Dopamine and glutamate control each other's release in the basal ganglia: a microdialysis study of the entopeduncular nucleus and substantia nigra.

This study utilized microdialysis in conscious rats to investigate dopaminergic control of excitatory amino acid release in the entopeduncular nucleus (EPN), and glutamatergic control of dopamine release in the substantia nigra pars reticulata (SNr). EPN dialysates contained both glutamate and aspartate, which were elevated by dopamine depletion with reserpine and 6-hydroxydopamine (6-OHDA), reduced by the D2/3 agonist LY 171555 and unaffected by the D1 agonist SKF 38393, in line with current theory. The D2/3 agonist RU 24213 was behaviourally active but paradoxically increased glutamate and aspartate release in EPN, possibly via kappa opioid receptor blockade. 6-OHDA-hemilesioned rats also showed a significant increase in glutamate and aspartate contralaterally, suggesting that nigrostriatal dopamine affects EPN neurotransmission bilaterally. In reserpine-treated rats, basal levels of dopamine in the SNr were greatly reduced, and were further lowered by focal application of NMDA antagonists, suggestive of the removal of a high glutamatergic tone. A threshold amount of L-DOPA applied to the SNr elevated dopamine output about two-fold and 5-HT output about 13-fold, indicating L-DOPA effects the release of monoamines other than dopamine. Concomitant addition of the NMDA antagonists potentiated these releases synergistically, suggesting that this could be how they facilitate the antiparkinsonian action of L-DOPA.

Stimulation of basal and L-DOPA-induced motor activity by glutamate antagonists in animal models of Parkinson's disease.

In parkinsonism, glutamate pathways within the basal ganglia become overactive, leading to the suggestion that glutamate antagonists might possess antiparkinsonian qualities. This report examines the motor properties of antagonists of NMDA and AMPA-type glutamate receptors, as well as some inhibitors of glutamate release, in animal models of idiopathic Parkinson's disease. High affinity NMDA open-channel blockers (e.g. MK 801, phencyclidine), are highly potent antagonists with inconsistent antiakinetic and strong myorelaxant activity. Other compounds are better tolerated and are capable of relieving immobility and muscular rigidity by themselves (e.g. 1-aminoadamantanes, polyamine site antagonists, kappa agonists, riluzole). Yet others do not restore movements alone (e.g. dextromethorphan, ketamine), but may interact with and strengthen the antiparkinsonian action of L-DOPA (e.g. competitive NMDA and AMPA antagonists, lamotrigine). They may do this by potentiating dopaminergic behaviours mediated by D1 or D2 receptors, or by some other mechanism.

Regional changes in brain dopamine utilization during status epilepticus in the rat induced by systemic pilocarpine and intrahippocampal carbachol.

Systemic administration of pilocarpine (400 mg/kg i.p.) or intrahippocampal injection of carbachol (100 micrograms/1 microliters) induced limbic motor seizures in rats, characterized by head weaving and paw treading, rearing and falling, and forepaw myoclonus, developing into status epilepticus. After being in status for 30 min, rats were killed and levels of dopamine, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were determined in eight brain regions by high performance liquid chromatography. Pilocarpine-induced seizures significantly elevated dopamine in the striatum, and in both dorsal and ventral aspects of the hippocampus, but did not affect dopamine in substantia nigra, nucleus accumbens, olfactory tubercle, cingulate cortex or amygdala. Metabolite levels were increased in striatum, substantia, nigra, nucleus accumbens and cingulate cortex, and fell in the hippocampus, but remained unchanged in the olfactory tubercle and amygdala. Intrahippocampal carbachol significantly raised the dopamine contents of striatum and nigra, and in both ventral and dorsal aspects of the hippocampus, but not elsewhere. DOPAC and/or HVA were elevated in all brain regions tested, save for amygdala and dorsal hippocampus. These changes translated into seizure-induced increases in dopamine utilization in the nucleus accumbens, olfactory tubercle and cingulate cortex, and to a fall in dopamine utilisation in the hippocampus, with no net change in amygdala. In addition pilocarpine (but not carbachol) increased dopamine utilization in the nigrostriatal axis, possibly through a seizure-unrelated mechanism. The relevance of these findings to seizure development are discussed.

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.

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.

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.

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.

Differential effects of intrastriatal and intranigral injections of glutamate antagonists on motor behaviour in the reserpine-treated rat.

