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B S Starr

Publications and source records attributed to B S Starr.

29 records · Page 2Linked to original sources
PubMed1990

Opposite effects of stimulation of D1 and D2 dopamine receptors on the expression of motor seizures in mouse and rat.

The ability of drugs, selective for dopamine D1 and D2 receptors, to influence the production of motor seizures was studied in mice and rats. Mice, which had been injected with reserpine (5 mg/kg) to deplete stores of monoamines in brain, could be made to convulse 24 hr later by injecting the D1 agonists, SKF 38393 (15-30 mg/kg) and CY 208-243 (0.3-3 mg/kg). The D2 agonists, lisuride (0.5-5 mg/kg) and RU 24213 (0.5-15 mg/kg) and the mixed D1/D2 agonist, apomorphine (0.05-0.5 mg/kg), had no effect on the seizure thresholds by themselves. However, the proconvulsant action of SKF 38393, 15 mg/kg, was prevented by the simultaneous injection of lisuride (5 mg/kg), RU 24213 (5 mg/kg) or apomorphine (0.5 mg/kg) and also by the selective D1 blocking drug, SCH 23390 (0.1 mg/kg). Rats were made to convulse by injecting the cholinergic agonist, pilocarpine (200-600 mg/kg) coupled with methyl scopolamine (1 mg/kg), to prevent peripheral autonomic effects. The smallest dose of pilocarpine (200 mg/kg) was subconvulsant, whereas the larger ones (400 and 600 mg/kg) dose-dependently induced tonic convulsions. The drug SKF 38393 (30 mg/kg) was found to be proconvulsant and caused seizures to develop in 100% of animals, at all dose levels of pilocarpine. This effect was blocked by SCH 23390 (0.25 mg/kg) which, by itself, reduced the severity and increased the latency of pilocarpine-induced convulsions, but not their frequency. The D2 agonist LY 171555 (0.5 mg/kg) was also anticonvulsant in this model and was antagonised by the D2 blocking drug metoclopramide (1.25 mg/kg), which was ineffective alone.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1990

Seizure promotion and protection by D-1 and D-2 dopaminergic drugs in the mouse.

Mice injected with pilocarpine (100-400 mg/kg plus 1 mg/kg methylscopolamine), picrotoxin (0.75-6 mg/kg) or strychnine (0.75-6 mg/kg) exhibited clonic or clonic/tonic convulsions. Pretreatment with the D-1 agonist CY 208-243 (0.375-1.5 mg/kg) dose-dependently potentiated the convulsions elicited by 100 mg/kg pilocarpine, but had neither a convulsant nor anticonvulsant effect in mice receiving picrotoxin (3 or 6 mg/kg) or strychnine (0.75 or 1.5 mg/kg). This facilitatory effect of CY 208-243 was abolished by the D-1 antagonist SCH 23390 (0.2 mg/kg). SCH 23390 by itself (0.05-0.8 mg/kg) dose-dependently protected mice against pilocarpine (400 mg/kg) seizures. Stimulating D-2 receptors with LY 171555 (0.167-4.5 mg/kg) dose-dependently protected mice against seizure activity induced by pilocarpine, but neither protected nor sensitised mice given picrotoxin or strychnine. The neuroleptics haloperidol (1-4 mg/kg), sulpiride (10-50 mg/kg), metoclopramide (1.25-6.25 mg/kg), thioridazine (0.5-2 mg/kg) and clozapine (0.5-2 mg/kg) had no effect on the seizure threshold to 100 mg/kg pilocarpine by themselves, although 10 mg/kg thioridazine and clozapine caused 100% convulsions, possibly through a toxic action. When administered in conjunction with a minimally effective quantity of CY 208-243 (0.375 mg/kg), however, all five neuroleptics interacted synergistically with the D-1 agonist to promote convulsions to pilocarpine (100 mg/kg). No such interaction occurred between submaximally protective doses of the D-1 blocker SCH 23390 (0.05 and 0.2 mg/kg) and a wide range of doses of the D-2 stimulant LY 171555 (0.167-4.5 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Differential behavioural interactions between the dopamine D-1 antagonist SCH 23390 and the dopamine D-2 antagonists metoclopramide and sulpiride in nonhabituated mice.

