Biomedical subjects

M S Starr

Publications and source records attributed to M S Starr.

At least 55 records · Page 3Linked to original sources

PubMed1993

Glutamate-dopamine interactions in the production of pilocarpine motor seizures in the mouse.

An assortment of glutamate antagonists with differing selectivities for NMDA and AMPA-type glutamate receptors, were tested for their effects in the mouse pilocarpine model of complex partial seizures. MK 801 (0.1-0.8 mg/kg) and high doses of HA 966 (50 mg/kg) were proconvulsant, whilst CGP 40116 (1-8 mg/kg) and low doses of HA 966 (0.4-10 mg/kg) inhibited pilocarpine-induced convulsions. CPP (5-20 mg/kg) and NBQX (1-50 mg/kg) were without effect. The dopamine D1 agonist SKF 38393 (10 mg/kg) facilitated the convulsant effects of low-dose pilocarpine (100 mg/kg). MK 801 (0.1-0.2 mg/kg) and HA 966 (50 mg/kg) interacted synergistically with SKF 38393 to promote the proconvulsant effects of D1 stimulation, whilst CPP (10-20 mg/kg) and HA 966 (10 mg/kg) had the opposite effect. CGP 40116 and NBQX were without effect. These results show that the convulsant qualities of MK 801 and SKF 38393, that have been detected in animal models of Parkinson's disease, can be reproduced in the pilocarpine model of epilepsy. Whilst the glutamate antagonists all interact synergistically with SKF 38393 to improve its antiparkinson activity, only MK 801 and high doses of HA 966 similarly potentiate the convulsions associated with D1 stimulation. An appropriate mixture of a glutamate antagonist and a D1 agonist could theoretically be used beneficially in the treatment of Parkinson's disease, without causing epilepsy as a side effect.

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

PubMed1993

Paradoxical facilitation of pilocarpine-induced seizures in the mouse by MK-801 and the nitric oxide synthesis inhibitor L-NAME.

The sensitivity of pilocarpine-induced seizures to NMDA receptor blockade with MK-801, or to inhibition of synthesis of the second messenger nitric oxide (NO) with N omega-nitro-L-arginine methyl ester (L-NAME), was studied in mice. The NO precursor L-arginine (100-500 mg/kg, IP) and L-NAME (1-125 mg/kg, IP) had no overt effects on animals' behaviour by themselves, while MK-801 (0.1-0.8 mg/kg, IP) caused motor excitability at low doses and sedation and paraplegia at high ones. Contrary to expectation, MK-801 and L-NAME failed to protect mice against limbic motor seizures induced by pilocarpine (400 mg/kg, IP), and L-arginine was not proconvulsant in mice challenged with a threshold convulsant dose of the cholinomimetic (100 mg/kg, IP). Surprisingly, both MK-801 and L-NAME were found to be proconvulsant when injected in conjunction with 100 mg/kg pilocarpine, and in both cases this convulsant action synergised with that produced by the dopamine D1 agonist SK&F38393 (10 mg/kg, IP). Concomitant administration of L-arginine (500 mg/kg) prevented the convulsant effect of 5 mg/kg L-NAME but was ineffective against 25 mg/kg L-NAME and MK-801. It is concluded that glutamate, acting through the NMDA receptor and NO production, normally suppresses epileptogenesis in the mouse pilocarpine model of limbic epilepsy.

Animals↗

PubMed1993

Dopaminergic modulation of pilocarpine-induced motor seizures in the rat: the role of hippocampal D2 receptors.

This study examined the role of hippocampal dopamine D2 receptors in the genesis of limbic seizures induced by muscarinic agonists in the rat. Pilocarpine, 600 mg/kg, elicited rapid and usually fatal convulsions. These were not affected by focal injections of saline (1 microliter) into both hippocampi. Pretreatment of the dorsal, but not the lateral hippocampus, with the D2 agonist trans-(+)-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-2H-pyrazolo-(3,4-g)quinol ine hydrochloride (LY 171555, 2 micrograms per side), did not alter the frequency of pilocarpine-induced convulsions, but significantly delayed their appearance and reduced their intensity. LY 171555 similarly increased the latency of seizures induced by focal hippocampal injection of carbachol (100 micrograms), without changing the frequency or the severity. The selective D2 antagonist raclopride, injected dorsally into both hippocampi dose-dependently facilitated motor seizures evoked by pilocarpine (100 mg/kg), the cholinomimetic at this dose being ineffective as a convulsant in saline-treated animals. Intrahippocampal administration of the D1 agonist 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine hydrochloride (SKF 38393, 2 micrograms per side) did not facilitate pilocarpine seizures and did not potentiate the proconvulsant action of raclopride. These data demonstrate that activation of the dopaminergic system, via D2 receptors in the dorsal hippocampus, is capable of protecting the animal against limbic motor seizures arising from excessive muscarinic stimulation of the hippocampus. Since the blockade of D2 receptors in the hippocampus markedly lowered the seizure threshold to pilocarpine, this would suggest that the dopaminergic input to the hippocampus is normally tonically active and functions physiologically to prevent epileptogenesis.