A variety of N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonists, and the antiepileptic drug lamotrigine, were examined for their ability to restore locomotion and other behaviours when injected stereotaxically via indwelling cannulae into the striatum or substantia nigra pars reticulata of rats rendered akinetic with reserpine (5 mg/kg i.p. 24 h beforehand). Only the competitive N-methyl-D-aspartate antagonists 3-((+)-2-carboxypiperazin-4-yl)-propyl-1-phosphonate and R-DL-(E)-2-amino-4-methyl-5-phosphono-3-pentanoate stimulated locomotion from the striatum, whereas 2-amino-phosphonopentanoic acid, the N-methyl-D-aspartate channel blockers dizocilpine maleate and phencyclidine, and the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid antagonist 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo(f)-quinoxaline-dione, were additionally effective in the substantia nigra pars reticulata. The N-methyl-D-aspartate glycine site antagonist (RS)-3-amino-1-hydroxypyrrolidin-2-one and the glutamate release inhibitor lamotrigine failed to restore locomotion at these sites, and the N-methyl-D-aspartate polyamine site antagonist eliprodil was ineffective in the substantia nigra pars reticulata, although all compounds tested (except lamotrigine) induced orofacial, head and/or limb movements to some degree. Except for 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo(f)-quinoxaline-dione, locomotion was accompanied dose-dependently by increasingly pronounced ataxia and postural abnormalities. These results show that the monoamine-depleted substantia nigra pars reticulata has a broader spectrum of responsitivity to the antiparkinsonian actions of N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid antagonists than does the striatum, and that the harmful as well as the beneficial effects of these compounds on locomotion arise from these two structures.

Role of the substantia nigra in the expression of dopamine D1 receptor-mediated and D2 receptor-mediated behaviours.

This study examines the proposal that striatonigral pathways support circling mediated by dopamine D1 receptors, but not D2 receptors, in unilaterally 6-hydroxydopamine-treated rats. In this model the D1/D2 agonist apomorphine, the D1 agonist 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine hydrochloride and the D2 agonists N-n-propyl-N-phenylethyl-P-(3-hydroxyphenyl) ethylamine hydrochloride, trans-(-)-4aR,4,4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo-(3, 4-g) quinolino monohydrochloride and lisuride evoked a characteristic spectrum of motor responses when administered systemically. In addition apomorphine, 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine hydrochloride and lisuride replicated their systemic effects following stereotaxic injection into the supersensitive caudate nucleus. Three months after injecting the pars reticulata of the dopamine-denervated nigra with kainic acid (1 microgram in 1 microliter), all motor responses to intracaudate dopamine agonists were reduced or abolished. Systemic responses were modified differentially, often as early as one day post-kainate. Contraversive circling and posturing were reduced, or even reversed (apomorphine only), grooming was attenuated (all drugs) and 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine hydrochloride-induced forepaw nibbling and dyskinesia were abolished. By contrast, sniffing, movements of the head and locomotion were either unaffected, or significantly potentiated, suggesting these components of behaviour arose from dopamine receptors outside the denervated striatum. These behavioural changes showed no signs of recovery three months after kainate, and were not produced by partial lesions of the reticulata (1 microgram kainate in 0.2 microliter). Contrary to earlier opinion our results indicate that the structural integrity of the substantia nigra pars reticulata is essential for the development of all forms of dopamine behaviour mediated by striatal D1 and D2 receptors, though not necessarily by dopamine receptors present at other locations.

Topography of dopamine behaviours mediated by D1 and D2 receptors revealed by intrastriatal injection of SKF 38393, lisuride and apomorphine in rats with a unilateral 6-hydroxydopamine-induced lesion.

Stereotaxic injections of a dopamine D1 receptor agonist (SKF 38393) into different regions of the supersensitive striatum of rats with a unilateral 6-hydroxydopamine-induced lesion duplicated the systemic effects of the drug in a topographical manner. Although there was considerable overlap, it was possible to recognize discrete active zones or "hot-spots" giving rise to prominent sniffing, head movements and contralaterally directed circling, posture and grooming, both in the coronal plane and along the rostro-caudal axis. Two behaviours peculiar to D1 stimulation included contralateral forepaw myoclonus and forepaw nibbling, which paradoxically was directed mainly ipsilaterally. Each of the behavioural elements occurred independently of the others and after an inexplicably long latency. They were inhibited by the D1 antagonist SCH 23390, but not by the D2 blocking drug metoclopramide. Comparable circling responses were evoked by a D2 agonist (lisuride) injected into the neostriatum after a short delay, and instantaneously by apomorphine (D1/D2 agonist). Both drug behaviours originated diffusely from all parts of the denervated striatum with no obvious "hot-spots", except for circling which exhibited a bimodal distribution rostro-caudally. The actions of lisuride were blocked by systemic metoclopramide, but not by SCH 23390, while the actions of apomorphine were inhibited by both antagonists. Topographies of D2 receptor-mediated events were quite different from those encountered for D1 receptor stimulation by SKF 38393, though neither corresponded to the autoradiographic distribution of D1 and D2 binding sites in the intact striatum. These results reiterate the importance of D1 receptors in motor control and provide a basis for future investigations of the output pathways subserving D1-mediated behaviours.

