Effects of intracerebroventricular injection of opioid peptides selective for μ, δ and κ receptors on discriminative stimulus properties of pentazocine in the rat

The present study was designed to investigate the effects of centrally administered morphine and opioid peptides on the discriminative stimulus properties of pentazocine in the rat. Rats were trained to discriminate 3 mg/kg (s.c.) of pentazocine from vehicle in a shock avoidance paradigm. A 3 mg/kg (s.c.) dose of pentazocine produced stimulus effects in common with those induced by a training dose (3 mg/kg, s.c.) of pentazocine. Morphine (0·1–3 μg, i.c.v.) produced a dose-dependent increase in responding appropriate for pentazocine lever. The μ-selective opioid receptor agonist [D-Ala²,NMePhe⁴,Gly-ol] enkephalin (DAMGO) (0·0003–0·03 μg, i.c.v.) generalized to pentazocine cue. d -Pen², l -Pen⁵] enkephalin (DPLPE) (3 and 10 μg, i.c.v.), a δ-selective opioid receptor agonist, produced partial generalization to pentazocine cue. However, the κ-selective opioid receptor agonist dynorphin A-(1–13) (3 and 10 μg, i.c.v.) did not generalize to pentazocine cue. The pentazocine-like discriminative stimulus effects of morphine (3 μg, i.c.v.) and DAMGO (0·03 μg, i.c.v.) were fully reversed by intracerebroventricular injection of the μ-selective opioid receptor antagonist β-funaltrexamine (5 μg, i.c.v.). These results suggest that μ-opioid receptors play a major role in the discriminative stimulus effects of pentazocine, while δ-opioid receptors only partially contribute to them. © 1998 John Wiley & Sons, Ltd.     

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.     

Rolipram inhibits airway microvascular leakage induced by platelet-activating factor,histamine and bradykinin in guinea-pigs

Abstract— Rolipram (0·1–1000 μg kg^?1, i.v.) reduced the increase in microvascular permeability induced by platelet-activating factor (PAF; 50 ng kg^?1, i.v.) at different sites of the guinea-pig airways. Rolipram (1–100μg kg^?1, i.v.) inhibited histamine (30μg kg^?1, i.v.)-and bradykinin (0·3 μg kg, i.v.)-induced airway microvascular leakage. These effects of rolipram were obtained at doses which inhibit histamine (7–20 μg kg^?1 min^?1)-induced bronchoconstriction (IC50 = 3 ± 1 μg kg, i.v.) without depressing arterial blood pressure in the guinea-pig. Aminophylline (50 mg kg^?1) did not change the effect of PAF. The anti-exudative effect of rolipram is of potential therapeutic value in asthma.     

A central site of action for benzamide facilitation of gastric emptying

Gastric emptying of the fed guinea-pig was measured using a non-invasive X-ray fluoroscopic technique to determine passage from the stomach of polystyrene-coated barium sulphate spheroids. Peripherally administered metoclopramide (0.1-10 mg/kg i.p.), clebopride (1-10 mg/kg i.p.), (-)-sulpiride (40 mg/kg i.p.), haloperidol (1 mg/kg i.p.) and domperidone (1-10 mg/kg i.p.) failed to modify gastric emptying. Stress inhibited emptying, and this was considered to explain the effects of eserine and high dose metoclopramide. Gastric emptying was decreased by peripherally administered atropine (0.5 mg/kg i.p.) and apomorphine (0.1-0.5 mg/kg s.c.); the apomorphine response was antagonised by pretreatment with haloperidol, domperidone, (-)-sulpiride, metoclopramide and clebopride but not by prazosin + propranolol. Gastric emptying was facilitated by intracerebroventricular (i.c.v.) administrations of metoclopramide and clebopride (40, 100 and 200 micrograms) but not by i.c.v. domperidone, haloperidol, fluphenazine or (-)-sulpiride (100, 200 micrograms) and was inhibited by i.c.v. apomorphine (100, 200 micrograms); the response to i.c.v. apomorphine was antagonised by i.c.v. pretreatments with haloperidol, domperidone, (-)-sulpiride, metoclopramide and clebopride (40-50 micrograms). Facilitation of emptying by i.c.v. metoclopramide was prevented by peripheral pretreatment with atropine (0.5 mg/kg i.p.). It is concluded that the actions of apomorphine and metoclopramide/clebopride to respectively inhibit and facilitate gastric emptying may be mediated, at least in part, via central mechanisms. Whilst apomorphine's action may be mediated via dopamine receptor mechanisms, metoclopramide and clebopride act at additional unspecified sites, metoclopramide's action being expressed via cholinergic mechanisms.     

