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Treatment of degenerating basal forebrain cholinergic neurons with nerve growth factor (NGF) in Alzheimer's disease has long been contemplated, but an effective and safe delivery method has been lacking. Towards achieving this goal, we are currently developing CERE-110, an adeno-associated virus-based gene delivery vector that encodes for human NGF, for stereotactic surgical delivery to the human nucleus basalis of Meynert. Results indicate that NGF transgene delivery to the targeted brain region via CERE-110 is reliable and accurate, that NGF transgene distribution can be controlled by altering CERE-110 dose, and that it is possible to achieve restricted NGF expression limited to but covering the target brain region. Results from animals examined at longer time periods of 3, 6, 9 and 12 months after CERE-110 delivery indicate that NGF transgene expression is stable and sustained at all time points, with no loss or build-up of protein over the long-term. In addition, results from a series of experiments indicate that CERE-110 is neuroprotective and neurorestorative to basal forebrain cholinergic neurons in the rat fimbria-fornix lesion and aged rat models, and has bioactive effects on young rat basal forebrain cholinergic neurons. These findings, as well as those from several additional non-clinical experiments conducted in both rats and monkeys, led to the initiation of a Phase I clinical study to evaluate the safety and efficacy of CERE-110 in Alzheimer's disease subjects, which is currently ongoing.

The colocalization of neurotensin- and cholecystokinin-like immunoreactivities was demonstrated in neurons of the ventral mesencephalon of the rat by using a double-labeling indirect immunofluorescence procedure for the simultaneous detection of two antigens in the same tissue section. Greater than 90% of the neurotensin-positive perikarya distributed throughout the ventral midbrain (primarily located in the ventral tegmental area, medial substantial nigra, and rostral and caudal linear raphe nuclei) were found to also contain cholecystokinin immunoreactivity. Neurons single-labeled for either peptide were also present, with those immunoreactive for cholecystokinin alone far outnumbering those containing only neurotensin. By combining the double-labeling colocalization technique with fluorescence retrograde tracing, some of the forebrain projections of these neurons were determined. Ventral mesencephalic neurons containing both neurotensin and cholecystokinin were found to project to the nucleus accumbens, prefrontal cortex, or amygdala. The present results, combined with those of previous studies, suggest that there are complex heterogeneous subpopulations of presumed dopaminergic ventral mesencephalic neurons which give rise to the ascending mesotelencephalic systems and which may contain both neurotensin and cholecystokinin, either peptide alone, or neither of these two peptides.

Local infusions of the nonselective dopaminergic agonist apomorphine into the subthalamic nucleus of rats has been shown to elicit orofacial dyskinesia which can be blocked by D1 but not D2 receptor antagonists. In the present study, we show that the selective D1 agonist A77636 also induces orofacial dyskinesia when injected into the subthalamic nucleus of awake rats, thus confirming a role for D1 receptors in this effect. We also examined the dyskinesia induced by intrasubthalamic injections of apomorphine in rats with an ipsilateral lesion of the nigrostriatal pathway. The orofacial response to local administration of apomorphine (1.0 μg) into the subthalamic nucleus was markedly increased in the lesioned rats. As in control rats, the enhanced behavioral response seen in lesioned rats was blocked by peripheral administration of D1 antagonists. Although D1 receptor binding autoradiography revealed no difference in D1 receptor binding in the subthalamic nucleus on the side of the lesion compared to controls, D1 binding was higher in the subthalamic nucleus on the side of the lesion compared to the contralateral side. The increased behavioral response observed after unilateral dopamine denervation suggests that the subthalamic nucleus is tonically regulated by dopaminergic projections from the substantia nigra. Furthermore, the data suggest that subthalamic D1 receptors may be involved in the development of dyskinesia induced by dopaminergic drugs. Synapse 37:298–307, 2000. © 2000 Wiley‐Liss, Inc.

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