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.

Role of the ventromedial nucleus of the thalamus in motor behaviour--I. Effects of focal injections of drugs.

An assortment of drugs was injected into one or both ventromedial nuclei of the thalamus, to see how these influenced stereotypy, locomotion and posture in spontaneously behaving and actively rotating rats. Unilateral intrathalamic muscimol promoted weak ipsiversive circling, while bilateral treatment gave catalepsy. Similar injections of 4-amino-hex-5-enoic acid, which inhibits gamma-aminobutyrate metabolism, raised gamma-aminobutyrate levels in the ventromedial nuclei more than three-fold yet had none of these behavioural effects. The indirectly acting gamma-aminobutyrate agonists flurazepam and cis-1,3-aminocyclohexane carboxylic acid had little effect on posture and locomotion and, like muscimol and 4-amino-hex-5-enoic acid, elicited only very weak stereotypies. Procaine behaved like the gamma-aminobutyrate antagonist bicuculline, provoking vigorous locomotor hyperactivity and teeth chattering if given uni- or bilaterally. Pretreatment of one ventromedial nucleus with muscimol or 4-amino-hex-5-enoic acid, and to a lesser extent flurazepam or cis- 1,3-aminocyclohexane carboxylic acid, gave rise to pronounced ipsilateral asymmetries when combined with a large systemic dose of apomorphine. Contraversive rotations were initiated by unilateral stereotaxic injection of muscimol into the substantia nigra pars reticulata, or with apomorphine from the supersensitive striatum in unilaterally 6-hydroxydopamine lesioned rats. Drug treatments in the ipsilateral ventromedial nucleus showed a similar rank order of potency at inhibiting these circling behaviours, seemingly by reducing apomorphine-induced posture and muscimol-induced hypermotility. The suppression of circling by muscimol in these tests was highlighted by introducing the compound into the ventromedial nucleus at the height of circling activity. Both types of circling stimulus lost the capacity to increase locomotion, but still caused head turning and stereotypy in rats made cataleptic with bilateral ventromedial muscimol. Treating one ventromedial thalamus with muscimol greatly intensified any pre-existing posture directed towards that side, and vice versa. These data suggest that the ventromedial nucleus is not involved with the expression of stereotyped behaviours, but can profoundly influence posture and locomotion, especially in the presence of some other motor stimulus. The recovery of circus movements in rats with impaired ventromedial nucleus function implies this nucleus is not essential for the execution of circling in these models.

Role of the ventromedial nucleus of the thalamus in motor behaviour--II. Effects of lesions.

Rotational behaviour was initiated in naive rats by injecting muscimol into one substantia nigra pars reticulata, or in unilaterally 6-hydroxydopamine-treated rats with systemic or intracaudate apomorphine. Electrolytic or kainic acid lesions were made in one or both ventromedial nuclei of the thalamus and their effects on the components of circling studied. A unilateral ventromedial electrolesion imposed a weak ipsilateral posture and occasionally elicited weak ipsiversive circling acutely, but not chronically. Challenging these rats with a large subcutaneous dose of apomorphine invariably provoked ipsiversive circling, however old was the lesion. Bilateral electrolesions caused slight hypoactivity. Kainic acid treatments of one or both ventromedial thalami produced uncontrolled hypermotility initially, with subsequent loss of ventromedial neurones and recovery of normal motor behaviour. No form of ventromedial lesion affected the incidence of stereotypy. Acute (but not chronic) contralateral or ipsilateral ventromedial electrolesions, or both, slowed muscimol and apomorphine-induced circling (often in different ways) through complex changes in posture and/or locomotor drive. Animals lesioned during the course of a circling episode often showed the biggest changes in circling to begin with, only to recover minutes later. Rapidly circling rats were sometimes more readily inhibited than slowly circling rats. Toxin injury of the ventromedial nucleus appeared to suppress muscimol and not apomorphine circling. Any ventromedial lesion (electrical or chemical, acute or chronic), if positioned opposite a contraversive circling stimulus, intensified the associated posture. Ipsilateral lesions tended to abolish posture altogether or, like bilateral treatments, to suppress locomotion. Sham operations had none of these effects. Acute electrical lesions and drug-induced inhibition of one or both ventromedial thalami were more or less identical in their effects on rat circling behaviour, save that bilateral muscimol injection caused profound catalepsy while lesions did not. It is suggested that the ventromedial thalamus is more concerned with the registration of striatal dopamine-mediated behaviours in drug-stimulated than in spontaneously behaving rats, and that other output pathways may rapidly compensate for any impairment of function in the ventromedial nuclei.