Occurrence of yawning and decrease of prolactin levels via stimulation of dopamine D2-receptors after administration of SND 919 in rats

Summary SND 919 ((S)-2-amino-4,5,6,7-tetrahydro-6-propylamino-benzothiazole) is expected to have a potent and selective dopamine D₂-receptor agonistic activity. From this information, the present study was performed to investigate effects of SND 919 on yawning behavior and prolactin secretion in rats. Subcutaneous injections of SND 919 (25–500 gm/kg, s. c.) elicited yawning responses. Its dose-response curve was bell-shaped with maximal effects at a dose of 100 g/kg. Yawning behavior was also evoked by the putative dopamine autoreceptor agonists, talipexole (6-allyl2-amino-5,6,7,8-tetrahydro-4H-thiazolo [4,5-d]azepine) (BHT 920) (5–100 g/kg, s. c.) and (+)-3-PPP ((+)-3-(3-hydroxyphenyl)-N-n-propylpiperidine) (5–15 mg/kg, s. c.). The yawning induced by SND 919 (100 g/kg, s. c.) as well as talipexole (25 g/kg, s. c.) was inhibited by pretreatment with dopamine D2-receptor antagonists such as spiperone (0.5 mg/kg, i.p.) and YM-09151-2 (cis-N-(1-benzyl-2methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-methylaminobenzamide) (0.1 mg/kg, i. p.), or the muscarinic receptor antagonist, scopolamine (0.5 mg/kg, i.p.). However, the yawning was not affected by the dopamine D₁-receptor antagonist, SCH 23390 (R(+)-8-chloro-2,3,4,5-tetrahydro-3methyl-5-phenyl-1 H-3-benzazepine-7-ol) (0.5 mg/kg, i. p.). Stereotypy such as licking and biting was not observed following the administration of SND 919, talipexole and (+)-3-PPP. Administration of SND 919, talipexole or (+)-3-PPP in respective yawn-inducing doses caused a reduction in both the basal prolactin levels and the a-methyl-p-tyrosine-induced hyperprolactinemia. The results suggest that SND 919 as well as talipexole exerts selective agonistic activities for specific dopamine D2-receptors, which are not related to the occurrence of stereotypy and have a high affinity for dopamine receptor agonists quite similar to that of the pituitary lactotroph dopamine D₂-receptors.Send offprint requests to K. Yamada at the above address     

Antidepressant-like effect of ursolic acid isolated from Rosmarinus officinalis L. in mice: Evidence for the involvement of the dopaminergic system

Ursolic acid, a constituent from Rosmarinus officinalis, is a triterpenoid compound which has been extensively known for its anticancer and antioxidant properties. In the present study, we investigated the antidepressant-like effect of ursolic acid isolated from this plant in two predictive tests of antidepressant property, the tail suspension test (TST) and the forced swimming test (FST) in mice. Furthermore, the involvement of dopaminergic system in its antidepressant-like effect was investigated in the TST. Ursolic acid reduced the immobility time in the TST (0.01 and 0.1 mg/kg, p.o.) and in the FST (10 mg/kg, p.o.), similar to fluoxetine (10 mg/kg, p.o.), imipramine (1 mg/kg, p.o.) and bupropion (10 mg/kg, p.o.). The effect of ursolic acid (0.1 mg/kg, p.o.) in the TST was prevented by the pretreatment of mice with SCH23390 (0.05 mg/kg, s.c., a dopamine D₁ receptor antagonist) and sulpiride (50 mg/kg, i.p., a dopamine D₂ receptor antagonist). The administration of a sub-effective dose of ursolic acid (0.001 mg/kg, p.o.) in combination with sub-effective doses of SKF38393 (0.1 mg/kg, s.c., a dopamine D₁ receptor agonist), apomorphine (0.5 μg/kg, i.p., a preferential dopamine D₂ receptor agonist) or bupropion (1 mg/kg, i.p., a dual dopamine/noradrenaline reuptake inhibitor) reduced the immobility time in the TST as compared with either drug alone. Ursolic acid and dopaminergic agents alone or in combination did not cause significant alterations in the locomotor and exploratory activities. These results indicate that the antidepressant-like effect of ursolic acid in the TST is likely mediated by an interaction with the dopaminergic system, through the activation of dopamine D₁ and D₂ receptors.     

