CENTRAL NORADRENERGIC LESIONING USING ANTI-DBH-SAPORIN - ANATOMICAL FINDINGS

The ability to create lesions of discrete neuronal populations is an i mportant strategy for clarifying the function of these populations. Th e power of this approach is critically dependent upon the selectivity of the experimental lesioning technique. Anti-neuronal immunotoxins of fer an efficient way to produce highly specific neural lesions. Two pr evious immunotoxins have been shown to be effective in both the CNS an d PNS. They are OX7-saporin, which is targeted at Thyl, and 192-sapori n, which is targeted at the low affinity neurotrophin receptor, p75(NT R). I,the present study, we sought to determine if an immunotoxin targ eted at the neurotransmitter synthesizing enzyme, dopamine beta-hydrox ylase (DBH), could selectively destroy central noradrenergic neurons a fter intraventricular administration. This immunotoxin, which consists of a monoclonal antibody to DBH coupled by a disulfide bond to sapori n (a ribosome inactivating protein), has been shown to be selectively toxic to peripheral noradrenergic sympathetic neurons in rats after sy stemic injection. in the present study, immunohistochemical and Cresyl violet staining showed that the noradrenergic neurons of the locus co eruleus are destroyed bilaterally after intraventricular (i.c.v.) inje ction of 5, 10, and 20 mu g of anti-DBH-saporin (alpha-DBH-sap) into r ats. Complete bilateral lesioning of the A5 and A7 cell groups occurre d at the two higher doses. Lesions of the A1/C1 and A2/C2/C3 cell grou ps were incomplete at all three doses. Dopaminergic neurons of the sub stantia nigra and ventral tegmental area and serotonergic neurons of t he raphe, arl monoaminergic neurons that do not express DBH, survived all alpha-DBH-sap doses. The cholinergic neurons of the basal forebrai n, which are selectively killed by i.c.v, injection of 192-saporin, an d cerebellar Purkinje cells which are killed by OX7-saporin, were not killed by alpha-DBH-sap. These results show that alpha-DBH-sap efficie ntly and selectively destroys CNS noradrenergic neurons after i.c.v. i njection. The preferential destruction of locus coeruleus, A5, and A7 over A1/C1 and A2/C2/C3 may be due to more efficient access of the imm unotoxin to these neurons and their terminals after i.c.v. injection.