Recovery of function after mesotelencephalic dopaminergic injury in senescence.

ABSTRACT

After intracerebral 6-hydroxydopamine injections that extensively damage the ascending mesotelencephalic dopaminergic projection, young adult rats develop severe sensorimotor deficits, including an inability to orient toward somatosensory stimuli. Many rats with such damage recover their localization of touch, and this recovery depends on the survival of a small proportion of the neostriatal dopaminergic terminals. Behavioral recovery appears to be mediated by an increased dopamine synthesis and release within surviving terminals and an increased responsiveness to dopamine of neostriatal neurons. The ability of aged rodents to increase activity at neostriatal dopaminergic synapses following partial injury to these neurons is remarkably intact, despite the reduced basal level of transmission at these synapses in senescence. First, 27-28-month-old rats recovered somatosensory localization after injury as readily as did 4-5-month-old animals that had equivalent neostriatal dopamine depletions. Second, old and young rats developed a similar degree of behavioral supersensitivity to apomorphine (0.25 mg/kg, i.p.) after unilateral 6-hydroxydopamine injections, as measured by contralateral turning. Third, injury to these neurons produced an equivalent increase in [3H]spiroperidol binding in the neostriatum of old and young rats at 5-7 weeks. Old rats suffered more extensive neostriatal dopamine depletions after intracerebral 6-hydroxydopamine injections than did young adult animals, particularly when small quantities (2 micrograms) of the neurotoxin were injected. This enhanced susceptibility to 6-hydroxydopamine of dopaminergic neurons in old rats could not be attributed to age differences in the placement of the injection cannula or the extent of the non-specific damage at the injection site. The implications of this enhanced susceptibility to the neurotoxin are discussed.