Mesulergine antagonism towards the fluoxetine anti-immobility effect in the forced swimming test in mice

Abstract— The anti-immobility effect of fluoxetine (40 mg kg^?1) in the forced swimming test in mice was antagonized by the 5-HT_1c/2 antagonist mesulergine (7·5 mg kg^?1) and the dopamine D₂ antagonist (±)-sulpiride (12.5 mg kg^?1) but not by the 5-HT_2/1C antagonist ritanserine (2 mg kg^?1), the 5-HT_1A/1B antagonist (–)-propranolol (20 mg kg^?1) or the 5-HT₃ antagonist DAU 6215 (0·1 mg kg^?1). All compounds were administered intraperitoneally (i.p.) 6 min before fluoxetine, given i.p. 30 min before testing. The anti-immobility effect of fluoxetine was also prevented by pretreat-ment with p-chlorophenylalanine (300 mg kg^?1 twice daily for 3 days) which produced an 80% reduction of 5-HT in brain. The results suggest that fluoxetine reduces immobility time in mice forced to swim, by acting indirectly through a mesulergine-sensitive site, probably the 5-HT_1C receptor.     

Intravenously injected CDP-choline increases blood pressure and reverses hypotension in haemorrhagic shock: effect is mediated by central cholinergic activation

Intravenous (i.v.) administration of cytidine-5′-diphosphate choline (CDP-choline) (100, 250 and 500 mg/kg) increased blood pressure in normal rats and reversed hypotension in haemorrhagic shock. Choline (54 mg/kg; i.v.), at the dose equimolar to 250 mg/kg CDP-choline decreased blood pressure of rats in both conditions and caused the death of all hypotensive animals within 2-5 min. Equimolar dose of cytidine (124 mg/kg; i.v.) did not change cardiovascular parameters. Choline levels in plasma, lateral cerebral ventricle and hypothalamus increased after CDP-choline administration. Intracerebroventricular (i.c.v.) hemicholinium-3 pretreatment (20 μg), greatly attenuated the pressor effect of CDP-choline in both conditions. Atropine pretreatment (10 μg; i.c.v.) did not change the pressor effect of CDP-choline while mecamylamine (50 μg; i.c.v.) abolished the pressor response to drug. Besides, acetylcholine (1 μmol; i.c.v.) produced similar increases in blood pressure in normal and hypotensive conditions to that observed in CDP-choline given rats. CDP-choline (250 mg/kg; i.v.) increased plasma catecholamines and vasopressin levels but not plasma renin activity. Pretreatment of rats with either prazosin (0.5 mg/kg; i.v.) or vasopressin V₁ receptor antagonist, [β-mercapto,β,β-cyclopentamethylenepropionyl¹,O-Me-Tyr²-Arg⁸]vasopressin (10 μg/kg; i.v.), attenuated the pressor response to CDP-choline while simultaneous administration of these antagonists before CDP-choline injection completely blocked the pressor effect. Results show that i.v. CDP-choline increases blood pressure and reverses hypotension in haemorrhagic shock. Activation of central nicotinic cholinergic mechanisms by the increases in plasma and brain choline concentrations appears to be involved in the pressor effect of this drug. Moreover, the increases in plasma catecholamines and vasopressin levels mediate these effects.     

