Biomedical subjects

M S Starr

Publications and source records attributed to M S Starr.

At least 73 records · Page 4Linked to original sources

PubMed1988

D-1/D-2 behavioural interactions in the rat involving striatal dopamine D-1 receptors.

Simultaneous systemic administration of SKF 38393 (1-15 mg/kg i.p.) and LY 171555 (0.625-20 mg/kg s.c.) showed clear evidence of dopamine D-1/D-2 behavioural interactions compared to either treatment given alone. Similar interactions were observed between an intermediate systemic dose of LY 171555 (5 mg/kg) and SKF 38393 (1-10 micrograms) microinjected bilaterally into the caudate-putamen, but not into the substantia nigra pars reticulata, suggesting that striatal dopamine D-1 receptors are the ones responsible for mediating the altered behavioural responses to D-2 agonists in the intact rat.

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

PubMed1988

Intracerebral SCH 23390 and catalepsy in the rat.

Stereotaxic injection of SCH 23390 (D-1 antagonist), but not water or ritanserin (5-HT antagonist), into all parts of the caudate-putamen, elicited an immediate and often long-lasting catalepsy in 79% of rats. Similar results were obtained with SCH 23390 delivered into the nucleus accumbens and globus pallidus, but not into a variety of other brain sites. The results support the idea that SCH 23390-induced catalepsy is related to the occlusion of dopamine D-1 receptors in the forebrain, particularly the striatum, although the topography of the catalepsy evoked by intrastriatal SCH 23390 did not match the distribution of D-1 sites labelled in autoradiographic studies.

Animals↗

PubMed1987

Behavioural evidence for the functionality of D-2 but not D-1 dopamine receptors at multiple brain sites in the 6-hydroxydopamine-lesioned rat.

Lisuride (D-2 agonist) and SKF 38393 (D-1 agonist) evoked characteristic circling and stereotyped orofacial movements when administered systemically or stereotaxically into the supersensitive caudate nucleus of unilaterally 6-hydroxydopamine-lesioned rats, which were respectively blocked by D-2 and D-1 antagonists. Lisuride induced similar behaviours from the accumbens, frontal cortex, pallidum, ventromedial thalamus, substantia nigra and periaqueductal grey, while SKF 38393 did not. Multiple brain sites may mediate D-2-induced (not D-1) behaviours following treatment with 6-hydroxydopamine.

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

In morphinised rats SKF 38393 converts dopamine D2 receptor-mediated forward locomotion into backward walking.

The behavioural responses to RU 24213 (D2 agonist) and SKF 38393 (D1 agonist) were studied in the morphine cataleptic rat. D2 stimulation evoked slow forward walking coupled with head-down sniffing that was blocked both by SCH 23390 (D1 antagonist) and metoclopramide (D2 antagonist). D1 stimulation was without effect by itself, but when administered together with RU 24213 it reversed the direction of walking and initiated licking and chewing. Backward walking was attenuated by metoclopramide and restored to forward locomotion by SCH 23390. These data further show that D1 receptors exert an important modulatory influence on motor behaviours mediated by the D2 site.

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

PubMed1987

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.

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

PubMed1987

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.

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↗

PubMed1985

Multiple opiate receptors may be involved in suppressing gamma-aminobutyrate release in substantia nigra.

Slices of rat substantia nigra were preloaded with tritiated gamma-aminobutyrate (GABA) or dopamine (DA) and perfused with Krebs solution containing 5 microM aminooxyacetic acid or 10 microM nialamide to inhibit the catabolism of GABA and DA respectively. Repeated brief exposures to high potassium medium (+ 30 mM K+ for 1 min) evoked a consistent pattern of calcium-dependent 3H efflux against which the effects of opiates (10-400 microM) were assessed. Opiate agonists inhibited K+-induced 3H-GABA efflux in the following decreasing order of potency: bremazocine greater than D-Ala2-Met5-enkephalinamide (ENK) greater than SKF 10047 much greater than morphine, consistent with the participation of kappa, delta, sigma and to a lesser extent mu opiate receptors respectively. Naloxone (1 microM) partially antagonised the response to morphine and ENK, while ICI 154129 attenuated ENK only. Save for a GABA-releasing action of SKF 10047 at high doses, none of the compounds altered basal outflow of 3H-GABA. Naloxone, in the dose range 10-400 microM, also significantly inhibited depolarisation-induced release of 3H-GABA. In parallel experiments none of the compounds tested were found to influence 3H-DA release in concentrations up to 40 microM, but thereafter suppressed K+-induced 3H-DA outflow indiscriminately. The results are discussed with reference to the possible mechanism(s) via which injected and endogenous opiates may affect motor performance by attenuating GABA transmission in the nigra.

Aminooxyacetic Acid↗

PubMed1985

SKF 38393 and apomorphine modify locomotion and exploration in rats placed on a holeboard by separate actions at dopamine D-1 and D-2 receptors.

Horizontal motor activity, rearing and head dipping were recorded automatically in rats placed on a holeboard and taken as indices of locomotion and exploration. Other behaviours were assessed visually using a video camera. SKF 38393, 15-30 mg/kg (D-1 agonist), suppressed all three behavioural measures more effectively in habituated than in naive rats. These actions were blocked by SCH 23390 (0.05 mg/kg, D-1 antagonist) but not by haloperidol (0.05 mg/kg, D-2 antagonist). Apomorphine modified behaviour biphasically, causing haloperidol-resistant sedation at a low, presynaptic dose (0.05 mg/kg) and haloperidol-sensitive hyperactivity and stereotyped sniffing at a larger, postsynaptic dose (0.5 mg/kg, especially after habituation). Neither action was antagonised by SCH 23390. The results support the conclusion that D-1 and D-2 dopamine recognition sites can separately influence the processes controlling locomotion and exploratory activity in normal rats.

