Effects of intra-striatal GDNF on motor coordination and striatal electrophysiology in aged F344 rats  Kathryn E. Bowenkamp, Livia Ujhelyi, Elizabeth J. Cline, Paula C. Bickford* Department of Pharmacology, C-236, University of Colorado Health Sciences Center, Denver, CO 80262, USA Received 9 September 1999; revised 30 November 1999; accepted 6 December 1999 Abstract The purpose of this study was to examine whether improvement in motor function could be demonstrated in old rats, and to see if GDNF affected post-synaptic DA function. Aged (20 month old) versus young rats were tested following GDNF treatment for postural control by using an inclined balance beam and a wire grip strength test. Rats were also examined electrophysiologically for spontaneous striatal cell firing rate alone and in the presence of DA receptor agonists, and histologically for the intensity of striatal TH staining, and number of DA containing nigral cells. Behavior was significantly improved in the aged animals who received central GDNF infusions, although the extent of improvement was less than what has been observed in 16-month-old rats. There was no effect of GDNF treatment in the aged animals on spontaneous firing rate in the striatum, or on the post synaptic response to locally applied D 1 and D 2 receptor family agonists. However, there was an effect of age alone on firing rate, and on the response to locally applied SKF 38393 and quinpirole. By using unbiased cell counting we observed no age-related decline in the number of TH positive cells in the substantia nigra. There was no effect of GDNF on the number of TH positive cells in the substantia nigra in either young or aged rats, although there were morphological improvements in DA neurons of the GDNF treated aged rats. These results replicate earlier studies showing an effect of age on striatal firing rate and dopamine receptor function, and suggest that the GDNF mediated improvement in behavior may be located other than post synaptically within the striatum. © 2000 Published by Elsevier Science Inc. All rights reserved. Keywords: Aging; GDNF; Trophic factors; Striatum; Substantia nigra; Dopamine; Electrophysiology 1. Introduction Numerous previous studies have demonstrated that aging is associated with many central nervous system changes. These changes produce marked behavioral and biochemical alterations in many neurotransmitter systems. One of the more important changes described in both aged humans and animals is the degeneration of dopamine systems in the basal ganglia. For example, studies have shown changes in pharmacological responsiveness and thus differential effects on receptor function in DA systems due to age [13]. Addi- tionally, aged animals have shown decreased number of DA receptor binding sites in striatum and midbrain [1,6,14,16, 19]. Behavioral studies have repeatedly shown deficits in performance due to the effects of age. For example, aged animals show cholinergic and dopaminergic mediated mo- tor deficits [18] decreased labelling of DA neurons in the mesostriatal system that accompanies sensorimotor dys- function [4], and other behavioral impairments where DA systems are implicated [5,7,27]. DA involvement in move- ment disorders found in aged rats has also been demon- strated by the reversal of these disorders following dopa- mine receptor stimulation [22], and the prevention of nigrostriatal degeneration following neuroprotection with DA agonists [20]. Using electrochemistry, changes in pre- synaptic DA function have also been demonstrated in aged animals [10]. Aging caused decreased presynaptic DA clearance and attenuated neural DA release in these studies. Electrophysiological studies have shown an increase in cell firing rate of striatal neurons in aged rats which is accom- panied by a decrease in the post-synaptic sensitivity to both D1 and D2 agonists [13]. Freeman and coworkers reported  This work was supported by U.S. Public Health Services Grants AG04418 and AG00728 and the VAMRS and AMGEN. VAMRS = Department of Veterans Affairs Medical Research Service. AMGEN is not an abbreviation it is the name of a company. * Corresponding author. Tel.: +1-303-399-8020; fax: +1-303-331- 8324. E-mail address: Paula.Bickford@uchsc.edu (P.-C. Bickford). www.elsevier.com/locate/neuaging Neurobiology of Aging 21 (2000) 117–124 0197-4580/00/$ – see front matter © 2000 Published by Elsevier Science Inc. All rights reserved. PII: S0197-4580(00)00112-8