Increased dopamine receptor sensitivity in the rat following acute administration of sufentanil,U50,488H and d-Ala2-d-Leu5-enkephalin

Summary The effects of acutely administered opioid receptor agonists sufentanil, U50,488H and [d-Ala², d-Leu⁵]-enkephalin (DADL) were observed upon dopamine D₁ and D₂ binding site density in the striatum of the rat. In addition, the functional implications of opioid-induced changes in dopamine receptor sensitivity were studied using the behavioural profile elicited by apomorphine in the rat. The -agonist sufentanil (1 or 20 Erg/kg, i. p.), the -agonist U50,488H (10 mg/kg, i. p.) and DADL (1 g/animal, i. c. v.) all significantly elevated D₂ but not D₁ binding site density in rat striatum. Pretreatment with sufentanil (1 g/kg, i. p.) induced an elevation in apomorphine-induced sterotyped behaviour, but attenuated locomotor activity. Following administration of U50,488H (10 mg/kg, i. p.), both the degree of stereotypy and the intensity of the locomotor activity were enhanced. Contralateral rotation was observed in animals pretreated with DADL (1 g/animal, i. c. v.) following challenge with apomorphine. It is concluded that the opioid agonists studied induce a significant elevation in functional D₂ sites to the exclusion of D₁ sites. However, the precise mechanism by which this effect is elicited remains to be established. Send offprint requests to R. D. E. Sewell at the above address     

The dopamine receptors mediating inhibition of the sympathetic vasopressor outflow in pithed rats: pharmacological correlation with the D(2) -like type

This study investigated in pithed rats whether dopamine can inhibit the sympathetic vasopressor outflow and analysed the pharmacological profile of the receptors involved. Male Wistar pithed rats were pre-treated with intravenous (i.v.) bolus injections of gallamine (25 mg/kg) and desipramine (50 μg/kg). The vasopressor responses to electrical stimulation of the sympathetic vasopressor outflow (0.03-3 Hz; 50 V and 2 msec.) were analysed before and during i.v. continuous infusions of the agonists dopamine (endogenous ligand), SKF-38393 (D(1) -like) or quinpirole (D(2) -like). If inhibition was produced by any agonist, then its capability to inhibit the vasopressor responses to i.v. bolus injections of exogenous noradrenaline (0.03-3 μg/kg) was also investigated. Dopamine (3-100 μg/kg min.) inhibited the vasopressor responses to both electrical stimulation and noradrenaline. In contrast, SKF-38393 (10-100 μg/kg min.) failed to inhibit the vasopressor responses to electrical stimulation; whereas quinpirole (0.1-30 μg/kg min.) inhibited the vasopressor responses to electrical stimulation but not those to noradrenaline. The sympatho-inhibition by quinpirole (1 μg/kg min.) remained unaltered after i.v. SCH 23390 (300 and 1000 μg/kg; D(1) -like receptor antagonist), but was abolished after i.v. raclopride (1000 μg/kg; D(2) -like receptor antagonist). These doses of antagonists did not modify per se the sympathetically-induced vasopressor responses. In conclusion, quinpirole-induced inhibition of the sympathetic vasopressor outflow is primarily mediated by activation of dopamine D(2) -like receptors.     

Antagonism of the renal vasodilator activity of dopamine by metoclopramide

Summary The interaction of metoclopramide with renal dopamine receptors has been characterized in anesthetized dogs surgically prepared with arterial blood pressure catheters and renal artery blood flowprobes.In normal dogs, i. v. dopamine (3 g/kg) produced consistent and selective decrements in renal vascular resistance (RVR) and increments in renal blood flow over a 220 min test period; mean arterial blood pressure and cardiac rate were minimally affected. Pretreatment with metoclopramide, 1 and 10 mg/kg i. v., resulted in dose-related inhibition (maximum inhibition 44% and 94%, respectively) of the renal vasodilator activity of dopamine without altering baseline parameters. The duration of antagonism produced by 1 mg/kg of metoclopramide was approximately 30 min, while 10 mg/kg resulted in significant attenuation for the entire test period. Decreases in RVR produced by prostaglandin A₁ (0.03 and 0.3 g/kg, i. v.) and bradykinin (3 and 15 g/kg, i. v.) that were comparable to those of dopamine were unaltered by metoclopramide. Furthermore, metoclopramide did not affect the diastolic blood pressure responses to noradrenaline (0.1–3 g/kg, i. v.) or isoproterenol (0.03–0.3 g/kg, i. v.), nor did it alter dopamine-induced vasoconstriction of the iliac vasculature.In phenoxybenzamine (3 mg/kg, i. v.) treated dogs, dopamine (0.3–30 g/kg, i. v.) produced dose-related reductions in RVR. Administration of metoclopramide (10 mg/kg, i. v.) resulted in a 10-fold parallel displacement, to the right, of the RVR dose-response curve to dopamine.These findings demonstrate that metoclopramide is an effective antagonist of renal dopamine receptors following systemic administration in the dog. The results are not consistent with the classification of metoclopramide as a selective antagonist of D-2 receptors.     

