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 γ-aminobutyrate metabolism, raised γ-aminobutyrate levels in the ventromedial nuclei more than three-fold yet had none of these behavioural effects. The indirectly acting γ-aminobutyrate agonists flurazepam and cis-1,3-aminocyclohexane car☐ylic 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 γ-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 car☐ylic 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.     

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

Summary 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 -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.     

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

The γ-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 γ-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 γ-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 > medial sites). Contraversive circling to unilateral intranigral 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 μg) 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.     

Enhanced GABA function in the angular complex (lateral periaqueductal grey matter and adjacent reticular formation) alters the postural component of striatal- or nigral-derived circling

Summary Unilateral injection of muscimol into the angular complex (lateral periaqueductal grey matter and adjacent reticular formation) caused ipsiversive rotation. Focal injection of picrotoxin into the same site produced contraversive rotation. Administration of apomorphine to animals with a unilateral 6OHDA lesion of the left medial forebrain bundle caused contraversive rotation. Focal injection of muscimol into the angular complex reversed the direction of rotation such that apomorphine administration now produced ipsiversive circling. Unilateral injection of muscimol into substantia nigra zona reticulata caused contraversive rotation. Focal injection of picrotoxin into the same site produced ipsiversive rotation. The prior injection of muscimol into the ipsilateral angular complex prevented the contraversive rotation induced by intranigral administration of muscimol such that animals now showed ipsiversive circling. In both 6-OHDA-lesioned animals and animals receiving intranigral muscimol, focal injection of muscimol into the angular complex caused a reversal in the direction of circling through loss of the postural component with no obvious change in locomotor activity. Bilateral electrolytic lesions of the angular complex overall had no effect on amphetamine-induced locomotion. Manipulation of GABA function in the angular complex alters circling behaviour initiated from the striatum or substantia nigra by altering the postural component without affecting the locomotor response of the animals. The data suggest a critical role for the angular complex as an outflow station from basal ganglia.     

Interactions between dopamine and γ-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 γ-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 γ-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 γ-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 γ-aminobutyrate levels in other brain areas, since similar ipsiversive rotations occurred if γ-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 γ-aminobutyrate and thereby impede striatonigral outflow ipsilaterally.     

Role of thalamic gamma-aminobutyrate in motor functions: catalepsy and ipsiversive turning after intrathalamic muscimol

Bilateral intrathalamic microinjections of nanogram amounts (5–50 ng) of muscimol, a γ-aminobutyrate (GABA) receptor agonist, elicited catalepsy in rats. Like neuroleptic-treated rats, those injected with muscimol in the thalamus remained suspended on a vertical grid but, unlike opioid-treated rats, they failed to remain horizontal on two book-holders. The righting reflex was present, while ptosis was absent. The areas with the highest sensitivity to the cataleptogenic effects of muscimol were the ventromedial and ventral-anterior nuclei of the thalamus. These thalamic areas were also characterized by the shortest latency for the induction of catalepsy. Injection of up to 50 ng of muscimol into the caudate, globus pallidus or entopeduncular nucleus failed to produce catalepsy. Catalepsy was also obtained after intrathalamic microinjection of other GABA analogs, such as 3-aminopropanesulphonic and imidazolacetic acid, which are known to be potent GABA receptor agonists, and β-p-chlorophenyl-GABA , a compound which has GABA mimetic activity. The catalepsy produced by 10 ng of muscimol was reversed by an intrathalamic microinjection of picrotoxin, a GABA receptor antagonist. Muscimol-induced catalepsy, unlike neuroleptic-induced catalepsy, was not reversed by systemic administration of high doses of apomorphine, a dopamine receptor agonist, or of scopolamine, a muscarine antagonist, or by intranigral injection of muscimol, and was not prevented by kainic acid-induced lesions of the striatum or of the nigra. Vice versa, injection of cataleptogenic doses of muscimol in the thalamus failed to prevent the stereotyped gnawing produced by systemic apomorphine or intranigral muscimol. Therefore, in these animals, catalepsy and stereotyped gnawing coexisted. The unilateral intrathalamic microinjection of muscimol resulted in a postural asymmetry consisting of turning towards the injected side. This ipsilateral posturing was converted into an ipsilateral circling by systemic administration of apomorphine.The results indicate that thalamic GABAergic mechanisms play an important role in the regulation of posture and in the mediation of certain motor responses arising in the striatum.     