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

PubMed1992

Dopaminergic modulation of pilocarpine-induced motor seizures in the rat: the role of hippocampal dopamine D1 receptors.

The present study addressed the role of dopamine D1 receptors in pilocarpine-induced motor seizures in rats. Bilateral pretreatment of the hippocampus with the D1 agonist SKF 38393 (0.1-5 micrograms) did not alter the animals' sensitivity to a threshold (200 mg/kg i.p.) or fully convulsant dose (600 mg/kg i.p.) of pilocarpine, as compared to hippocampal saline-treated controls. Similarly, direct injection of pilocarpine (200 micrograms per side) into both hippocampi elicited low level seizure activity that was not modified by SKF 38393, either coadministered (2 micrograms per side) or injected systemically (30 mg/kg i.p.). On the other hand, intrahippocampal microinjections of the D1 antagonist, SCH 23390 (2 micrograms per side), whilst unable to prevent epileptogenesis to 600 mg/kg pilocarpine, delayed the onset of seizures and reduced their severity. These results suggest that hippocampal dopamine lowers the seizure threshold by activating D1 receptors, an effect which is only disclosed by D1 receptor blockade and is not surmountable by additional D1 stimulation.

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

PubMed1992

Motor responses to dopamine D1 and D2 agonists in the reserpine-treated mouse are affected differentially by the NMDA receptor antagonist MK 801.

The akinesia induced by reserpine in mice was effectively reversed by the dopamine D1 receptor agonists SKF 38393 (5-30 mg/kg IP) and CY 208-243 (1-5 mg/kg IP), and by the mixed D1/D2 agonist pergolide (5 mg/kg SC), but less well by the D2 agonists lisuride, PHNO, LY 171555 and RU 24213 (each at 5 mg/kg SC) and not at all by the NMDA receptor antagonist MK 801 (0.1-10 mg/kg IP). MK 801 potentiated D1-dependent locomotion, but always suppressed rearing and grooming. D2-dependent locomotion was inhibited by MK 801. The D2 agonist RU 24213 was antagonised by as little as 6.25 micrograms/kg MK 801, while PHNO and LY 171555 were antagonised by 0.1 mg/kg MK 801. Lisuride was not inhibited by up to 1.6 mg/kg MK 801. Importantly, all animals showed signs of incapacitation with MK 801 in certain elements of their behaviour, most notably ataxia and hind limb abduction. Thus whilst NMDA receptor blockade can facilitate the restoration of movement by dopamine D1 (though not D2) agonists in monoamine-depleted mice, the fluency of the motor response is adversely affected.

Animals↗

PubMed1992

Putative neurotoxicity of SKF 38393 and other D1 dopaminergic drugs investigated in rat striatum.

The recently alleged neurotoxicity of the D1 receptor agonist, SKF 38393, was investigated in rat striatum by measuring the enzymes acetylcholinesterase (AChE) and glutamate decarboxylase (GAD). First, unilateral intrastriatal microinjection of the excitotoxin kainic acid (2 micrograms in 1 microliter) was shown to evoke vigorous contraversive circling, followed 1 or 2 weeks later by profound decreases in striatal AChE (24 and 54%), GAD (51 and 75%), and protein (36 and 47%), as well as loss of GAD (45% at 2 weeks) in the ipsilateral substantia nigra. Similar striatal treatments with SKF 38393 (30 micrograms in 0.5-1 microliter), the related benzazepines SKF 82526 (D1 agonist, 30 micrograms in 1 microliter) and SCH 23390 (D1 antagonist, 5 micrograms in 1 microliter), or the phenanthridine D1 agonist CY 208-243 (5 micrograms in 1 microliter) failed to affect the rats' behaviour or their striatal levels of AChE, GAD, and protein. Intrastriatal SKF 38393 (30 micrograms in 0.5 microliter) also had no influence on these enzymes in the substantia nigra. It is concluded that none of the D1 dopaminergic compounds examined here was neurotoxic toward the many different cell groups that contain AChE and/or GAD in the striatum.