This study investigated the effects of the selective D-1 antagonist SCH 23390, when administered alone and in combination with a typical (metoclopramide) or atypical neuroleptic (sulpiride), on species-typical behaviours in nonhabituated mice. When tested singly, all three compounds caused a progressive dose-dependent inhibition of locomotion, rearing and grooming, though their potencies varied widely. Mixtures of a threshold dose of 0.01 mg/kg SCH 23390 and metoclopramide (0.05-1.25 mg/kg) interacted synergistically to promote hypomotility and to decrease rearing, but did not affect grooming. By contrast, combinations of 0.01 mg/kg SCH 23390 and sulpiride (2-10 mg/kg) resulted in a marked potentiation of grooming, but only additive reductions in horizontal and vertical movements, consistent with sulpiride and metoclopramide occluding different populations of D-2 receptors. The results show that blockade of D-1 receptors and certain populations of D-2 receptors can interact positively to modify animal motor behaviour, and add a fresh perspective to the concept that these two types of dopamine receptor normally work interdependently to control movements of the body.

Animals↗
PubMed1990

Motor depression: a new role for D1 receptors?

The aims of this study were two-fold. Firstly, to characterize the behavioral properties of a potential new dopamine D1 receptor agonist, (-)-4,6,6a,7,8,12b-hexahydro-7-methyl-indolo[4,3-ab]phenanth ridine (CY 208-243), to determine its suitability as a tool for investigating D1 receptor function in vivo. Secondly, to investigate how the behavioural properties of D1 agonists are modified in the presence of D2 receptor blocking drugs. For this purpose, using mice, we employed CY 208-243 and 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine hydrochloride (SKF 38393) as reference D1 agonists, and the substituted benzamides metoclopramide and sulpiride as selective D2 antagonists. CY 208-243 (0.25-10 mg/kg) caused only a modest increase in grooming in non-habituated mice, but stimulated locomotion, rearing, grooming and orofacial activities in habituated animals. These responses were inhibited by a D1 antagonist, but not by D2 antagonists, suggesting CY 208-243 behaves as a selective agonist of D1 receptors in vivo. In non-habituated mice, doses of metoclopramide and sulpiride which had little or no effect on motor behaviour by themselves, interacted synergistically with CY 208-243 (4 mg/kg) and SKF 38393 (30 mg/kg) to cause extended periods of immobility. Other species-typical behaviours were not affected in this way. For example, grooming was decreased by metoclopramide and increased by sulpiride, indicating that an increase in behavioural competition from this parameter was not the cause of the hypokinesia. To explain the apparent ability of D1 receptor stimulation to increase exploratory activity in earlier experiments and to decrease it here, it is proposed that this behaviour is regulated by D1 receptors coupled to two functionally opposite postsynaptic D2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1989

Circling evoked by intranigral SKF 38393: a GABA-mediated D-1 response?

Intranigral injection of microgram doses of the dopamine D-1 receptor agonist SKF 38393, in rats acutely anaesthetised with halothane, did not overtly alter the animals' behaviour. The adenylate cyclase activator forskolin, the GABA uptake inhibitor nipecotic acid and the GABA potentiator pentobarbital, were similarly ineffective when administered singly to one substantia nigra pars reticulata. However, all three treatments interacted synergistically with coinjected SKF 38393 to promote active circling. It is suggested this SKF 38393-induced behavioural response is mediated by GABA released from D-1 receptor-bearing striatonigral neurones.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1989

Behavioural synergism between the dopamine agonists SKF 38393 and LY 171555 in dopamine-depleted mice: antagonism by sulpiride reveals only stimulant postsynaptic D-2 receptors.

