Opposite effects of intranigral ibotenic acid and 6-hydroxydopamine on motor behavior and on striatal neuropeptide Y neurons

Abstract

Unilateral lesions of the basal ganglia circuitry induce a disequilibrium of motor processing, most obviously expressed by the resulting circling behavior. Compensatory events, which reduce the motor asymmetry, could be accompanied by changes in neurotransmitter/modulator parameters in the involved brain regions. In the present investigation, the effects of an interruption of the striato-nigro-thalamic loop by ibotenic acid (IBO)-induced lesions of total substantia nigra (SN) on circling behavior and on striatal neuropeptide Y (NPY) neurons were compared with those after the selective destruction of the dopaminergic nigrostriatal projection with 6-hydroxydopamine (6-OHDA). Directly after the operation, IBO-lesioned rats showed a high circling rate to the side contralateral to the lesion, whereas 6-OHDA-lesioned rats showed ipsiversive circling. With the lesion-induced development of dopamine receptor supersensitivity, 6-OHDA-treated rats, when stimulated with the dopaminergic agonist apomorphine, change their circling direction to the contralateral side. Complete IBO lesions of the SN abolished this effect: rats continued to circle to the contralateral side. These observations suggest that not only the dopaminergic denervation of the striatum but also the imbalance in the activity of the thalamo-cortical projection (reduced after 6-OHDA, augmented after IBO) are instrumental in determining the degree and direction of circling. Quantification of NPY-immunoreactive neurons in striatum revealed a decrease in 6-OHDA lesioned rats after 3 days on the side contralateral to the lesion, an effect even more pronounced after 4 month's survival time. IBO-induced lesions of the SN had an opposite effect on NPY-immunoreactivity in the striatum: neuron counts were lower on the ipsi- than on the contralateral side. In addition, a time-dependent variation in total number of NPY- neurons was noted: during the early postoperative periods an increase, followed by a prolonged decrease to values below 50% of the controls after 4 months. Taken together, these results provide evidence that a dopaminergic deafferentation and its consequences on the nigro-thalamo-cortical loop will determine NPY expression in the striatal interneurons. In particular, it is suggested that the number of striatal NPY-neurons and the imbalance in cortical activity are tightly coupled in terms of a negative correlation.