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

PubMed1991

CY 208-243 behaves as a typical D-1 agonist in the reserpine-treated mouse.

The object of this study was to determine if the newly developed phenanthridine derivative, CY 208-243, retains its apparent in vivo preference for dopamine D-1 receptors under conditions of dopamine depletion, as a starting point to understanding why CY 208-243 possesses antiparkinson activity and the selective D-1 agonist SKF 38393 does not. Three hours after receiving reserpine (5 mg/kg), mice were strongly sedated and completely unresponsive to the motor stimulant effects of CY 208-243 (0.1-10 mg/kg) or the selective D-2 agonist RU 24213 (0.5-5 mg/kg) administered alone. After 24 h reserpine, the akinesia was partially and dose-dependent reversed by both CY 208-243 (0.1-10 mg/kg) and RU 24213 (0.5-5 mg/kg) alone. CY 208-243 also stimulated rearing and grooming, while RU 24213 gave rise to strong head-down sniffing. The response to 1 mg/kg CY 208-243 was practically abolished by pretreatment with the D-1 antagonist SCH 23390 (0.2 mg/kg). On the other hand, blocking D-2 receptors with metoclopramide (0.25 mg/kg) unexpectedly facilitated CY 208-243-induced locomotion and rearing, but suppressed grooming. When CY 208-243 (1 mg/kg) was injected together with RU 24213 (0.5-5 mg/kg), the two drugs interacted synergistically to stimulate locomotion at all times after reserpine. These animals also exhibited a greater preponderance of grooming, sniffing, gnawing and oral dyskinesia. Apart from the potentiation of some elements of CY 208-243-stimulated motor behaviour by D-2 blockade, these results are qualitatively indistinguishable from those previously obtained with the prototype D-1 agonist SKF 38393.(ABSTRACT TRUNCATED AT 250 WORDS)

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

PubMed1991

D-2 agonists protect rodents against pilocarpine-induced convulsions by stimulating D-2 receptors in the striatum, but not in the substantia nigra.

This study employed the pilocarpine model of epilepsy to determine the relative systemic anticonvulsant potencies of five different D-2 agonists in the mouse, and to investigate the site of anticonvulsant action of LY 171555 in the rat's brain following intracerebral microinjection. Control mice pretreated with saline developed motor seizures when challenged with pilocarpine (400 mg/kg, 11/13 convulsed). D-2 agonists protected mice against pilocarpine-induced seizures in the rank order of potency PHNO greater than pergolide greater than greater than lisuride = LY 171555 much greater than RU 24213, with ED50 values ranging from 0.17 mg/kg for PHNO to greater than 4.5 mg/kg for RU 24213. The response to LY 171555 was abolished by the D-2 blocker metoclopramide (1.25 mg/kg), but not by the D-1 antagonist SCH 23390 (0.25 mg/kg). All D-2 agonists induced head-down sniffing and forward locomotion, consistent with central D-2 activation. LY 171555 (ED50 0.19 mg/kg), but not RU 24213 (ED50 greater than 4.5 mg/kg), was similarly efficacious in the rat. When injected into both hemispheres of the conscious rat via indwelling cannulae, intrastriatal saline failed to afford protection against the convulsant action of pilocarpine (600 mg/kg, 13/15 convulsed), whereas LY 171555 did (1 microgram, 1/12 convulsed). Intrastriatal RU 24213 (1 microgram per side) was without effect (7/10 convulsed). Similarly, no protection resulted when saline (15/16 convulsed) or LY 171555 (1 microgram, 17/23 convulsed) were delivered into both nigras. It is concluded that in this model of limbic seizures in the mouse and rat, D-2 agonists exert a powerful anticonvulsant effect which is mediated by D-2 receptors in the striatum, but not by D-2 receptors in the substantia nigra.

Animals↗

PubMed1991

Anticonvulsant effect of striatal dopamine D2 receptor stimulation: dependence on cortical circuits?

In the pilocarpine model of epilepsy, dopamine can either inhibit (via D2 receptors) or facilitate (via D1 receptors) the spread of limbic motor seizures. The anticonvulsant action of D2 receptor activation has been localized to the anterior striatum, but disappears if excessive damage is caused to the overlying cerebral cortex. This study examines the possibility that the corticostriatal projection is involved in the anticonvulsant response to striatal D2 receptor stimulation, by comparing the seizure-protecting efficacy of intrastriatal trans-(+)-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-2H-pyrazolo-(3,4-g)quinol ine hydrochloride (LY 171555) in control rats, and in rats bearing discrete bilateral kainic acid lesions of the cerebral cortex. The results show that neurotoxin injection induces a punctate lesion of the primary motor area of the cortex in each hemisphere, with no injury to the underlying caudate-putamen, or to more distant structures such as the hippocampus. The lesion, however, was sufficient to abolish the protective effect of intrastriatal LY 171555 against pilocarpine challenge. To explain these findings, an interplay between nigrostriatal dopaminergic and corticostriatal glutamatergic neurons is proposed, in which the anticonvulsant tendency of the excitatory amino acid is accentuated by dopamine, probably by acting on D2 receptors which facilitate the release of glutamate from axon terminals.