Behavioural effects mediated by unilateral nigral dopamine receptor stimulation in the rat

Summary Unilateral intranigral injections of dopamine in conscious rats pretreated with nialamide resulted in either ipsiversive or contraversive rotation depending upon the site of injection. Injection of dopamine (50 g) into the zona compacta of the substantia nigra induced weak ipsiversive or mixed ipsiversive and contraversive rotation. Injection of dopamine (12.5–50.0 g) into zona reticulata of substantia nigra induced only contraversive circling. Destruction of the ipsilateral medial forebrain bundle (MFB) using 6-hydroxydopamine (6-OHDA) abolished ipsiversive circling but enhanced contraversive circling produced by dopamine or apomorphine. The combination of a unilateral 6-OHDA lesion of MFB with a kainic acid or electrolesion of the ipsilateral strio-nigral and pallido-nigral pathways reduced contraversive circling to intranigral apomorphine (10 g). Ipsiversive circling produced following intranigral injection of dopamine is dependent upon the integrity of ascending dopamine neurones. Contraversive rotation is independent of ascending dopamine pathways but is reliant upon afferent input to the substantia nigra from the striatum and/or globus pallidus.     

Differences in the behavioral profile of circling under amphetamine and apomorphine in rats with unilateral lesions of the substantia nigra

In rats with severe depletion of striatal dopamine, produced by a unilateral injection of 6-hydroxydopamine into the substantia nigra, amphetamine (2 mg/kg) induces circling towards the side of the lesion and apomorphine (0.25 mg/kg) induces circling in the opposite direction. In Experiment 1 we showed that under apomorphine, circling may be related to an asymmetry in stepping, but under amphetamine it is not. Specifically, under apomorphine, rats rotate almost exclusively by stepping (backwards) with the contralateral hindlimb while pivoting on the ipsilateral hindlimb. In contrast, under amphetamine, they rotate using a variety of stepping patterns, and there is no consistent asymmetry in using one hindleg for stepping and the other one for bearing weight. Considering the stepping patterns, it is suggested that rotations induced by apomorphine and amphetamine involve at least one and two variables, respectively (turning and turning plus forward progression). Furthermore, the results of Experiment 2 revealed that under apomorphine the direction of circling in a pool of water is reversed by edges, but under amphetamine it is not. In particular, under apomorphine, rats swim in the contraversive direction when in the middle of the pool but in the ipsiversive direction when swimming along the edge of the pool. In contrast, under amphetamine, they show little attraction for the edge and continue swimming in the ipsiversive direction, regardless of their position in the pool. It seems, therefore, that different behavioral mechanisms may underlie the rotations induced by apomorphine and amphetamine.     

Perioral biting reflex and turning after intranigral injection of a GABA- or metenkephalin-agonist: Role of the thalamus and superior colliculus

Summary Unilateral destruction of the ventromedial thalamus (VMT) with a radiofrequency lesion attenuated turning induced by injection of muscimol (40 ng/0.4 l) but not of a metenkephalin-analogue (DAME; 2.5 g/0.4 l) into the substantia nigra, pars reticulata (SNR). Unilateral lesions in the deep layers of the superior colliculus (DLSC) attenuated both muscimol- and DAME-induced turning. Lesions in the DLSC but not in the VMT blocked the sensitization of the perioral biting reflex by injection of muscimol or DAME into the SNR on the same side of the lesion. When injected with apomorphine (0.5 mg/kg) all rats with lesions turned ipsiversive to the lesion side and reacted to tactile stimulation of the perioral area on both sides with orienting towards and then biting into the stimulus probe.This work was supported by grant IIb5-9211.13 from the Ministry of Science of the State of North-Rhine Westphalia, FRG. D-Ala²-Metenkephalinamide was kindly provided by Dr. F. Esser, Boehringer, Ingelheim     

Multifocal brain sites for apomorphine-induced circling and other stereotyped motor behaviour in the 6-hydroxydopamine-lesioned rat

Rats pretreated with 6-hydroxydopamine (6-OHDA, 8 micrograms in 4 microliters) in one medial forebrain bundle exhibited an assortment of stereotyped activities and pronounced circling towards the unlesioned side when apomorphine was administered either subcutaneously (0.5 mg/kg), or by discrete stereotaxic injection (5 micrograms in 0.2 microliter) into the caudate nucleus, nucleus accumbens, amygdala, lateral habenula, ventromedial thalamus, substantia nigra zona reticulata, periaqueductal grey or superior colliculus (but not a variety of other areas) ipsilateral to the lesion. These rotational responses were absent in unlesioned animals and, where tested, were attenuated by intraperitoneal haloperidol (0.5 mg/kg). It is suggested that multiple brain sites become sensitive to apomorphine following dopamine depletion by 6-OHDA.     