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

PubMed1985

Dysfunction of the midbrain angular complex can accentuate or attenuate circling behaviour in the rat.

The role of the midbrain angular complex (AC) in the execution of motor behaviours was investigated in the rat. In an automated holeboard apparatus bilateral AC electrolesions attenuated exploration and increased locomotor performance of drug-free rats on the first and second test occasions respectively; the latter result may signify a retarding of between-session habituation. Apomorphine also decreased locomotion and almost abolished head dipping and rearing in the holeboard; bilateral AC lesions reinstated locomotion to a normal level without modifying the other behavioural parameters. An electrolesion of one AC did not affect the animal's posture or spontaneous locomotion in the open field, but gave rise to pronounced ipsiversive circling when coupled with systemic administration of apomorphine. In unilaterally 6-hydroxydopamine (6-OHDA) treated rats subcutaneous injection of apomorphine evoked robust contraversive circling. A concomitant lesion of the ipsilateral AC introduced an additional ipsilateral bias to these animals' movements; contraversive circling was initially curtailed and posture reduced (or reversed), while stereotyped activities (particularly grooming) were suppressed. Contralateral orientation and circling were restored by subsequently lesioning the contralateral AC as well; bilateral AC lesions significantly potentiated circling to systemic apomorphine. Contralateral locomotor asymmetry was also produced by depositing apomorphine stereotaxically into the supersensitive caudate, or by microinjecting one substantia nigra zona reticulata with muscimol (in naive rats). Both rotational responses were facilitated by injury to the ipsilateral AC. The effects of electrocoagulating the AC were generally duplicated by discrete microinjection of muscimol or gamma-vinyl GABA into this area, suggesting GABA-mediated synapses are normally operative in this part of the brain. These results do not support the claim that the AC is specifically engaged in mediating postural asymmetry in the unilaterally 6-OHDA denervated rat. Instead, we believe that impairment of neurotransmission through one AC imposes an independent and reciprocal tendency to move towards that side of the brain, as well as attenuating stereotypy and facilitating locomotion. The resultant behavioural response to systemic apomorphine shown by animals bearing these two types of lesion embodies these separate actions.

Animals↗

PubMed1985

Brain dopamine activity following intranigral or intrathalamic drug injections in the rat.

Stereotaxic injection of muscimol into a restricted region of one substantia nigra of the rat provoked robust circling and a concomitant rise in ipsilateral nigrostriatal dopamine activity, as revealed by a greater accumulation of 3,4-dihydroxyphenylacetic acid and homovanillic acid in the caudate-putamen together with depleted nigral dopamine concentrations. Considered with earlier evidence, these data are taken to indicate that dopamine may be involved in the mediation of this particular rotational behaviour. On the other hand, focal application of bicuculline to the substantia nigra or ventromedial thalamus, or intrathalamic kainate, all evoked a closely similar and vigorous hypermotility (not circling) that could not be correlated with the assorted changes in dopamine utilisation occurring in the substantia nigra, caudate-putamen or nucleus accumbens, either uni- or bilaterally. These changes were therefore probably casually rather than causally related to the mechanisms underlying the behaviour of the animals. Whilst the regional concentrations of noradrenaline were unaltered by these focal drug treatments, the induction of halothane anaesthesia coupled with a unilateral intranigral saline injection produced bilateral elevations in regional dopamine utilisation when assessed 15 min after injection. Such changes were not apparent in tissue taken 30 or 60 min post-injection. We conclude that dopamine cell activity and/or other indices of dopamine utilisation cannot be used to predict the behavioural state of the individual and that an imbalance between the dopamine systems in the two hemispheres does not per se lead to postural or locomotor asymmetry.

Animals↗

PubMed1984

Muscarinic action of acetylcholine in the rat ventromedial thalamic nucleus.

Several lines of evidence suggest a role for ACh in the mediation of cerebello-thalamic transmission. The physiological, pharmacological and biochemical experiments described were designed to test this hypothesis for the rat cerebello-thalamic pathway. Unilateral electrolytic lesions of the superior cerebellar peduncle resulted in modest falls of CAT from both ventromedial thalamic nuclei (contralateral 35%, ipsilateral 15%). Iontophoretic application of ACh to relay cells evokes three types of response (i) excitation (ii) inhibition (iii) polyphasic combinations of (i) and (ii). The type of response evoked was directly related to the firing pattern of the cell. Thus, for example, excitatory responses were never recorded during high-frequency bursting but were easily evoked following a switch to tonic, single-spike activity. All responses to ACh and synaptic responses to cerebellar stimulation were sensitive to muscarinic but not to nicotinic cholinergic antagonists. The nicotinic antagonist mecamylamine was a potent blocker of excitant amino acid responses but had no effect on cerebellar-evoked synaptic responses. Cholinergic and anticholinergic agents had a profound action on relay cell firing pattern. ACh promoted single-spike activity whereas atropine promoted high-frequency bursting. The actions of ACh are discussed with reference to recently discovered voltage-sensitive ionic conductances. Because of the modulatory action of ACh on relay cell firing pattern and excitability no firm conclusion can be reached concerning the hypothesis under test here. We tentatively suggest a dual role for ACh as both neurotransmitter and neuromodulator.

Acetylcholine↗

PubMed1983

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.

Amino Acids↗

PubMed1983

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.

Animals↗

PubMed1983

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.

Amino Acids↗