The behavioural effects of the D-1 agonist SKF 38393 (0.56-45 mg/kg) and the D-2 agonist LY 171555 (0.05-6.25 mg/kg) were studied in mice rendered akinetic with a combination of reserpine and alpha-methyl-p-tyrosine (alpha-MPT). Under these conditions both agonists were behaviourally ineffective by themselves, but interacted synergistically to restore locomotor and orofacial movements. High levels of D-1 stimulation did not promote stereotypies at the expense of locomotion in dual reserpine- and alpha-MPT-treated mice, suggesting that the concomitant stimulation of D-1 receptors is essential both for the genesis and subsequent development of all components of D-2 behaviours. The motor stimulant effects of LY 171555 (0.05-1.25 mg/kg), administered in conjunction with a near-maximal dose of SKF 38393 (15 mg/kg), were dose-dependently inhibited by sulpiride at all doses tested (1, 10 and 50 mg/kg). The augmentation of D-2 behaviours by low doses of sulpiride, noted in an earlier study, was not observed here. Results with this particular combination of drugs therefore do not support the concept of mixed excitatory and inhibitory postsynaptic D-2 receptors. The results are discussed in terms of different D-2 agonists interacting with discrete subpopulations of D-2 receptors at postsynaptic sites.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1987

Behavioural interactions involving D1 and D2 dopamine receptors in non-habituated mice.

The effects of SKF 38393 (D1-agonist) and SCH 23390 (D1-antagonist) were compared with those of haloperidol (D2 greater than D1-antagonist) and metoclopramide (D2-antagonist) in the absence or presence of apomorphine (D1/D2-agonist) and RU 24213 (D2 agonist) in non-habituated mice. The motor behaviour studied which was typical of the species included sniffing, grooming, rearing and locomotion. Apomorphine and RU 24213 induced frozen inactivity, in small doses and head-down sniffing, coupled with ponderous forward walking, in large doses, consistent with the stimulation of D2 receptors at pre- and postsynaptic sites, respectively. Neither SKF 38393 nor metoclopramide modified rearing or locomotion over a wide range of doses. SKF 38393 promoted sniffing and grooming, while metoclopramide suppressed this behaviour. Apart from increased grooming with SCH 23390 in small doses, both this drug and haloperidol dose-dependently decreased all motor activity. In combination studies, the D2 blockers reversed the effects of stimulation of D2 receptors and released normal behaviour, whereas SCH 23390 converted both the behavioural syndromes mediated by pre- and postsynaptic D2-receptors into severe inactivity (but not catalepsy). The drug SKF 38393 had the opposite effect and promoted motor responding in the presence of D2 stimulation, in doses that were otherwise ineffective by themselves. In this model, SCH 23390 modified behaviour mediated by D2-receptors in a different manner to the D2-receptor antagonists, haloperidol and metoclopramide, suggesting it may interact with a different population of D2-receptors, or with D1-receptors. These and earlier data can be interpreted to mean that both subclasses of the dopamine receptor have distinct and probably interdependent roles in the management of motor behaviour.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1987

Behavioural role of dopamine D1 receptors in the reserpine-treated mouse.

