A parametric study of the effects of the noradrenaline neurotoxin DSP4 on avoidance acquisition and noradrenaline neurones in the CNS of the rat

Abstract

1 The effects of various doses of DSP4 on two-way active avoidance acquisition in rats and on central noradrenaline neurones were compared. 2 Doses of DSP4 from 3 mg kg-i.p. and upwards injected one week before the onset of the avoidance trials significantly impaired two-way avoidance learning. 3 The learning impairment caused by DSP4 (50mg kg-i.p.) lasted for at least 10 weeks. 4 Desipramine (20mg kg-1) injected either 30 or 60 min before DSP4 (50mg kg-1) antagonized the active avoidance impairment.5 A high dose of DSP4 (50mg kg-i.p.) produced profound decreases in dopamine-p-hydroxylase activity in the frontal cortex and in the concentrations of noradrenaline in various brain regions indicating degeneration of the locus coeruleus noradrenaline system. 6 Low doses of DSP4 (3 and 6mg kg Ii.p.) produced small but significant decreases in the concentrations of noradrenaline (NA) in some regions, e.g. cerebral cortex, hippocampus, olfactory bulb and spinal cord. 7 The avoidance impairment caused by the low dose of DSP4 (3 mg kg-) was absent when rats were tested 10 weeks after treatment nor was NA depletion present when NA was analysed 3 months after treatment.

Neurotoxic effects of DSP-4 on the central noradrenergic system in male zebra finches

“…Brain areas like the hypothalamus and basal forebrain that are innervated by the LT are much less affected. [3,26]. The neural distribution of DBH-ir fibers is affected in a similar fashion following DSP-4 treatment, except that significant decreases in DBH-ir are not seen until four days after treatment with profound decrements by day 5 [26].…”

“…In this species, DSP-4 treatment causes a rapid, dose-dependent reduction in NE levels and NE-ir which is maximal by 8−16 hours after treatment [3,26]. NE depletion is most pronounced in brain areas innervated by the LoC, including the hippocampus, cortex, and olfactory bulb.…”

“…Birds were fed a vitamin-supplemented (8 in 1, Pet Products) commercial finch seed mix, grit, water and cuttlebone ad libitum, supplemented with fresh greens and oranges. During the experiment, males were housed in individual cages (56 cm) 3 and stimulus females were group housed until needed. All animal care, experimental procedures, and euthanasia were carried out in accordance with protocols approved by the Institutional Animal Care and Use Committee of Hunter College of the City University of New York…”

“…We also wanted to verify that the hypothalamic NE innervation would be spared as it was previously when we administered DSP-4 systemically. To make our results more comparable to work done in rats and other species e.g., [3,26,65], we quantified the effects of DSP-4 treatment in male zebra finch brains using standard immunocytochemical procedures to visualize dopamine--hydroxylase (DBH)-containing neurons. DBH is the enzyme that catalyzes the conversion of dopamine to NE, and as such is a good marker of noradrenergic cells.…”

Lesioning of Locus coeruleus Projections by DSP‐4 Neurotoxin Treatment: Effect on Amphetamine‐Induced Hyperlocomotion and Dopamine D2 Receptor Binding in Rats

“…However, in more complex learning tasks, the locus coeruleusdenervated rats are less successful and the animals fail to engage in active behaviour necessary to cope with environmental changes (Archer 1983;Archer et al 1984), possibly due to an increase in neophobia and some reduction in their motivation to explore (Harro et al 1995).…”