The anatomical substrate of the turning behaviour seen after lesions in the nigrostriatal dopamine system

Studies of the fibre connections of the substantia nigra suggest that the behavioural results of changes in the activity in the striatal dopamine-containing system are mediated by a pathway from the striatum to the substantia nigra and thence to the thalamus. Small discrete electrolytic lesions in the appropriate part of the crus cerebri interrupt the striatonigral axons without damage to the nigrostriatal system. Such lesions inhibit turning induced by activation of striatal dopamine receptors.Similarly, turning induced by apomorphine in rats lesioned with 6-hydroxydopamine is inhibited by damage to the ipsilateral ventromedial area of thalamus which receives fibres from the substantia nigra.     

Rotational behaviour and neurochemical changes in unilateral N-methyl-norsalsolinol and 6-hydroxydopamine lesioned rats

In earlier studies the tetrahydroisoquinoline derivative N-methyl-norsalsolinol (2-MDTIQ) was discovered in lumbar cerebrospinal fluid and brain of patients with Parkinson's disease. To establish whether 2-MDTIQ is toxic to the dopaminergic system, 2-MDTIQ or 6-hydroxydopamine (6-OHDA) were stereotactically injected into the left medial forebrain bundle, and rotational behaviour and neurochemical changes were measured in female Wistar rats. Three weeks after lesioning rotational behaviour was assessed after administration of S(+)-amphetamine (5 mg/kg) and apomorphine (0.1 mg/kg). As expected, after 6-OHDA lesions S(+)-amphetamine as well as apomorphine markedly induced rotations ipsiversive or contraversive, respectively, to the lesion, and dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) levels of the ipsilateral caudate-putamen and accumbens nucleus decreased. Although a decline in the dopamine/DOPAC ratio indicated an enhanced dopamine turnover, striatal monoamine oxidase (MAO) activity remained unchanged when tested in vitro. After a 2-MDTIQ lesion S(+)-amphetamine also caused animals to rotate strongly, ipsiversive to the lesion, but there was no response to apomorphine administration. This 2-MDTIQ effect was not due to a reduction in dopamine metabolism of the ipsilateral caudate-putamen or mesencephalic structures, or, for example, a partial neurodegeneration of dopaminergic neurons, since dopamine metabolites levels and MAO activity were nearly unchanged. Thus, we suggest that 2-MDTIQ interacts with the effect of S(+)-amphetamine and probably leads to an insensitivity of the dopamine uptake/transporter system to S(+)-amphetamine in dopaminergic nigrostriatal neurons. An effect of 2-MDTIQ on presynaptic membranes of dopaminergic synaptosomes has never been reported, but will be an objective of our further studies.     

Evidence for a GABAergic nigrothalamic pathway in the rat

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.     

Dopamine neurons grafted unilaterally to the nucleus accumbens affect drug-induced circling and locomotion

Summary The purpose of the present study was to investigate the amplifying function of the nucleus accumbens septi region (NAS) in 6-hydroxydopamine (6-OHDA)-induced rotational behaviour by implanting fetal dopamine (DA)-rich mesencephalic cell suspensions unilaterally in the NAS of rats previously subjected to combined mesostriatal (MS) and NAS 6-OHDA lesions. First, all the rats received a unilateral 6-OHDA lesion of the ascending MS DA pathway, which produced an amphetamine-induced rotational asymmetry towards the lesioned side. In a second step, the rats received a local bilateral 6-OHDA lesion of the NAS which, as previously shown, caused a significant attenuation of the amphetamine-induced locomotor (1.5 mg/kg) and rotational (5 mg/kg) behaviour. Finally, some of these MS + NAS lesioned rats received a unilateral mesencephalic DA graft into the NAS ipsilateral to the original MS lesion. The unilateral DA-rich grafts in the NAS significantly elevated the amphetamine-induced locomotion and ipsilateral circling (opposite to the direction of rotation produced when a graft is placed in the ipsilateral caudate-putamen), suggesting that the NAS plays only an amplifier role in locomotor behaviour and not a directional role. In addition, these grafts significantly attenuated the supersensitive locomotor response observed in lesioned rats when given apomorphine (0.05 mg/kg). The findings emphasize the amplifying role of the NAS in locomotion and circling behaviour and they extend previous findings demonstrating the functional heterogeneity of the striatal complex as well as the regional specificity of the graft-derived functional effects. Moreover, the results argue against the notion that DA grafts can function through a diffusion of transmitter over large distances since, despite the large size of the grafts, the functional graft effects were well localized to the reinnervated NAS and ventromedial striatal regions. We conclude, therefore, that graft-induced amelioration of postural and locomotor deficits are affected through different parts of the striatal complex, and that multiple graft placements are required to produce more complete recovery of motoric behaviour in the DA-depleted brain.     