Evidence that the enhancement of dopamine function by repeated electroconvulsive shock requires concomitant activation of D1-like and D2-like dopamine receptors

In this study, the behavioural response to dopamine D₁-like receptor agonists (SKF 38393, SKF 81297 and SKF 77434) and D₂-like receptor agonists (quinpirole and RU 24213), administered alone and in combination to rats treated repeatedly with electroconvulsive shock (five ECS over 10 days) or sham, was tested. Agonist-induced behaviour was monitored by automated activity meters and direct observation using a checklist scoring method. Repeated ECS (compared to sham controls) had no significant effect on the behavioural response to SKF 38393 (7.5 mg/kg SC), SKF 81297 (0.2 mg/kg SC), SKF 77434 (0.1 mg/kg SC), quinpirole (0.1 and 0.25 mg/kg SC) or RU 24213 (0.3 mg/kg SC), when administered alone. In contrast, repeated ECS markedly increased locomotion (activity counts and scores) induced by the non-selective dopamine agonist apomorphine (0.5 mg/kg SC) and by co-administration of a D₁-like agonist plus a D₂-like agonist [SKF 38393 (7.5 mg/kg SC) plus quinpirole (0.25 mg/kg SC), SKF 81297 (0.2 mg/kg SC) plus quinpirole (0.1 mg/kg SC), and SKF 77434 (0.1 mg/ kg SC) plus RU 24213 (0.3 mg/kg SC)]. This ECS-induced enhancement of dopamine-mediated behaviour was observed for up to 3 weeks after cessation of ECS treatment. In addition, ECS also enhanced the locomotor response to intra-accumbens SKF 38393 plus quinpirole (0.4 and 1.0 μg/side, respectively). These results provide evidence that the enhancement of dopamine function by repeated ECS requires concomitant stimulation of both D₁-like and D₂-like receptors, and that this effect is long-lasting. Received: 24 January 1997 /Final version: 5 March 1997     

U-46619-induced Ischaemic Electrocardiographic Changes in Rats: Preventive Effects of Prostacyclin and Nitroglycerin

Abstract— The anti-anginal effect of nitroglycerin and prostacyclin was examined using, as an index, the ischaemic electrocardiogram (ECG) change (ST elevation) induced by intracoronary arterial injection of 9,11-dideoxy-11α,9α-epoxymethano-PGF_2α (U-46619), a stable thromboxane A₂ agonist, in anaesthetized rats. The ST elevation induced by U-46619 (5–20 μg kg^?1, i.c.a.) was dose-dependent and reproducible. U-46619-induced ST elevation was markedly prevented by the pretreatment of intravenous administration of prostacyclin (0·01 μg kg^?1), and to a lesser extent by nitroglycerin (0·3 mg kg^?1). Simultaneously, platelet count decreased significantly in the coronary arterial blood which indicated that platelet aggregation was enhanced by U-46619. The decrease of platelet count in coronary arterial blood at the time of ST elevation was significantly suppressed by prostacyclin (0·1 μg kg^?1, i.v.), but not by nitroglycerin (0·3 mg kg^?1, i.v.). These results suggest that the ST elevation induced by intracoronary arterial injection of U-46619 may be derived from spasm of coronary artery and platelet aggregation in the intracoronary artery in rats.     

