receptors act synergistically in this impairment, as they do in their effects on locomotion. The involvement of D1 and D2 receptors is qualitatively similar in each of these behaviors, although some small differences may exist.     

The hypothermic response of mice to delta-9-tetrahydrocannabinol is enhanced by chlorpromazine, thioxanthenes, alpha-adrenoceptor antagonists and pentolinium but not by SCH 23390 or sulpiride

Chlorpromazine, given either subcutaneously (0.375 mg/kg) or unilaterally into the preoptic/anterior hypothalamic area through a chronically implanted cannula (20 micrograms), was found to enhance the hypothermic response to delta-9-tetrahydrocannabinol (THC; 5 mg/kg i.p.) in unrestrained adult male MF1 mice, kept at 22 degrees C. In mg/kg terms, chlorpromazine was no more potent when injected into the preoptic/anterior hypothalamic area than when given subcutaneously. Phentolamine (54 micrograms) had no significant effect on hypothermia induced by THC when injected into the hypothalamus although it did enhance this response when given subcutaneously (15 mg/kg). Hypothermia induced by THC was also enhanced by flupentixol (0.375 mg/kg s.c.), piflutixol (23.4 micrograms/kg s.c.), pentolinium (5 mg/kg s.c.), prazosin (0.1875 mg/kg s.c.) and indoramin (6 mg/kg s.c.) but not by SCH 23390 (6 mg/kg s.c.) or sulpiride (40 mg/kg s.c.). When taken together with the results from a previous study, these data support the hypothesis that chlorpromazine enhances hypothermia induced in mice by THC by antagonizing alpha-adrenoceptors so as to decrease the capacity of the animals to minimise peripheral blood flow by vasoconstriction. The present data also support the hypothesis that flupentixol and piflutixol interacted with THC not by antagonizing dopamine at D1 or D2 receptors but rather by blocking alpha-adrenoceptors.     

Influences of dopamine receptors on chewing behaviour in rats.

1. Intraperitoneal (i.p.) injection of different doses of pilocarpine induced purposeless chewing in rats. Physostigmine (i.p.), but not neostigmine (i.p.) also induced chewing behaviour. 2. Subcutaneous (s.c.) pretreatment of animals with the D-1 receptor blocker SCH 23390 decreased the number of chews induced by pilocarpine. 3. The D-2 dopamine antagonist sulpiride (i.p.) and anticholinergic atropine (i.p.) pretreatment also decreased the frequency of chews induced by the drug. 4. The response induced by pilocarpine (1 mg/kg i.p.) also was dose-dependently decreased in animals pretreated with apomorphine (0.25-1 mg/kg s.c.). 5. Administration of low doses of apomorphine (s.c.) also induced chewing, which was decreased with increasing the doses of the drug. 6. Chewing-induced by apomorphine was decreased by sulpiride or atropine and increased by SCH 23390 pretreatment. 7. Single administration of D-2 dopamine agonist bromocriptine also showed a slight but significant purposeless chewing, which was decreased by sulpiride pretreatment. 8. Single administration of D-2 agonist quinpirole, D-1 agonist SKF 38393 or D-1 antagonist SCH 23390, but not sulpiride caused a slight chewing. 9. It may be concluded that D-1 or D-2 activation exert opposite influences on chewing behaviour in rats, although to prove this effect more elucidation is needed.     

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)