The role of the midbrain reticular formation in the expression of two opposing nigral denervation syndromes

The present study investigated the role of the midbrain reticular formation (MRF) in the expression of opposing locomotor asymmetries elicited from the medial and lateral substantia nigra pars compacta (SNC). It was found that unilateral MRF lesions produced ipsiversive circling that was potentiated by amphetamine. Lateral SNC lesions produced contraversive circling while medial SNC lesions caused ipsiversive circling. When SNC lesions were combined with MRF lesions animals circled ipsiversively as they did with MRF lesions alone regardless of whether the SNC lesion was in the medial or lateral part of the SNC. Taken together, the results are consistent with the notion that a striato-nigral-MRF system is an output path for circling derived from both the medial and lateral SNC.     

Reduction of apomorphine-induced rotational behaviour by subthalamic lesion in 6-OHDA lesioned rats is associated with a normalization of firing rate and discharge pattern of pars reticulata neurons

The effect of subthalamic nucleus (STh) lesion on apomorphine-induced rotational behaviour and unit activity of substantia nigra pars reticulata (SNr) neurons was studied in normal, sham-control and unilateral 6-OHDA-lesioned rats [SN pars compacta (SNc)-lesioned]. In the latter, contraversive rotational behaviour was greatly reduced by an additional ipsilateral STh lesion. A moderate ipsiversive rotation was observed in rats with a single STh lesion. Concurrently, SN unit extracellular recordings were performed in age-matched normal rats, sham-controls for both lesions, STh-lesioned rats, SNc-lesioned rats, and SNc-lesioned rats with an ipsilateral STh lesion (SNc+STh-lesioned). Pars reticulata neurons had a higher mean firing rate in SNc-lesioned rats than in control rats. Furthermore, 68% of SNr neurons in SNc-lesioned rats had a tonic discharge pattern (against 92.3% in control rats) and 32% a mixed or bursting pattern. After STh lesion, a clear decrease in SNr firing rate was observed in SNc-lesioned rats. Moreover, STh lesion improved interspike interval regularity and decreased the occurrence of bursting patterns. In rats with a single STh lesion, the firing rate was no different from that of the sham-controls but the discharge pattern was more regular. These data show that STh lesion decreased apomorphine-induced rotational behaviour in dopamine-depleted animals. This effect could be related to the suppression of the exitatory effect of STh efferents on the SNr neurons. STh lesion both counterbalanced the increased activity of SNr neurons and regularized their discharge pattern.     

GABA(A) agents injected into the ventral pallidum differentially affect dopaminergic pivoting and cholinergic circling elicited from the shell of the nucleus accumbens