Ritanserin potentiates the stimulatory effects of raclopride on neuronal activity and dopamine release selectively in the mesolimbic dopaminergic system

The atypical profile of clozapine and some other new atypical antipsychotic drugs has been attributed to a relatively selective effect on the mesolimbic dopaminergic system, as well as to their potent serotonin 5-HT₂ receptor antagonism and high ratio of 5-HT₂ to dopamine D₂ receptor affinities. It is unclear, however, how concurrent 5-HT₂ and D₂ receptor antagonism specifically affects the mesoaccumbens and the mesocortical dopaminergic systems.The present study examined the effect of pretreatment with the 5-HT₂ receptor antagonist, ritanserin, on changes in midbrain dopamine neuronal activity as well as in forebrain, extracellular concentrations of dopamine, induced by relatively low doses of the D₂ receptor antagonist raclopride, utilizing in vivo extracellular single cell recording techniques and voltammetry in anesthetized rats, as well as microdialysis in freely moving rats. Raclopride alone (10–2560 g/kg, i.v.) induced a dose-dependent increase in three parameters of neuronal activity, i.e. burst firing, firing rate and variation coefficient, of midbrain DA neurons. This effect of raclopride was more pronounced in cells of the ventral tegmental area than in cells of the substantia nigra-zona compacta. Ritanserin alone (1.0 mg/kg, i.v.) also increased all three parameters of neuronal activity in dopamine cells of the ventral tegmental area, but only firing rate in the cells of the substantia nigra. Ritanserin pretreatment (30 min) significantly enhanced the stimulatory effects of low doses of raclopride (10–20 g/kg) on burst firing in dopamine neurons, preferentially in the ventral tegmental area. Raclopride alone (50 g/kg, s.c.) increased extracellular concentrations of dopamine in the medial prefrontal cortex and the dorsolateral striatum by 75 and 110%, respectively, as measured by microdialysis. Ritanserin alone (1.5 mg/kg, s.c.) did not significantly affect cortical and striatal extracellular dopamine concentrations; however, pretreatment (40 min) with ritanserin elevated the raclopride-induced increase of dopamine concentrations in the medial prefrontal cortex to about 250%, but failed to affect the action of raclopride on striatal dopamine levels. Raclopride alone (10 and 320 g/kg, i.v.) dose-dependently increased extracellular concentrations of dopamine in the nucleus accumbens and the dorsolateral striatum to about 500%, as determined by voltammetry. Ritanserin alone (1.0 mg/kg, i.v.) did not significantly affect the voltammetric dopamine signal in the nucleus accumbens or the dorsolateral striatum; however, ritanserin pretreatment (30 min) enhanced the raclopride-induced increase in accumbal but not striatal dopamine concentrations to about 1600%. The stimulatory effect of the combined ritanserin plus raclopride treatment on neuronal activity and DA release was more pronounced in the mesolimbic than the nigrostriatal dopaminergic system.The present data indicate that concurrent 5-HT₂ and D₂ receptor antagonism selectively affects the activity of the mesolimbic dopaminergic system. These findings provide an experimental basis for the notion that combined 5-HT₂ and D₂ receptor antagonism may underlie the limbic mode of action of at least some atypical antipsychotic drugs and consequently contribute to their unique therapeutic effects.     

Dopamine D<Subscript>3</Subscript> receptor antagonists improve the learning performance in memory-impaired rats

