6-OHDA Lesions Of Substantia Nigra Research Articles

Behavioral and subthalamic effects of combining a fetal ventral mesencephalic transplant in striatum with an electrolytic lesion of the entopeduncular nucleus in the rat with a unilateral 6-OHDA lesion of substantia nigra.

Behavioral and electrophysiological methods were used to determine whether a transplant of dopamine-rich fetal tissue in striatum combined with an electrolytic lesion of the entopeduncular nucleus have additive effects in the unilaterally lesioned rat model for Parkinson's disease. The subjects were rats with the left substantia nigra lesioned with 6-hydroxydopamine (6-OHDA) and responding to systemic amphetamine with rotation toward the side of the lesion (ipsilateral rotation). The motor response to amphetamine was fractionated into six aspects, half reflecting the unilateral deafferentation in striatum and half representing those aspects of the response evoked in normal rats. After collection of baseline values, 25 rotators received a transplant of fetal ventral mesencephalic tissue in the left striatum and 20 received a transplant and, at the same time, an electrolytic lesion of the left entopeduncular nucleus. Testing for the motor response to amphetamine resumed after 4 weeks of recovery and continued at weekly intervals for 5 weeks. Upon completion of these tests, each rotator was implanted with multiple electrodes in the subthalamic nucleus. After recovery, multiunit responses to amphetamine and apomorphine were recorded from several electrodes in parallel during the motor response to the drugs. In rotators with transplant only, treatment with amphetamine evoked oral stereotypy and an attenuated ipsilateral rotation response. In rotators with combined transplant and entopeduncular lesion, ipsilateral rotation did not change or increased. Subthalamic responses to amphetamine and apomorphine were larger in rotators with combined transplant and entopeduncular lesion than in rotators with transplant alone. These findings indicate that the combination of transplant and pallidotomy in the 6-OHDA rat model for parkinsonism does not lead to additive benefits, an effect that may have been due to the nonselectivity of the electrolytic damage and/or of the lesion extending beyond the entopeduncular nucleus into the lateral hypothalamus.

Collicular picrotoxin alleviates akinesia but not sensory neglect in rats with bilateral 6-hydroxydopamine lesions of ventral midbrain

Anatomical and biochemical investigations have suggested that GABA transmission in the superior colliculus consequent upon activity of the nigrotectal pathway is increased following 6-hydroxydopamine (6-OHDA) lesions of the ascending dopamine systems. Moreover, it has been proposed that this increase in inhibitory activity within the colliculus may be responsible for the sensory neglect commonly observed after dopamine denervation. The present experiment sought to test this proposal by examining the effects of injections of the GABA antagonist picrotoxin into the superior colliculus of 6-OHDA lesioned rats, in the hope that the neglect caused by the 6-OHDA would be reversed. However, in 33 of 36 cases studied intracollicular microinjections of picrotoxin produced no detectable improvement in orientation to sensory stimuli, although a wide range of other behavioural effects was observed. These included stereotyped exploratory movements (e.g. head waving, walking, sniffing and rearing) similar to those produced in the 6-OHDA treated rats by systemic injection of apomorphine (0.1 mg/kg). These data indicate that 6-OHDA lesions of substantia nigra and ventral midbrain areas do not produce sensory neglect simply by increasing GABA transmission within the nigrotectal pathway. Instead, such an increase in nigrotectal activity may impair production of particular kinds of movement, possibly related to exploratory behaviour.

Handedness in rats: Blockade of reaching behavior by unilateral 6-OHDA injections into substantia nigra and caudate nucleus