Effects of dopamine D3 receptor agonists on pilocarpine-induced limbic seizures in the rat.

The discrete localization of D3 receptors in the nucleus accumbens and subjacent islands of Calleja bears a close resemblance to the dopamine-sensitive anticonvulsant site in the anteroventral striatum. To determine if these D3 receptors were capable of attenuating limbic motor seizures induced by pilocarpine, dopamine agonists with preferential or non-selective D3 affinity were injected stereotaxically into these limbic brain regions of the rat via indwelling cannulae prior to pilocarpine challenge. Reliable clonic seizures were obtained by administering the proconvulsive dopamine D1 agonist SKF 38393 (10 mg/kg i.p.) followed by a subconvulsant dose of pilocarpine (280-300 mg/kg i.p.). Bilateral intra-accumbens pretreatment with the D3 > D2 agonist RU 24213 (0.2 pmol-7 nmol) significantly delayed the onset of seizures, with a minimum effective dose of 2 pmol, without altering their frequency or severity. The more selective D3 agonist LY 171555 (0.2 pmol-7.8 nmol) was less potent, and only attenuated pilocarpine-induced seizures at a dose (500 pmol) that would have stimulated accumbens D2 receptors as well. Intra-accumbens injections of the highly potent and selective D3 agonist 7-OH-DPAT (20 pmol to 7 nmol) afforded no protection against pilocarpine-induced seizures. Apomorphine, a mixed D1/D2/D3 agonist, delayed seizure onset at 100-500 pmol, but not at higher doses. RU 24213, LY 171555 and 7-OH-DPAT were all modestly anticonvulsant when microinjected into the islands of Calleja at D2/D3 unselective doses. These data support the notion that dopamine systems limit seizure propagation through the limbic forebrain, but suggest this protective effect is mediated by D2 rather than D3 receptors.

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.

Interactions between dopamine and gamma-aminobutyrate in the substantia nigra: implications for the striatonigral output hypothesis.

Experiments employing a rodent circling model were conducted to test the predictive capacity of the theory which states that striatonigral gamma-aminobutyrate neurones transmit striatal information influencing the animal's locomotion and orientation. In agreement with this proposal, blocking nerve conduction in one substantia nigra with procaine, or nigral gamma-aminobutyrate receptors with bicuculline administered stereotaxically, frequently forced rats to move ipsiversively to systemic apomorphine, as though the treatment had impaired striatonigral transmission on that side of the brain. Attempts to reverse the direction of apomorphine circling by stimulating gamma-aminobutyrate receptors with muscimol, by facilitating the amino acid's action with flurazepam, or by increasing its synaptic concentration either with a breakdown inhibitor (ethanolamine O-sulphate or 4-amino-hex-5-enoic acid) or an uptake blocker (cis-1,3-aminocyclohexane carboxylic acid) in one nigra, proved unsuccessful. In fact, ethanolamine O-sulphate, flurazepam and muscimol all gave the appearance of hindering rather than enhancing the passage of striatal-derived motor information through the nigra. Broadly speaking, these drugs gave predictable behavioral responses from the ventromedial thalamus, suggesting they were acting in accordance with known mechanisms. The anomalous behaviour with ethanolamine O-sulphate may be attributed to its elevating gamma-aminobutyrate levels in other brain areas, since similar ipsiversive rotations occurred if gamma-aminobutyrate catabolism was prevented at a wide variety of extranigral sites. A simple explanation for the paradoxical ipsiversive behaviours produced by intranigral flurazepam or muscimol in combination with systemic or intracerebral injection of dopamine agonists, is that they act via presynaptic receptors to inhibit the release of endogenous gamma-aminobutyrate and thereby impede striatonigral outflow ipsilaterally.

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)

Evidence for the participation of nigrotectal gamma-aminobutyrate-containing neurones in striatal and nigral-derived circling in the rat.

