Psychopharmacology (1984) 83:56-61 Psychopharmacology Springer-Verlag 1984 Effects of inescapable shock and norepinephrine depletion induced by DSP4 on escape performance Hymie Anisman, Christine Beauchamp, and Robert M. Zacharko Department of Psychology, Carleton University, Ottawa, Ontario, Canada Abstract. The potential contribution of dorsal bundle norepinephrine (NE) in the induction of escape disturbances engendered by inescapable shock was evaluated following administration of the NE neurotoxin, DSP4. Treatment with DSP4 produced marked NE reductions in the hippocampus and cortex, a moderate reduction of NE in the locus coeruleus, but only small effects on hypothalamic NE. In contrast to the effect of inescapable shock, DSP4 was found not to influence escape behavior among naive mice or mice that had received inescapable shock. Moreover, DSP4 was without effect on escape performance irrespective of whether animals were indi- vidually or group housed, a treatment that has been shown to be sensitive to manipulations that influence escape per- formance. Treatment with DSP4 was found not to influence the escape interference ordinarily provoked by either haloperidol or ~-MpT. Interestingly, the escape interference ordinarily engendered by the dopamine-13-hydroxylase inhibi- tor, FLA-63, was ehminated among mice that had been pre- treated with DSP4. The interference effect induced by inescap- able shock is probably not attributable to NE alterations in the hippocampus and locus coeruleus. Serial or parallel effects of shock on more than a single transmitter system are likely to be responsible for the behavioral interference. Key words: Norepinephrine - DSP4 - Inescapable shock - Escape behavior Exposure to uncontrollable shock has reliably been shown to provoke deficits of subsequent escape performance, characterized by passivity and repeated failures to escape from the aversive Stimulus (Anisman et al. 1978; Maier and Seligman 1976; Weiss et al. 1976). The finding that inescapable shock reduced concentrations of norepinephrine (NE) in several brain regions, including the hypothalamus, hippocampus, cortex and locus coeruleus (Anisman et al. 1981 a; Weiss et al. 1976, 1981) prompted the suggestion that the escape interference was subserved by the NE decline (e.g., Anisman et al. 1979a; Weiss et al. 1976, 1981). In accordance with such a formulation, it has been demon- strated that pharmacological manipulations that reduce central NE concentrations mimic the escape interference engendered by inescapable shock (e.g., Anisman et al. 1979; Glazer et al. 1975). Such treatments were found to disrupt escape performance exclusively under those test conditions where inescapable shock was effective in this respect (Anis- man et al. 1979a; Weiss et al. 1976). Offprint requests to: H. Anisman Although considerable evidence has accumulated im- plicating NE involvement in the stress-induced escape interference, limited data are available concerning the par- ticular brain regions fundamental to the provocation of the behavioral disturbances. The finding that reductions of NE are attained more readily in the hypothalamus than in other brain regions (Anisman et al. 1983; Nakagawa et al. 1981) and escape deficits are evident even when NE reductions are not evident in regions other than the hypothalamus (e.g., Anisman et al. 1983) suggests that alterations of hypo- thalamic NE subserve the interference. However, Weiss et al. (1981) indicated that the time course for the behavioral disturbances induced by inescapable shock in a swim task paralleled the NE reductions in locus coeruleus more closely than the hypothalamic NE alterations. Accordingly, the sug- gestion was made that the interference effect is mediated by alterations of NE in the locus coeruleus. On the basis of experiments involving intracranial administration of drugs, Sherman and Petty (1980) suggested that behavioral disturbances would result either from a deficiency of septal serotonin (5-HT) release, or from a failure of hippocampal NE release. The present investigation was undertaken to assess further the contribution of NE alterations in forebrain structures and in the locus coeruleus on the escape perfor- mance. It was recently shown that systemic administration of the neurotoxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzyl- amine (DSP4), markedly reduces NE in the hippocampus and cortex, has lesser effects on NE in the locus coeruleus, but has only limited effects on hypothalamic NE neurons (Bruto et al. 1984; Jaim-Etcheverry and Zieher 1980; Jons- son et al. 1981 ; Ogren et al. 1980). Moreover, this compound has limited effects on DA concentrations, and does not appreciably influence 5-HT concentrations in cortex (Jons- son et al. 1981; Ogren et al. 1980). Thus, substantial and selective reductions of NE can be achieved without the neces- sity of subjecting animals to the stress of stereotaxic surgery and anesthesia. If the escape interference is due to reductions of NE in the dorsal bundle, then systemic admin- istration of DSP4 should result in escape deficits comparable to those seen after inescapable shock or after treatment with a dopamine-13-hydroxylase inhibitor that results in more widespread NE reductions. Experiment I If alterations of dorsal bundle NE are responsible for the escape interference engendered by inescapable shock, then treatment with DSP4 should engender an escape interference