Adrenocortical responses to ether stress and neural stimuli in rats following the injection of 6-hydroxydopamine into the medial forebrain bundle

Adrenocortical responses, as expressed by changes in plasma corticosterone concentrations, after ether stress, or photic, acoustic, or sciatic nerve stimulation were studied in rats, with 6-hydroxydopamine or vehicle injected into the medial forebrain bundle (MFB). The neurotoxin partially inhibited the response to photic stimulation only, indicating the involvement of MFB catecholaminergic fibers in the transmission of this response which stimulates adrenocortical secretion.     

Differential adrenocortical responses to neural stimuli following intracerebroventricular injection of nicotinic acetylcholine receptor antibodies in rats

The aim of the present study was to investigate the involvement of central nervous system nicotinic receptors for acetylcholine in the adrenocortical responses to neural stimuli. Adult male rats received a daily intraventricular injection of partially purified nicotinic acetylcholine receptor antibodies (anti-AchR), obtained from a patient with myasthenia gravis, for 5 consecutive days. Control animals were treated similarly with immunoglobulins obtained from normal human serum. Blood samples were obtained under basal conditions or following photic, sciatic nerve stimulation, and acoustic stress. Treatment with anti-AchR increased basal ACTH and corticosterone levels (by approximately twofold) but inhibited the response to acoustic stress. The response to photic and sciatic nerve stimulation stress was not affected. This study demonstrated that nicotinic acetylcholine receptors may be differentially involved in the mediation of adrenocortical responses to neural stimuli.     

Single-cell responsiveness to sensory stimuli in the mediobasal hypothalamus of rats with partial hypothalamic deafferentations and medial forebrain bundle lesions

Neuroendocrine studies have demonstrated that photic, acoustic, and sciatic nerve stimulation produce adrenocortical discharges and these can be blocked by partial hypothalamic deafferentations and medial forebrain bundle (MFB) lesions. The effects of these sensory stimuli on single-cell activity of mediobasal hypothalamic (MBH) neurons were studied in intact male rats and in animals with anterior, anterolateral, and posterolateral hypothalamic deafferentations and bilateral MFB lesions. The data were analyzed as to changes in responsiveness, facilitation: inhibition ratio, patterns of firing, magnitude of response, frequency distribution, and sensory convergence. Photic projections enter the MBH both anteriorly and posteriorly and via the MFB, acoustic afferent fibers utilize the MFB, and the sciatic impulses arrive posteriorly. The MFB has also an inhibitory modulation on the photic, acoustic, and sciatic responses and AHD has the same effect on the latter. MFB lesions reduced most markedly the sensory convergence of the three modalities. The relation of these electrophysiologic findings to neuroendocrine studies on the neural pathways mediating adrenocortical responses are discussed.     

Effect of central serotonin depletion on adrenocortical responses to neural stimuli

In view of the possible role of serotonin in adrenocortical regulation, basal plasma corticosterone concentrations and the response to ether stress, photic, acoustic, or sciatic nerve stimulation, were studied in rats with 5,7-dihydroxytryptamine or vehicle injected into the raphe nuclei. The neurotoxin inhibited the response to photic stimulation without affecting the other modalities. This may suggest that the depletion of brain serotonin has a differential effect on the transmission of neural impulses which activate the adrenal cortex.     

Response of medial septal neurons to the lontophoretic application of glucocorticoids

Neuroendocrine studies have demonstrated that photic, acoustic, and sciatic nerve stimulation produce adrenocortical discharges and these can be blocked by partial hypothalamic deafferentations and medial forebrain bundle (MFB) lesions. The effects of these sensory stimuli on single-cell activity of mediobasal hypothalamic (MBH) neurons were studied in intact male rats and in animals with anterior, anterolateral, and posterolateral hypothalamic deafferentations and bilateral MFB lesions. The data were analyzed as to changes in responsiveness, facilitation: inhibition ratio, patterns of firing, magnitude of response, frequency distribution, and sensory convergence. Photic projections enter the MBH both anteriorly and posteriorly and via the MFB, acoustic afferent fibers utilize the MFB, and the sciatic impulses arrive posteriorly. The MFB has also an inhibitory modulation on the photic, acoustic, and sciatic responses and AHD has the same effect on the latter. MFB lesions reduced most markedly the sensory convergence of the three modalities. The relation of these electrophysiologic findings to neuroendocrine studies on the neural pathways mediating adrenocortical responses are discussed.     