Rationale The dopamine D₃ receptor has been extensively studied in animal models of drug abuse and psychosis; however, less is known on its possible role in cognitive functions.Objectives This study investigated the effects of different D₃ antagonists and a partial agonist on spatial learning performance in a water labyrinth test.Methods Rats had to swim through a labyrinth system by making correct directional turns at three choice-points. The number of errors was recorded in three daily trials for 3 days.Results D₃ antagonists such as the highly selective SB-277011 (24 mg/kg p.o.) and RGH-1756 (1 mg/kg p.o.), the moderately selective U-99194A (12 mg/kg s.c.) and the selective partial D₃ agonist BP-897 (1 mg/kg i.p.) all significantly attenuated the learning deficit caused by FG-7142. Against scopolamine-induced amnesia, SB-277011 (24 mg/kg p.o.) was equally potent in showing protective efficacy; however, two times higher dose levels of U-99194A (24 mg/kg s.c.) and RGH-1756 (2 mg/kg p.o.) were required to attenuate the scopolamine-induced impairment. In contrast to the full antagonists, against scopolamine-induced amnesia, the partial agonist BP-897 (2 mg/kg i.p.) was inactive, even at the two times higher dose level.Conclusions These data suggest that dopamine D₃ receptor antagonists possess cognition-enhancing activity which may be of benefit in the treatment of cognitive dysfunction associated with several psychiatric disorders.     

An α-adrenoceptor-mediated mechanism of hypoactivity induced by β-amyrin palmitate

Abstract— Inhibitory effects of β-amyrin palmitate in locomotor activity of mice were studied by combining this compound with α-adrenergic agonists or antagonists and a dopaminergic agonist. β-Amyrin palmitate (2·5, 5·0 and 10·0 mg kg^?1, i.p.) decreased locomotor activity of mice in a dose-dependent manner. It enhanced hypoactivity of mice treated with clonidine (0·025 mg kg^?1, i.p.) and antagonized hyperactivity produced by phenylephrine (40 μg, i.c.v.). The inhibitory action of β-amyrin palmitate was not affected by yohimbine (1·5 mg kg^?1, i.p.), but was potentiated by prazosin (0·75 mg kg^?1, i.p.). When combined with a dopaminergic agonist, apomorphine (2·0 mg kg^?1, i.p.), β-amyrin palmitate (5·0 and 10·0 mg kg^?1, i.p.) did not affect locomotor stimulation produced by apomorphine. These results suggest that β-amyrin palmitate might inhibit α₁-adrenoceptors.     

Dynorphin A(1-13) preferentially inhibits behaviors induced by the D2 dopamine agonist RU 24213 but not by the D1 dopamine agonist SK&F 38393.

The effects of dynorphin A(1-13) on the D1 dopamine agonist SK&F 38393- and the D2 dopamine agonist RU 24213-induced behavioral alterations in the mouse were determined by using multidimensional behavioral analyses based upon a capacitance system. Although dynorphin A(1-13) (3.0 or 12.5 micrograms) alone did not produce any significant effects on behaviors, the peptide (12.5 micrograms) caused an inhibitory effect on the RU 24213 (3.0 mg/kg)-induced increase in behavioral patterns such as linear locomotion and circling except rearing and grooming behaviors. The antagonistic effects of dynorphin A(1-313) (12.5 micrograms) were fully reversed by the opioid antagonist M(r) 2266 (10.0 mg/kg). However, dynorphin A(1-13) (3.0 or 12.5 micrograms) failed to affect behaviors elicited by SK&F 38393 (10.0 mg/kg). These results suggest that dynorphin A(1-13) plays an inhibitory role in behaviors induced by the D2 dopamine agonist but not by the D1 dopamine agonist, possibly through the mediation of kappa-opioid receptors.     

Characterization of the dopamine D3 receptor agonist R(+)‐7‐hydroxy‐N,N‐di‐n‐propyl‐2‐aminotetralin‐induced hypo‐ and hypermotility in mice

