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Extracellular recordings were made from neurones in the ventromedial and parafasicular 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 approximately 3 ms) attributed to activation of corticofugal collaterals. Longer latency, presumably oligosynaptic excitations (latency approximately 8 ms) and inhibitions (approximately 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.

The GABA system was studied in different regions of the rat's brain following inhibition of brain GABA catabolism with intracisternal ethanolamine-O-sulphate or intraperitoneal aminooxyacetic acid. Both treatments lowered GABA aminotransferase and glutamate decarboxylase activities to similar extents in equivalent nuclei on either side of the brain. However, GABA contents were elevates to a consistently higher level in the right-hand substantia nigra, superior colliculus and nucleus accumbens, and in the left-hand ventral tegmentum, ventromedial thalamus and caudate nucleus, with no bilateral asymmetry evident in globus pallidus. These findings are discussed with reference to possible inherent inequalities in the functional states similar GABA systems on opposite sides of the brain.

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.

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.

Unilateral stereotaxic microinjection of muscimol into the caudal region of the substantia nigra (SN) evoked tight, dose-related contralateral locomotor asymmetry and stereotypy. These behaviours were partially attenuated by various pretreatments, including 6-hydroxydopamine lesions of the nigrostriatal dopamine pathway, intraperitoneal (i.p.) haloperidol, and inhibition of thalamic GABA-transaminase activity by local intrathalamic injection of ethanolamine-O-sulphate. Electrolytic or kainic acid lesions of the medial thalamic nuclei (MTN) partially reduced the contraversive rotation to intranigral muscimol, and completely abolished the similar behaviour elicited by apomorphine (25 microgram) injected into the ipsilateral caudate nucleus. Contraversive turning to intranigral muscimol was completely inhibited by kainic acid lesions of the ipsilateral SN, but potentiated by intrahalamic injection of picrotoxin. Muscimol (40 ng--4 microgram) administered to the MTN complex in one hemisphere stimulated rats to move in ipsilateral circles that were unaffected by haloperidol. The results of these behavioural experiments suggest that the nigrostriatal dopamine pathway, the nigrothalamic projection and possibly other non-dopaminergic SN efferents all play important roles in mediating the influences of the SN on motor and stereotyped behaviours. Disruption of the nigrothalamic pathway following electrical or chemical injury to the SN was accompanied by falls in GABA and its synthesising enzyme in the corresponding MTN. These data, together with the findings of our electrophysiological study presented in the following paper, are consistent with the nigrothalamic system having a GABAergic inhibitory function.

Dopamine (DA) utilisation has been determined in the medial bank of the prefrontal cortex (FCx) and the agranular insular cortex (AgCx) of the rat in response to a unilateral reduction of gamma-aminobutyric acid (GABA)-mediated inhibition in the thalamic mediodorsal nucleus (MD). The ratios of 3,4-dihydroxyphenylacetic acid (DOPAC): DA and 4-hydroxy-3-methoxyphenylacetic acid (homovanillic acid, HVA): DA were used as indices of DA utilisation. A bilateral increase in both ratios was found in FCx and AgCx following unilateral infusion of GABA antagonists (1 mM) into MDc. When this concentration was infused into one MDL no change was detected in DA utilisation of FCx, although a bilateral increase was observed in AgCx. However, a correspondence with the known anatomical connections was attained following infusion of lower concentrations (0.5 mM) into MDL in that a significant bilateral elevation of DA utilisation was shown in FCx. The changes induced in these ratios by the above treatments were, in general, due to increases in the concentration of metabolite and slight decreases in that of DA. However, unilateral lesions to the presumed GABA-containing neurones of the rostrodorsal thalamic reticular nucleus (TRNd), which topographically innervate MDL, produced increases in both metabolite and DA concentrations in FCx of both hemispheres, whilst those in AgCx were unaffected. Despite the slightly different results obtained using these two experimental approaches, it is argued that a reduction of tonic GABA-mediated inhibition in MD may tend to activate the DA system in cortical target regions.