Michael S. Starr

Evidence for a GABAergic nigrothalamic pathway in the rat

SummaryExtracellular recordings were made from neurones in the ventromedial and parafascicular nuclei of the rat thalamus, many of which had demonstrable capsular or caudate projections. These cells responded to electrical stimulation of the ipsilateral substantia nigra with a short latency (4 ms) inhibition presumed to be monosynaptic. This inhibitory response was often preceded by a brief period of increased excitability (latency ∼3 ms) attributed to activation of corticofugal collaterals. Longer latency, presumably oligosynaptic excitations (latency ∼8 ms) and inhibitions (∼18 ms) were also obtained, but were more commonly evoked in non-projection neurones. All units were inhibited by iontophoretically applied GABA, glycine or 5-HT. Short and long latency synaptic and GABA-induced inhibitions were selectively blocked by bicuculline. Strychnine only antagonised glycine, while 5-HT was not affected by either convulsant. Intranigral injection of muscimol greatly elevated the spontaneous discharge rate of thalamic neurones, particularly those with a striatal projection. These data are compatible with nigrothalamic neurones maintaining a tonically active, GABA-mediated inhibition of cells in the ventromedial and parafascicular nuclei of the thalamus. It is speculated that intranigral muscimol indirectly activates these thalamic cells and thereby initiates contraversive circling behaviour by suppressing this inhibitory system.

Further studies on the effect of prostaglandin on intraocular pressure in the rabbit

The effects of prostaglandins E on intraocular pressure have been studied in rabbits. Prostaglandins E1 and E2 first raised the intraocular pressure and then lowered it, but failed to constrict the pupil to any extent. The sensitivity of individual eyes to prostaglandin E1 varied more widely with intracameral than intravenous administration. The latter route gave more reliable pressure responses in both eyes, but slightly bigger doses of prostaglandin were needed. Prior injection of polyphloretin phosphate into the vitreous completely blocked the rise in intraocular pressure to prostaglandin E1 but not the fall in pressure, while systemic pretreatment with polyphloretin phosphate was much less effective.

EFFECTS OF SUBSTANCE P INJECTED INTO THE SUBSTANTIA NIGRA

1 Behavioural and biochemical effects of substance P (SP, 1 to 10 μg) administered in a small volume to discrete areas of the rats brain were studied by means of a refined microinjection technique. 2 SP injected unilaterally into the zona reticulata of the substantia nigra elicited dose‐dependent contraversive circling and an increase in dopamine turnover in the ipsilateral striatum. SP applied to the zona compacta or zona lateralis, or to the medial lemniscus, evoked ipsiversive turning with a fall in dopamine turnover and a rise in 5‐hydroxytryptamine (5‐HT) turnover in the corresponding striatum. 3 In both cases the onset of turning was immediate, reached a peak at about 5 min and lasted for 10 min. Both types of behaviour were blocked by haloperidol and exaggerated by nialamide. 4 Unilateral injections of SP given into the crus cerebri, zona incerta, caudate nucleus, putamen or globus pallidus did not modify the animals behaviour. 5 In rats pretreated with apomorphine or amphetamine, SP induced contraversive circling which was followed by locomotion in the opposite direction. 6 Turning responses to a second dose of SP were diminished at 3 h and reproducible at 24 h after the first injection. 7 Bacitracin (50 ng) injected into the zona reticulata caused ipsiversive turning. Larger intranigral doses of bacitracin (10 μg), as with intracisternal SP (10 μg), evoked ‘barrel rotation’. 8 No changes in the free concentrations of aspartate, glutamate, γ‐aminobutyric acid, glycine or alanine were detected in any brain region following an intracisternal injection of 10 μg SP, although glutamine levels were elevated throughout the brain 30 to 60 min later.

Opposing Roles of Dopamine D1 and D2 Receptors in Nigral γ-[3H]Aminobutyric Acid Release?

Abstract: This study examined the effects of dopamine D1and D2 receptor agonists and antagonists on the spontaneous and calcium‐dependent, K+‐induced release of γ‐[3H]‐aminobutyric acid ([3H]GABA) accumulated by slices of rat substantia nigra. SKF 38393 (D1 agonist) and dopamine (dual D1/D2 agonist) were without effect on [3H]GABA efflux by themselves (1–40 μM), or in the presence of the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX) (0.5 μM), but potentiated evoked release in the presence of forskolin (0.5 μM), an adenylate cyclase activator. These increases in release were prevented by the D1 antagonist SCH 23390 (0.5 μM), but not by the D2 antagonist metoclopramide (0.5 μM), Higher concentrations of forskolin (10–40 μM) augmented stimulus‐evoked [3H]GABA release directly, whereas dibutyryl cyclic AMP (100–200 μM) depressed it. Apomorphine, noradrenaline, and 5‐hy‐droxytryptamine (1–40 μM) had no effect. The D2 stimulants lisuride, RU 24213, LY 171555, and bromocriptine dose‐dependently inhibited depolarisation‐induced but not basal [3H]GABA outflow. These inhibitory responses were not modified by the additional presence of SKF 38393 (10 μM) or SCH 23390 (1 μM), or by injection of 6‐hydroxydopamine into the medial forebrain bundle 42 days earlier, but were attenuated by metoclopramide (0.5 μM). Higher amounts (10 μM) of SCH 23390, metoclopramide, or other D2 antagonists (loxapine, haloperidol) reduced evoked GABA release by themselves, probably by nonspecific mechanisms. These results suggest D1 and D2 receptors may have opposing effects on nigral GABA output and could explain the variable effects of mixed D1/D2 dopaminomimetics in earlier release and electrophysiological experiments.