The effects of 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine (SKF 38393) (D1 agonist) on the motor behaviour of mice rendered hypokinetic with reserpine, were studied in the absence and presence of additional treatment with N-n-propyl-N-phenylethyl-p(3-hydroxyphenyl)ethylamine hydrochloride (RU 24213), lisuride (D2 agonists) or apomorphine (mixed D1/D2 agonist). Three hours after reserpine (5 mg/kg) stimulating dopamine D2 receptors evoked slow, ponderous walking and head-down sniffing. SKF 38393 (1.5-15 mg/kg) had no direct effect of its own, but greatly amplified the D2 response, giving more fluent locomotion, rearing and grooming. The facilitatory action of SKF 38393 was inhibited by the D1 antagonist (R)-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin l -7-ol (SCH 23390) (0.05 mg/kg), whereas D2-mediated responses were sensitive both to SCH 23390 and the D2 antagonist metoclopramide (0.5 mg/kg). Mice treated with reserpine for 24 h became more sensitive to the motor stimulant actions of all four agonists. SKF 38393 now promoted rapid locomotion, rearing and grooming directly. The effects of D2 stimulation were weak by comparison and often antagonistic (not synergistic) with those of the D1 agonist. Both sets of agonists were now attenuated only by their respective antagonists. Reserpine caused pronounced falls in the concentrations of dopamine, 5-hydroxytryptamine and noradrenaline in the striatum, olfactory tubercle and cerebral cortex, with correspondingly elevated metabolite levels. These results indicate that D1 and D2 agonists at doses that are relatively ineffective at stimulating behaviour when given in isolation 3 h after reserpine, interact when given together to partially restore locomotion, rearing and grooming. This interaction is not apparent 24 h post-reserpine, a time at which D1 and D2 agonists produce significant effects of their own.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1986

Differential effects of dopamine D1 and D2 agonists and antagonists on velocity of movement, rearing and grooming in the mouse. Implications for the roles of D1 and D2 receptors.

A system combining visual recording of rearing and grooming, with automatic measurement of slow and fast components of locomotion, was examined for its suitability as a means of studying the effects on behaviour of conventional and novel dopaminergic drugs in the mouse. Amphetamine (0.1-10 mg/kg) selectively stimulated fast movements and affected rearing bimodally. Apomorphine (0.01-5 mg/kg) influenced locomotion polyphasically, depressing fast movements and enhancing slow ones, and producing parallel changes in rearing. Both drugs reduced grooming monotonically. A dose of apomorphine (25 micrograms/kg) which is considered to act presynaptically produced haloperidol-resistant sedation, while a larger dose (0.5 mg/kg; with postsynaptic actions) evoked head-down sniffing and ponderous walking that were partially prevented by pretreatment with 0.05 mg/kg haloperidol (D2 blocker), but not 0.01 mg/kg SCH 23390 (D1 blocker). The behavioural effects of haloperidol (0.2-0.4 mg/kg) and SCH 23390 (0.05 mg/kg) were indistinguishable; both drugs caused sedation and inhibited all forms of motor activity. Small doses of SCH 23390 (2-10 micrograms/kg) and large doses of the D1 agonist SKF 38393 (3-10 mg/kg) evoked excessive grooming. The drug SKF 38393 (1-30 mg/kg) had no other effects on motor behaviour, whereas the whole spectrum of pre- and postsynaptic motor responses produced by apomorphine could be duplicated with the D2 agonist RU 24213 (0.05-15 mg/kg). The differential sensitivity of fast and slow components of locomotion to treatment with drug suggests these are qualitatively distinct responses. The results implicate D2 receptors in the mechanisms of locomotion and rearing, and D1 receptors in the expression of grooming.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1986

Grooming in the mouse is stimulated by the dopamine D1 agonist SKF 38393 and by low doses of the D1 antagonist SCH 23390, but is inhibited by dopamine D2 agonists, D2 antagonists and high doses of SCH 23390.

The effects of manipulating dopamine D1 and D2 receptors on grooming was studied in the mouse. SKF 38393 (D1 agonist) and low doses of SCH 23390 (D1 antagonist) promoted grooming activity. SCH 23390 in neuroleptic doses, RU 24213 (D2 agonist), apomorphine and amphetamine (mixed D1/D2 agonists) and haloperidol (D2 antagonist) all suppressed the tendency of normal mice to groom, though probably by different mechanisms. Duration and frequency of grooming could be influenced differentially by these drugs. The findings suggest opposing roles for dopamine D1 and D2 receptors in the expression of grooming in the mouse.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