The ability of GABA(A) receptors in the ventral pallidum to modulate shell-specific behavior was studied. Injections of the non-selective acetylcholine receptor agonist, carbachol (5 microg), into the shell of the nucleus accumbens elicited contraversive circling, namely turning marked by normal stepping; in contrast, injections of a mixture of dopamine D(1) (SKF 38393, 5 microg) and D(2) (quinpirole, 10 microg) receptor agonists into this brain structure elicited contraversive pivoting, namely turning marked by abnormal hindlimb stepping. Unilateral injections of the GABA(A) receptor agonist muscimol (10, 25 and 50 ng) into the ventral pallidum dose-dependently mimicked shell-specific circling, especially when given at a level +8.6mm anterior to the interaural line; this effect was GABA(A) receptor specific, because it was prevented by the GABA(A) receptor antagonist bicuculline (150 ng). Unilateral pallidal injections of a dose of muscimol that was ineffective per se (10 ng) abolished contraversive pivoting elicited by shell injections of dopamine receptor agonists; instead, it elicited moderate ipsiversive pivoting. Pallidal injections of bicuculline (150 ng) replaced the contraversive pivoting elicited by dopamine receptor agonist with ipsiversive circling. In contrast, unilateral pallidal injections of 10 ng muscimol (anterior +8.6mm level) suppressed the contraversive circling elicited by shell injections of carbachol; instead, it elicited moderate ipsiversive pivoting. Pallidal injections of bicuculline (150 ng) produced short-lasting ipsiversive circling that was followed by contraversive pivoting.We conclude that the ventromedial portion of the ventral pallidum contains GABA(A) receptors that are crucial for the transmission of information from the shell of the nucleus accumbens via the ventral pallidum towards other brain structures; this holds especially for information about shell-specific circling elicited by carbachol. The same portion of the ventral pallidum also contains GABA(A) receptors that control the transfer of information from the nucleus accumbens towards structures outside the ventral pallidum; this holds especially for information about shell-specific pivoting elicited by dopaminergic agonists.     

Opposed locomotor asymmetries following lesions of the medial and lateral substantia nigra pars compacta or pars reticulata in the rat

In animals with lesions in the medial or lateral portions of the substantia nigra pars compacta (SNC) amphetamine produces circling in opposite directions. The present study examined the relationships between lesion site and the direction of circling using glyoxylic acid histofluorescence to visualize DA cells. Lesions were produced by 6-hydroxydopamine (2–6 μg) or 0.05% ascorbate injected into the SN. After lesions in the medial SNC, amphetamine caused rats to circle ipsiversive to the lesion while after lateral SNC lesions rats circled contraversively. When the lesion extended to the middle of the SNC, or deeper into the SN pars reticulata (SNR), the direction of circling was unpredictable. When the damage produced by the cannula track and ascorbate injection was in the lateral SNR animals circled ipsiversively while medial SNR damage led to contraversive circling. Thus the medial and lateral SN, and the pars compacta and pars reticulata, are functionally antagonistic. This four way division of the SN is consistent with the topographic mapping of SNC to striatum and striatum to SNR.     

Opposite locomotor asymmetries elicited from the medial and lateral substantia nigra: role of the superior colliculus

The present study investigated the role of the superior colliculus (SC) in the expression of opposing locomotor asymmetries elicited from the medial and lateral substantia nigra pars compacta (SNC). In experiment one it was found that amphetamine stimulated ipsiversive circling produced by unilateral SC lesions was additive with the ipsiversive circling produced by alpha-flupenthixol microinjections into the lateral SNC but was not additive with the contraversive circling produced by such injections into the medial SNC. Experiment two showed that the amphetamine stimulated ipsiversive circling produced by unilateral SC lesions was additive with the contraversive circling produced by lateral SNC lesions but was not additive with the ipsiversive circling produced by medial SNC lesions. Both experiments were taken to suggest that the striato-nigral-colliculus system is an output path for medial SNC derived circling but is not an output path for the opposing circling behavior derived from the lateral SNC.     

Striatal grafts in rats with unilateral neostriatal lesions--III. Recovery from dopamine-dependent motor asymmetry and deficits in skilled paw reaching

This study investigated the functional capacity of intrastriatal grafts of embryonic striatal tissue in rats with unilateral ibotenic acid lesions of the neostriatum. The group of grafted rats was compared with lesion-alone and control groups for motor bias, as assessed by tests of rotation induced by dopaminergic, cholinergic and GABAergic drugs, and of skilled paw reaching. Unilateral striatal lesions induced marked ipsilateral turning to apomorphine and methamphetamine, which was substantially ameliorated in the grafted rats. Atropine induced similar rates of moderate (but non-significant) ipsilateral turning in the lesion and graft groups, whereas muscimol and gamma-acetylenic GABA induced no turning bias in any group. The lesioned rats showed a strong bias in their preference to use the paw ipsilateral to the lesion when reaching for food pellets, and a decline in reaching success with both paws. The grafts did not influence the ipsilateral paw preference in this task, but did provide a substantial improvement in the animal's reaching accuracy and ability to retrieve food with either paw. The results indicate that striatal grafts can provide a substantial amelioration of motor impairments induced by striatal lesions. Moreover they suggest that the graft's influence on the host brain is itself under the functional regulation of an afferent dopaminergic input from the host brain.