Evidence that the median raphé nucleus--dorsal hippocampal pathway mediates diazepam withdrawal-induced anxiety.
On the basis of our previous series of experiments we had postulated that the increased anxiety that occurred during diazepam withdrawal was mediated by increased 5-HT release in the hippocampus. The present series of experiments provide evidence for a major role of the median raphé nucleus (MRN) dorsal hippocampal pathway. Rats were treated once daily for 21 days with diazepam (2 mg/kg IP) and then tested after 24 h withdrawal in the social interaction test of anxiety. Relative to chronically vehicle treated animals, those withdrawn from diazepam were significantly more anxious and had significantly greater K(+)-evoked release of [3H]-5-hydroxytryptamine (5-HT) from slices of dorsal and of ventral regions of the hippocampus. Estimation of extracellular concentrations of 5-HT within the dorsal hippocampus, using in-vivo microdialysis, showed doubling in the levels of 5-HT in the rats withdrawn from chronic diazepam treatment. This just failed to reach significance, but 33% of the rats showed dramatic increases (650%). It was not possible to test these animals in the social interaction test, but it is proposed that only the diazepam-withdrawn rats with raised extracellular levels of 5-HT would have displayed increased anxiety. 5-HT1A receptor agonists injected into the MRN decrease the MRN firing rate, and hence the release of 5-HT in the dorsal hippocampus. As a further test of our hypothesis, we examined the effects of MRN injection of the 5-HT1A receptor agonist, 8-OH DPAT, on animals withdrawn from diazepam and tested in the low light familiar condition of the social interaction test. 8-OH DPAT (50-200 ng) dose-dependently reversed the anxiogenic effect of diazepam withdrawal, while having no effects in chronic vehicle-treated animals. These results provide clear evidence that the MRN-dorsal hippocampal 5-HT pathway is at least one of the pathways playing an important role in mediating diazepam withdrawal-induced anxiety.
Andrews
N
N
Psychopharmacology Research Unit, UMDS Division of Pharmacology, Guy's Hospital, London, UK.
File
S E
SE
Fernandes
C
C
Gonzalez
L E
LE
Barnes
N M
NM
D000818:Animals; D003975:Diazepam / Q000009:adverse effects*; D006624:Hippocampus / Q000737:chemistry / Q000503:physiopathology*; D007398:Interpersonal Relations; D008297:Male; D009434:Neural Pathways / Q000503:physiopathology*; D011903:Raphe Nuclei / Q000737:chemistry / Q000503:physiopathology*; D051381:Rats; D012701:Serotonin / Q000032:analysis / Q000378:metabolism; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology*
D012701:Serotonin; D003975:Diazepam