The present study was designed to characterize the dopamine D₃ receptor agonist R(+)‐7‐hydroxy‐N,N‐di‐n‐propyl‐2‐aminotetralin (R(+)‐7‐OH‐DPAT)‐induced changes in locomotor activity in mice. Although R(+)‐7‐OH‐DPAT (0·01–10 mg/kg) produced a significant decrease in horizontal and vertical motility within 15 min after the start of behavioural measurements, the dopamine D₁ receptor antagonist R(+)‐SCH23390 (0·05 mg/kg) and the dopamine D₃ receptor antagonist (+)‐UH232 (10 mg/kg) had no antagonistic effects on the R(+)‐7‐OH‐DPAT (3 mg/kg)‐induced hypomotility, while the dopamine D₂ receptor antagonist S(−)‐sulpiride (20 mg/kg) augmented it. Although R(+)‐7‐OH‐DPAT (0·01–1 mg/kg) had no marked effects on horizontal or vertical motility, higher doses (3 and 10 mg/kg) of the drug produced a significant increase in horizontal or vertical motility from 30 to 90 min after the start of the behavioural measurements. S(−)‐sulpiride (20 mg/kg) and (+)‐UH232 (10 mg/kg) almost completely inhibited the R(+)‐7‐OH‐DPAT (3 mg/kg)‐induced hypermotility, whereas the antagonistic effects of R(+)‐SCH23390 (0·05 mg/kg) were partial. These results suggest that the R(+)‐7‐OH‐DPAT‐induced hypermotility is mediated principally via dopamine D₂ and D₃ receptors, whereas it is unlikely that the hypomotility results from the activation of presynaptic dopamine D₂ or D₃ receptors. Copyright © 1999 John Wiley & Sons, Ltd.     

PRESYNAPTIC DOPAMINE RECEPTORS MEDIATE THE INHIBITORY ACTION OF DOPAMINE AGONISTS ON STIMULATION-EVOKED PRESSOR RESPONSES IN THE RAT

1 The effects of the dopamine agonists TL-99, M-7 (N, N-dimethyl analogues of aminotetralins) and N, N-din propyldopamine (NNPD) on stimulation-evoked pressor responses and tachycardia in pithed Sprague-Dawley rats were investigated when pressor responses to the compounds per se had subsided. Various antagonists were used to characterise the effects of the dopamine agonists. 2 M-7 (3 μg/kg i.v.) and NNPD (1 mg/kg i.v.), but not TL-99 (1–30 μg/kg i.v.), inhibited pressor responses evoked by low frequency electrical stimulation of the spinal cord in the pithed rat. 3 M-7 (3 μg/kg i.v.), but neither NNPD (1 mg/kg i.v.) nor TL-99 (1–30 μg/kg), inhibited tachycardia evoked by low frequency electrical stimulation of the spinal cord in the pithed rat. 4 The inhibition of stimulation-evoked pressor responses by M-7 and NNPD was prevented by pimozide, metoclopramide and sulpiride but not by yohimbine, atropine, cimetidine or propranolol. 5 The inhibition of stimulation-evoked tachycardia by M-7 was prevented by yohimbine (and to a certain extent by sulpiride) but not pimozide, metoclopramide, atropine or cimetidine. 6 Pressor responses elicited by TL-99, M-7 and NNPD were selectively antagonised by yohimbine, but not by prazosin, indicating that these responses were mediated by stimulation of vascular postsynaptic α₂-adrenoreceptors. 7 This study demonstrates that, in the rat, presynaptic dopamine receptors exist on sympathetic pre- or postganglionic nerve endings to blood vessels, but not on sympathetic pre- or postganglionic nerve endings to the heart, where inhibition by M-7 of stimulation-evoked tachycardia is mediated by stimulation of presynaptic α₂-adrenoreceptors.     

THE LACK OF β-ADRENOCEPTOR INVOLVEMENT IN THE CARDIAC ACTION OF Δ1-TETRAHYDROCANNABINOL IN RATS

1. Rat isolated hearts perfused with Δ¹-THC (0·5 μ/ml) showed a reduction in the rate of beating which was not altered by pretreatment with propranolol (2 μg/ml), atropine (4 μg/ml) or hexamethonium (4 μ/ml). 2. Propranolol (2 μg/ml) also caused a decrease in the rate of beating, which was not affected by pretreatment with Δ¹-THC (0·5 μg/ml). 3. In pithed rats, propranolol (2 mg/kg, i.v.) caused a decrease in the pulse rate, which was not altered by prior administration of Δ¹-THC (1 mg/kg, i.v.). 4. In both preparations, the responses to isoprenaline were markedly reduced or abolished by propranolol, but they were unaffected by Δ¹-THC. 5. It is concluded that the hypotensive and cardiac slowing actions of Δ¹-THC are not mediated by activation of parasympathetic nerves or by β-adrenoceptor blockade.