Neural pathways that mediate the effects of afferent stimuli on paraventricular nucleus multiunit activity in freely moving rats

The direct involvement of the hypothalamic paraventricular nucleus (PVN) in the control of adrenocortical secretion is now generally accepted. In order to contribute to our understanding of the electrical activity of cells in this region during adrenocortical activation, we have recorded multiunit electrical activity (MUA) in response to acute neural stimuli in freely moving male rats and have examined the pathways involved. Photic, acoustic, olfactory, and sciatic nerve stimulation all increased PVN MUA by between 130% and 250%. These responses were selectively blocked, according to the stimulus modality tested, by radiofrequency lesions of central neural structures. Thus PVN responses to photic stimulation were blocked by lesions of the suprachiasmatic nuclei and reduced by mammillary peduncle lesions but were unaffected by lesions of the bed nuclei of the stria terminalis. Responses to acoustic stimulation were blocked by lesions of the mammillary peduncles but not by those placed in the suprachiasmatic nuclei, the septum, or the bed nuclei of the stria terminalis. Lesions of the septum blocked the response to sciatic nerve stimulation but did not affect the response to olfactory stimulation with amyl acetate fumes, which was blocked by lesions of the bed nuclei of the stria terminalis. The data confirm those obtained in endocrine studies concerning the neural pathways involved in the transmission of neural stimuli that produce adrenocortical activation.     

Hypothalamic afferent connections mediating adrenocortical responses that follow hippocampal stimulation

This study identified some neural pathways which mediate the adrenocortical responses that follow hippocampal stimulation. The increase in plasma corticosterone following dorsal hippocampus stimulation, in rats with electrodes chronically implanted under pentobarbital anesthesia, was blocked by dorsal fornix and lateral septal lesions and by small posterior hypothalamic deafferentation. Fimbria transection, lateral septal lesions, and posterior hypothalamic deafferentation, but not midbrain reticular formation lesions, also blocked the adrenocortical responses to ventral hippocampus stimulation. Our present and previous studies indicate that the dorsal and ventral hippocampal effects on the hypothalamus, which increase plasma corticosterone concentrations, are mediated by the dorsal fornix and fimbria, respectively, as well as by the lateral septum. A posterior hypothalamic input, which does not involve the medial forebrain bundle or the midbrain reticular formation is also essential for the activation of this response.     

Adrenal responses and neurotransmitters in posterior hypothalamic deafferentation

The effects of a small posterior hypothalamic deafferentation (PHD) on adrenocortical responses to peripheral neural stimuli were investigated in rats. PHD inhibited the rise in plasma corticosterone (CS) following photic and acoustic stimulation, but did not affect the adrenocortical response following sciatic nerve stimulation. PHD did not change the content of norepinephrine in the paraventricular nucleus of the hypothalamus, however, it reduced the serotonin content by about 30%. The possible role of serotonin or of another tonic caudal input into the hypothalamus for the activation of the pituitary-adrenocortical axis, following certain neural stimuli, is discussed.     

The topographical organization of the hippocampal projection to the septal area: a comparative neuroanatomical analysis in the gerbil, rat, rabbit, and cat

An experiment was performed to determine the origin of the projection from the hippocampus to the septal area in the subrimate mammalian nervous system. Lesions were made by aspiration or by radio frequency in 4 gerbils, 17 rats, 8 rabbits, and 7 cats. Survival times varied from 2–5 days. Tissues were stained principally with the Fink Heimer I method for identification of degenerating axons and their terminals. Following lesions destroying any one or more of the fields of the dorsal hippocampus of the gerbil, rat, rabbit, or cat, terminal degeneration was observed only in the medial septal area, olfactory tubercle, and adjacent portions of the diagonal band. In addition, lesions producing total destruction of all dorsal hippocampal fields also resulted in the presence of terminal degeneration restricted to the medial septal area. In contrast, superficial lesions of field CA1 of the ventral hippocampus produced terminal degeneration in the lateral septal area, nucleus accumbens, olfactory tubercle, and adjacent portions of the diagonal band. Similar findings were also observed following more widespread lesions of the ventral hippocampus which produced damage to other CA fields as well. Superficial lesions of the posterior crus of the hippocampus (i.e., a position midway between dorsal and ventral hippocampus) resulted in terminal degeneration localized to an intermediolateral region of the septum. Combined lesions of the dorsal hippocampus and fimbria produced widespread terminal degeneration in both the lateral and medial septum indicating that the axons contained within the fimbria arise only from the ventral hippocampus. Finally, lesions of the medial and lateral segments of the fornix of the cat produced terminal degeneration in the medial and lateral regions of the septum, respectively. These findings, collectively, indicate that the origin of the topographical projection to the medial and lateral septum are the dorsal and ventral hippocampus, respectively. This projection is unrelated to cytoarchitectonic fields within the hippocampus and is also invariant among the species considered in this study.     