Animals↗

PubMed1990

Anticonvulsant action of SCH 23390 in the striatum of the rat.

This study investigates the role of forebrain D1 receptors in the motor expression of seizures induced by pilocarpine. Conscious rats receiving bilateral intracaudate injections of saline, just failed to convulse to 200 mg/kg pilocarpine, but responded vigorously to 600 mg/kg of the cholinomimetic. LY 171555 significantly protected rats against 600 mg/kg pilocarpine, when delivered into the anterior striatum, as also did SCH 23390, from all rostrocaudal levels of the striatum. Intrastriatal SKF 38393 or CY 208-243 neither facilitated nor ameliorated pilocarpine-induced convulsions. SCH 23390 was also anticonvulsant from the nucleus accumbens, while intra-accumbens CY 208-243 was without effect. It is concluded that SCH 23390 affords protection against pilocarpine-induced limbic motor seizures by blocking the effects of endogenous dopamine released tonically onto D1 receptors in the corpus striatum and nucleus accumbens. The inability of additional D1 receptor stimulation to intensify such seizures, could indicate that forebrain D1 receptors are already maximally stimulated by the endogenous transmitter.

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

PubMed1990

Proconvulsant effect of SKF 38393 mediated by nigral D1 receptors.

This study investigated the hypothesis that the proconvulsant action of systemically applied dopamine D1 receptor stimulants is mediated by D1 receptors in the substantia nigra. Rats were equipped with bilateral stainless steel guide cannulas under halothane anaesthesia, to allow drugs to be injected into both nigras of conscious, unrestrained animals 7-14 days later. Bilateral intranigral administration of saline, together with a subconvulsant dose of pilocarpine (200 mg/kg), produced no convulsions in 14 rats. By contrast, intranigral SKF 38393 (2.5 micrograms) and pilocarpine (200 mg/kg) caused 18/22 rats to convulse. This proconvulsant action of SKF 38393 was completely attenuated by pretreatment with SCH 23390 (0.25 mg/kg). SCH 23390 (1 microgram) delivered into both nigras reduced the number of rats convulsing in response to 600 mg/kg pilocarpine (7/15, one fatally) as compared to saline-injected controls (12/13, eight fatally). These results indicate that dopamine D1 receptors in the substantia nigra (pars reticulata) mediate a proconvulsant action of dopamine, which is opposite to the anticonvulsant effect of the amine at striatal D2 receptors.

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

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↗

PubMed1989

Differential effects of pallidal lesions on the behavioural responses to SKF 38393, LY 171555 and apomorphine in the rat.

The purpose of this study was to determine the role of the globus pallidus in the expression of dopamine D1- and D2-receptor mediated motor events. Rats were first injected stereotaxically with 6-hydroxydopamine in one medial forebrain bundle to denervate the ascending dopamine pathways in that hemisphere. Apomorphine and selective D1 and D2 agonists were then administered, at two dose levels, to establish characteristic response patterns. Subsequently the animals were given a secondary lesion by injecting kainic acid (0.2-1 microgram) into the ipsilateral globus pallidus and retested with the dopamine agonists over a period of two months. The kainate treatment itself caused spontaneous motor asymmetries, followed by aphagia, adipsia and hypersensitivity to touch. Contraversive circling, contralateral posture and grooming induced by systemic apomorphine were all abolished by the kainate treatment, whilst sniffing and head movements were facilitated. All activities induced by D1 stimulation were abolished or severely reduced under these conditions. By contrast, the contralateral posture and grooming elicited by D2 stimulation were spared, and only D2-dependent contraversive rotation, sniffing and head movements were reduced. All behavioural deficits were temporary and recovered partially or completely during the course of the experiment, but could not be overcome by increasing the dose of dopamine agonist. Post mortem histology revealed a consistent loss of pallidal neurons, together with more variable damage to extrapyramidal structures and the thalamus. The results show that all the D1-mediated, and certain of the D2-mediated motor responses depend on the integrity of the pallidum for their expression in the unilaterally 6-hydroxydopamine-treated rat.

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