Effect of dark adaptation on the GABA system in retina

Abstract The levels of l -glutamate-1-car☐y-lyase (GAD), 4-aminobutyrate-2-oxoglutarate-aminotransferase (GABA-T) and free amino acids, and the active accumulation of [3H]GABA and [14C]taurine have been measured in light- and dark-adapted retinae from rat, chicken, frog and goldfish. No significant changes in any of these parameters with state of adaptation to light were evident in rat or chicken retina. However, in retinae from goldfish and frog respectively, decreases in [3H]GABA accumulation and GAD activity were noted in the dark. In both cases these changes were accompanied by a fall in the endogenous GABA content of the tissue, but this difference was only significant in goldfish retina.

Behavioural depressant and antinociceptive properties of substance P in the mouse: Possible implication of brain monoamines

Abstract The peripheral administration of 5 μg substance P (SP) to mice decreased spontaneous locomotor activity and counteracted amphetamine-induced hyperactivity. The motor depressant action of SP was considerably enhanced when SP was administered in 0.01 N acetic acid, whether i.p. or s.c., and in this instance the response to SP was partially reversed by naloxone. Spontaneous exploratory behaviour was also lowered by SP, as determined by the attenuation of the duration of head dipping in a hole board test. Injections of vehicle alone had no effect on behaviour. Measurements of the levels of dopamine (DA), 5-hydroxytryptamine (5HT) and their principal metabolites, homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5HIAA), in the corpus striatum following 5 μg SP i.p. suggested that DA turnover was accelerated and 5HT turnover was retarded by the peptide. In vitro SP (10 −6 M) had no discernible effect on the uptakes or the spontaneous rates of release of radioactively labelled DA and 5HT, but may have facilitated the potassium-evoked release of these amines from striatal slices. Similar doses of SP (1 or 5 μg) were antinociceptive in the hot-plate test, but did not offset naloxone-induced withdrawal jumping in morphine-dependent mice. In conclusion the results are consistent with SP having a tranquilizing action in the mouse and brain amines may be implicated. The antinociception caused by SP outlasts the observed biochemical changes and is less easily explained, although SP appears not to be morphine-like.

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 Parkinsons 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.

GABA potentiates potassium-stimulated 3H-dopamine release from slices of rat substantia nigra and corpus striatum.

GABA (10-5--10-3 M) had no effect on the spontaneous outflow of previously accumulated 3H-DA or 3H-5HT from rat nigral or striatal slices. However, GABA markedly potentiated the potassium-stimulated release of 3H-DA in both brain regions, while the depolarization-induced output of 3H-5HT was only slightly increased. This action of GABA was blocked by pictotoxin but not by bicuculline. Amphetamine likewise evoked a dose-related efflux of 3H-DA and 3H-5HT from nigra and striatum, but these releases were unchanged by GABA. The data suggest that GABA acts presynaptically in these areas to regulate dopaminergic cell function.

Rotational behaviour elicited by 5‐HT in the rat: evidence for an inhibitory role of 5‐HT in the substantia nigra and corpus striatum

Unilateral intranigral microinjection of 5‐HT or Wy 25093, a selective inhibitor of 5‐HT uptake, elicited ipsiversive circling and a fall in striatal dopamine (DA) turnover. Conversely intranigral methysergide or unilateral lesions of the raphe‐nigral 5‐HT pathway produced contraversive turning and/or increased DA turnover. Both types of behaviour were accentuated by nialamide and attenuated by haloperidol. Caudate injections of 5‐HT or Wy 25093 provoked contraversive turning which was increased by nialamide and hyoscine, partially diminished by haloperidol and antagonized by eserine. Ipsiversive circling was induced by intracaudate methysergide, which was potentiated by nialamide and eserine, unaffected by haloperidol and depressed by hyoscine. It is proposed that 5‐HT normally subserves an inhibitory function both in the substantia nigra and corpus striatum.

Involvement of dopamine in circling responses to muscimol depends on intranigral site of injection

The intensity, direction and dopamine dependence of circling behaviour were determined following stereotaxic injections of 40 ng muscimol (in 0.2 microliter over 3 min) into different regions of the rats substantia nigra (SN). Weak, haloperidol-sensitive ipsilateral postural or locomotor asymmetries were invariably obtained from the rostral SN zona compacta (SNC), whilst robust contraversive rotational behaviour was always initiated from the SN zona reticulata (SNR) and caudal SNC. This was most rapid from the central SNR and was markedly attenuated by i.p. pretreatment with haloperidol (0.1 mg/kg) or pimozide (0.25 mg/kg), or by week-old 6-OHDA lesions of the nigrostriatal dopamine (DA) tract. Turning was significantly weaker from the lateral and ventral areas of the SNR, where it was not susceptible to DAergic blockade. Lower circling rates were also obtained if the SNR injections were made rapidly (in 30 sec), in a large volume (0.5 microliter) or at a supramaximal dose level (400 ng), possibly due to increased spread of the drug to remote neurones having an opposite effect on directional behaviour, or to exaggerated stereotypy. The variable action of muscimol at multiple sites in the SN is suggested to account for the earlier conflicting data in the literature.