Electrical signs of an oligosynaptic visual projection to the rat hippocampus

In rats with pons transection photic or optic nerve stimulation elicits a response in dorsal hippocampus with approximately with same latency, amplitude and time course as the response in striate cortex. After optic nerve stimulation a positive polyphasic deflection with the last peak at 10 ms is followed by a larger biphasic major deflection with peaks at 15 and 25 ms and later, slower deflections at intervals of 125 ms. The polyphasic deflection is maximal in the inferior part of the hippocampus but does not reverse polarity; the other deflections reverse above and below an isoelectric point in the hilum of the dentate gyrus, a distribution attributable to depolarization in the molecular layers, perhaps also cell bodies, of that structure. The major deflection is more sensitive to changes in optic nerve stimulus strength than the response in striate cortex and is more resistant to reduction in amplitude during repetitive stimulation, following frequencies up to 50/s. The pathway between retina and hippocampus for all parts of the response is interrupted by lesions in the tectum. The major deflection is abolished by lesions in the posterior cingulum. In the posterior cingulum the pathway has fast and slow components in the lower and upper portions, respectively, associated with the first and second parts, respectively, of the major deflection. The pathway is not interrupted by lesions in the fornix, septal nuclei, anterior cingulum, anterior medial thalamus or medial midbrain ventral to the superficial tectum. There are complex interactions, up to several hundred milliseconds in duration, between the response to optic nerve stimulation and those elicited by stimulation in the cingulum, midbrain and thalamus. Tonic influences on the dentate gyrus from cingulum and tectum are described.     

Neurogenic stimuli alter preoptic area and amygdala unit activity: central effects of olfactory projections on paraventricular nucleus units

Unit responses were recorded in the preoptic area and amygdala of conscious male rats during exposure to stressful neurogenic stimuli. Olfactory stimulation elicited increases in preoptic area activity on all occasions and also increased activity in the intercalating, medial, and basomedial nuclei of the amygdala, but not in other regions. Acoustic stimulation had less specific effects, even inhibiting unit activity in the central amygdala. A separate series of experiments using urethane-anesthetized rats was carried out to examine the effects of electrical stimulation of the medial amygdala and olfactory tubercle on single-unit activity within the hypothalamic paraventricular nucleus. Inhibition was the predominant response following olfactory tubercle stimulation while excitatory responses predominated following stimulation of the medial amygdala. This was the case particularly for those paraventricular nucleus units identified as projecting to the median eminence (P less than 0.005 vs unidentified cells). The results obtained may be related to the neural regulation of adrenocortical activity as well as higher central nervous activity and have been discussed within these contexts.     

The medial prefrontal cortex differentially regulates stress-induced c-fos expression in the forebrain depending on type of stressor

The medial prefrontal cortex (mPFC) plays an important inhibitory role in the hypothalamic-pituitary-adrenal (HPA) axis response. The involvement of the mPFC appears to depend on the type of stressor, preferentially affecting 'psychogenic' stimuli. In this study, we mapped expression of c-fos mRNA to assess the neural circuitry underlying stressor-specific actions of the mPFC on HPA reactivity. Thus, groups of mPFC-lesioned and sham-operated rats were restrained for 20 min or exposed to ether fumes for 2 min. In both cases, the animals were killed at 40 min from the onset of stress. Interestingly, bilateral lesions of the mPFC significantly enhanced c-fos mRNA expression in the hypothalamic paraventricular nucleus of restrained animals, an effect that was paralleled by potentiation of circulating ACTH concentrations in these animals. On the other hand, lesions of the mPFC did not affect neither PVN c-fos mRNA expression nor plasma ACTH concentrations in animals exposed to ether. Lesions of the mPFC also enhanced c-fos activation in the medial amygdala following restraint, but not following ether exposure. Additional regions whose activity was affected by mPFC lesions or stressor differences included the ventrolateral division of the bed nucleus of the stria terminalis, CA3 hippocampus, piriform cortex, and dorsal endopiriform nucleus. Expression of c-fos mRNA was nearly absent in the central amygdala of all stressed animals, regardless of lesion. Furthermore, prefrontal cortex lesions did not change stress-induction levels of c-fos in the CA1 hippocampus, dentate gyrus, anteromedial division of the bed nucleus of the stria terminalis, lateral septum, and claustrum. Taken together, this study indicates that the medial prefrontal cortex differentially regulates cellular activation of specific stress-related brain regions, thus exerting stressor-dependent inhibition of the HPA axis.     

