Research reportCombined lesions of GABAergic and cholinergic septal neurons increase locomotor activity and potentiate the locomotor response to amphetamine

Potentiated locomotor response to amphetamine has been associated with an increased sensitivity of the dopaminergic system and used as a model of the positive symptoms of schizophrenia in rodents. The hippocampus, through the subiculum, modulates dopamine transmission and hippocampal or subicular lesions potentiate the locomotor response to amphetamine. However, little is known about the upstream structures controlling hippocampal/subicular activity towards the regulation of dopamine transmission. The main modulatory input to the hippocampus is the septal area, composed of the medial septum and vertical limb of the diagonal band of Broca (MS/vDBB). The so-called septohippocampal pathway includes cholinergic and GABAergic fibers reaching the hippocampus through the fimbria-fornix. While electrolytic lesions of the MS/vDBB potentiate the locomotor response to amphetamine, cholinergic damage in the MS/vDBB does not affect this response. Moreover, the role of the GABAergic connections has never been investigated. Therefore, we performed in rats lesions of cholinergic or/and GABAergic septal neurons and assessed locomotor activity, (i) in an unfamiliar environment, (ii) under baseline conditions (separating light-on and light-off periods) and (iii) in response to an amphetamine challenge. While single lesions had no effects, rats with combined lesions were hyperactive in all three conditions. Thus, damage to cholinergic and GABAergic septohippocampal neurons induced locomotor alterations qualitatively comparable to those produced by hippocampal and/or subicular lesions. Our results further suggest that the septum, through both cholinergic and GABAergic fibers, modulates the functional contribution of the hippocampus/subiculum in the regulation of mesolimbic dopamine transmission.