Unilateral 6-hydroxydopamine (6-OHDA) injections into the nigrostriatal system of rats were used to interfere with a lateralized reaching-for-food habit, the so-called “handedness.” Experiment 1: Although injections of 6-OHDA into the substantia nigra (8 µg/4 µl) ipsilateral (n=7) to the preferred forelimb had no effect on the overlearned instrumental reaction, reaching was blocked 15 min after contralateral (n=12) injection of the neurotoxin and remained suppressed for the 8 days of testing. At the same time, retrieval of food with the nonpreferred forepaw significantly increased. Although the rats failed to reach into the feeder, behaviors like grasping, grooming, or holding food pellets were intact in the “neglected” forepaw. Nonspecific effects such as changes in activity level or motivation could be ruled out by the ipsilateral-contralateral test paradigm used. The early behavioral asymmetries (blockade of handedness, flexion of the forelimb, and ipsilateral turning) are interpreted as due to interference of 6-OHDA with membrane structures of dopaminergic neurons. Experiment 2: Injections of 6-OHDA into the caudate nucleus contralateral (30 µg/5 µl, n=9) to the performing forelimb initially blocked handedness similarly as in Experiment 1. However, in contrast to nigral injections, reaching recovered within 6 days. Experiment 3: One month after a unilateral 6-OHDA lesion of substantia nigra, naive rats (n=7) acquired the reaching-for-food habit with the paw ipsilateral to the lesion. It is concluded that the blockade of handedness produced by unilateral 6-OHDA lesions of substantia nigra is not due to paralysis of the forelimb but to faulty integration of the contralateral somatosensory signals with contralateral motor patterns.

Asymmetry of optokinetic trace phenomena induced by unilateral 6-OHDA lesion of substantia nigra in the rabbit

Prolonged (1 h) optokinetic nystagmus (OKN) is followed in darkness by reversed postoptokinetic nystagmus (RPN) lasting 20–30 min in intact rabbits. Unilateral 6-OHDA lesion (10 μg/5 μl) of left substantia nigra did not disturb symmetry of the OKN reactions to monocular stimulation of either eye but weakened RPN induced by stimulation of the right eye. This RPN asymmetry was unaffected by amphetamine (2.5 mg/kg) but was reversed by apomorphine (1 mg/kg). It is concluded that the nigrostriatal system contr ibutes to the development of the neural trace underlying RPN.

Conditioning compensates the neglect due to unilateral 6-OHDA lesions of substantia nigra in rats

The degree of the contralateral sensory neglect in rats with unilateral 6-OHDA lesions of substantia nigra was assessed by a conditioning procedure, employing lateralized CS. In the first experiment visual neglect (revealed by failure of the visually elicited placing reaction contralateral to the lesion) was shown to be accompanied by slower acquisition of a brightness discrimination task. The impairment was due to ipsilateral turning tendency rather then to visual deficit, however, since monocular relearning yielded equal savings with the ipsilateral and contralateral eyes. The second experiment showed that rats anesthetized with urethane reacted to noxious skin stimulation contralateral to the lesion with shorter-lasting EEG arousal than to ipsilateral stimulation of the same intensity. The electrophysiological asymmetry could be compensated by classical conditioning, i.e. by pairing habituated tactile stimuli with noxious tail shock. The conditioned arousal reaction could be elicited with the same efficiency from the neglected and intact body surface. It is concluded that neglect is due neither to a sensory nor to a motor failure, but that 6-OHDA lesions of substantia nigra in one hemisphere reduce the arousing efficiency of unconditioned stimuli and interfere with sensorimotor integrating mechanisms on the side contralateral to the lesion. Compensation of the neglect by conditioning indicates that the role of the nigrostriatal system can be partly substituted by other circuits.

The central effects of a novel dopamine agonist

A new peripheral dopamine agonist which causes dopaminergic renal vasolidation, was tested for central dopaminergic activity. SK & F 38393 stimulated the dopamine-sensitive adenylate cyclase in homogenates of rat caudate, as a partial agonist, and caused contralateral rotation in rats with unilateral 6-OHDA lesions of substantia nigra. Rotation was shown to be due to a direct effect on supersensitive dopamine receptors. Stimulation of cAMP formation and rotation were blocked by dopamine antagonists. In contrast to other dopamine agonists, SK & F 38393 did not cause stereotypy, emesis or inhibition of prolactin release, nor did SK & F 38393 affect dopamine turnover. The results suggest that SK & F 38393 may selectively stimulate supersensitive central dopamine receptors in vivo or may activate only a certain subclass of dopamine receptors including the receptor in the renal vasculature and the adenylate cyclase coupled postsynaptic receptor in the caudate.