The gamma-aminobutyrate-containing nature of nigrotectal neurones and the possible involvement of the tectum in circling behaviour were investigated in the rat. Electrolytic or kainic acid lesions of the substantia nigra reduced gamma-aminobutyrate levels on average by 19-29% in intermediate and deep, but not superficial superior colliculus. Placement of lesions or injection of muscimol (40 ng) into these gamma-aminobutyrate-innervated layers of superior colliculus gave only weak ipsilateral posturing or circling that was intensified by apomorphine, but which strongly antagonized contraversive apomorphine-induced circling in 6-hydroxydopamine pretreated rats(lateral greater than medial sites). Contraversive circling to unilateral muscimol (40 ng) was significantly attenuated by lesions or muscimol injections placed in the ipsi- or contralateral superior colliculus. Picrotoxin (40 ng) and tetanus toxin (30 mouse LD50 doses) evoked explosive motor behaviour from medial colliculus and vigorous contraversive circling when injected into the lateral colliculus. The latter offset ipsiversive asymmetries to kainate (0,8 micrograms) in the corresponding substantia nigra. Bilateral intratectal picrotoxin produced hyperactivity that reversed haloperidol catalepsy. Similar bilateral administration of muscimol did not produce catalepsy but a state of frozen immobility. Kainic acid introduced into the superior colliculus gave mixed excitatory-inhibitory responses initially followed by ipsiversive circling only and loss of tectal perikarya. None of these drug effects occurred from the overlying cerebral cortex or subjacent tegmentum. We propose that separate medial "non-postural" and lateral "postural" tectal locomotor regions may exist in the superior colliculus that are situated within a striato-nigrotectal outflow system capable of influencing the animal's motor activity and posture.

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.

Dual effects of L-3,4-dihydroxyphenylalanine on aromatic L-amino acid decarboxylase, dopamine release and motor stimulation in the reserpine-treated rat: evidence that behaviour is dopamine independent.

The comparative effects of L-3,4-dihydroxphenylalanine (L-DOPA) on dopamine synthesis, release and behaviour were studied in the reserpine-treated rat. Acute administration of L-DOPA (25-200 mg/kg) dose-dependently inhibited the activity of aromatic L-amino acid decarboxylase (AADC) in the substantia nigra and corpus striatum. The antiparkinsonian drugs budipine (10 mg/kg) and amantadine (40 mg/kg) enhanced AADC activity in these regions, and prevented or reversed AADC inhibition by L-DOPA. Dual probe dialysis revealed that low doses of L-DOPA (25-50 mg/kg) dose-dependently stimulated the release of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) in nigra and striatum, whilst high doses of L-DOPA (100-200 mg/kg) completely suppressed the release of dopamine, but not DOPAC. Sulpiride (50 microM) administered via the probes antagonized dopamine release in response to 25 mg/kg L-DOPA, but greatly facilitated release by 200 mg/kg L-DOPA. Dopamine release was blocked by the centrally acting AADC inhibitor NSD 1015, but facilitated by the central AADC activator budipine. In behavioural tests L-DOPA (plus benserazide, 50 mg/kg) only reversed akinesia at 200 mg/kg, and not at 25-100 mg/kg. Pretreatment with either NSD 1015 (100 mg/kg) or budipine (10 mg/kg) markedly potentiated the motor stimulant action of a threshold dose of L-DOPA (100 mg/kg). A combination of NSD 1015 (100 mg/kg) and benserazide (50 mg/kg) potentiated L-DOPA behaviour more effectively than either inhibitor alone. NSD 1015-facilitated L-DOPA behaviour was antagonized by sulpiride (100 mg/kg) and not by SCH 23390 (1 mg/kg), whereas budipine-facilitated L-DOPA behaviour was fully antagonized by SCH 23390 and only partially by sulpiride. These results show that behaviourally active doses of L-DOPA in the reserpinized rat are not accompanied by significant increases in extracellular dopamine and are therefore probably not dopamine mediated. We propose that L-DOPA is capable of directly stimulating dopamine D2 and possibly non-dopamine receptors, thereby inhibiting dopamine efflux presynaptically and promoting motor activation postsynaptically. A stimulant action of L-DOPA on motor behaviour, preferentially mediated by D1 > D2 receptors, suggests that L-DOPA may also be capable of yielding a dopamine-like response in the absence of detectable dopamine release. These findings are incorporated into a new model of L-DOPA's actions in the reserpinized rat, and their possible implications for our understanding of L-DOPA in Parkinson's disease are discussed.