Psychopharmacology (1991) 105:433-438 0033315891002297 Psychopharmacology © Springer-Verlag 1991 Effects of long-term administration of imipramine on reticular-elicited hippocampal rhythmical slow activity Xiao-ou Zhu and Neff McNaughton Department of Psychologyand Centre for Neuroscience, University of Otago, P.O. Box 56, Dunedin, New Zealand Received April 10, 1991 / Final version April 22, 1991 Abstract. All anxiolytics so far tested show a common reduction in the frequency of reticular-elicited hippocam- pal rhythmical slow activity (RSA). The present experi- ments tested whether imipramine, an antidepressant drug which has also been used to treat generalized anxiety disorders, shares the common characteristics of anxiolyt- ics on hippocampal RSA. Rats implanted with reticular stimulating electrodes and subicular recording electrodes received both acute and chronic injection of different doses of imipramine. Only relatively high doses (20 and 30 mg/kg, IP) of imipramine produced a reduction in RSA frequency after a single administration. Long-term administration of 20 mg/kg (but not 10 mg/kg, IP) imip- ramine induced an increase in baseline RSA frequency but there was no change in the acute frequency-reducing effect of the drug. These results suggest that changes in hippocampal RSA reflect different mechanisms of action for chronic versus acute treatment with antidepressant. It is possible that, at high doses, apparently anxiolytic effects of imipramine may be mediated by similar mech- anisms to conventional anxiolytic drugs. Key words: Imipramine - Rat - Reticular-elicited hippo- campal rhythmical slow activity Gray (1982) has proposed that anxiolytics owe their clinical effects to action on the septo-hippocampal sys- tem. In animals, anxiolytic drugs, septal lesions and hippocampal lesions all produce similar effects on a wide range of behavioural tasks. Hippocampal rhythmical slow activity (RSA) appears to provide the key to this similarity (Gray 1982; McNaughton 199 I). Of particular relevance to the present paper is the fact that anxiolytic drugs have a common action on RSA elicited by stimula- tion of the midbrain. All classical anxiolytics so far tested (the barbiturate amylobarbitone and the benzodiaze- pines chlordiazepoxide, diazepam and alprazolam), have Offprint requests to: N. McNaughton been shown to decrease the frequency of hippocampal RSA (McNaughton et al. 1986). This could arise because all of these classical anxiolytics or "minor tranquillizers" interact with the benzodiazepine-GABA receptor chloride ionophore complex. However, buspirone, a novel anxiolytic which does not interact with GABA and is not hypnotic, anticonvutsant or muscle relaxant, shares the same RSA frequency reducing effects as bar- biturates and benzodiazepines (McNaughton et al. 1988; Coop and McNaughton 1991). By contrast, haloperidol and chlorpromazine, two neuroleptics or "major tran- quillizers", which have in common with the anxiolytics a sedating action, did not affect the frequency of RSA (McNaughton et al. 1986). A variety of other compounds (alpha-methyl-p-tyrosine, p-chloro-phenylalanine, sco- polamine) are without effect in this test and also lack any known clinical anxiolytic action (McNaughton and Sedgwick 1978). Generally speaking, anxiety and depression are con- sidered to be two distinct psychopathological disorders. Anxiety disorder is most often treated with benzodiaze- pines or, more recently, the novel anxiolytic buspirone; whereas unipolar depression is most often treated with antidepressants. However, the symptoms of the two classes of disorder coexist in most patients and anti- depressants appear to show some anxiolytic effects in clinical treatment. This could arise because the apparent anxiolytic effects of antidepressants are secondary to changes in depression. However, in a clinical study of 242 patients diagnosed as having anxiety disorder excluding panic-phobic disorder, Kahn et al. (1986) found that imipramine had a powerful antianxiety effect and that this effect was neither dependent on the patient's baseline depression nor secondary to concurrent antidepressant effects. It is possible, therefore, that drugs which are nominally antidepressant or nominally anxiolytic may have some common actions in the central nervous system. An important characteristic of the treatment of de- pression as well as anxiety is that the antidepressants are clearly effective in humans only after 2 or more treatment