Norepinephrine depletion in the amygdala inhibits CRF-41, ACTH, and corticosterone responses following photic simulation

The effects of amygdaloid norepinephrine depletion by 6-hydroxydopamine on changes in corticotropin releasing factor-41 (CRF-41) and serum adrenocorticotropic hormone (ACTH) and corticosterone levels, following neural stimuli were investigated. In intact animals, photic or acoustic stimulation caused CRF-41 depletion from the median eminence and a rise in serum ACTH and corticosterone levels. In rats with amygdalar norepinephrine depletion there were no changes in basal CRF-41, ACTH, or corticosterone levels. However, the above responses of the hypothalamo-pituitary adrenocortical axis were blocked following photic, but not acoustic, stimulation. These results indicate that the facilitatory role of the amygdala on the above responses following photic stimulation depends on the presence of norepinephrine in this region.     

Habituation to stress and dexamethasone suppression in rats with selective basal forebrain cholinergic lesions

Previous studies suggest a role for basal forebrain cholinergic neurons in enhancing the inhibitory influence of the hippocampus and medial prefrontal cortex (mPFC) on glucocorticoid stress responses mediated by the hypothalamic-pituitary-adrenocortical (HPA) axis. An inhibitory action of the basal forebrain cholinergic (BFC) system may occur through facilitation of stress-related information processing and maintenance of glucocorticoid receptor (GR) expression and negative feedback signaling in these target regions. The current study investigated the possibility that BFC input to the hippocampus contributes to habituation of the glucocorticoid response following repeated exposure to a stressor. Cholinergic lesions were made by microinjections of the immunotoxin 192 IgG-saporin into the medial septum/vertical limb of the diagonal band, and 3 weeks later rats were subjected to six daily sessions of restraint stress. Blood samples taken before, during and after acute stress revealed a significant increase in peak activation and protracted elevation of corticosterone in cholinergic lesioned rats. After 5 days of repeated stress, however, both groups habituated to the stressor, as indicated by similarly low corticosterone profiles throughout both the response and recovery period. Against that habituated background, rats were administered a dexamethasone challenge on day 6, so that feedback status could be examined. Dexamethasone-induced suppression of endogenous corticosterone before, during, and after stress was significantly attenuated in lesioned rats. The profile of dysfunction in glucocorticoid regulation after selective cholinergic lesions in young animals may be relevant to the adrenocortical hyperactivity and negative feedback deficits seen in conditions such as normal aging and Alzheimer's dementia, in which integrity of the basal forebrain cholinergic system is compromised.     

Basal forebrain knife cuts and medial forebrain bundle self-stimulation

Current autoradiographic and electrophysiological data suggest that fibers coursing from the diagonal band/medial septum and lateral preoptic area through the medial forebrain bundle (MFB) to the midbrain may carry the reward signals generated by lateral hypothalamic stimulation. To test this hypothesis, 40 rats were given a unilateral lateral hypothalamic stimulating electrode and an ipsilateral guide cannula for knife cut transection. In baseline self-stimulation testing, both the animal's capacity to respond for the stimulation and the reward efficacy of the stimulation were measured. A coronal plane knife cut transection was given following stabilization of baseline behavior, and any changes in response capacity and stimulation reward efficacy were observed for up to two weeks, beginning 24 h after transection. Cuts to the diagonal band/medial septal region or the outflow therefrom did not permanently or significantly alter stimulation reward effectiveness. Cuts in the lateral preoptic area or in the MFB just anterior to the stimulating electrode decreased stimulation reward effects only if considerable concomitant rostrocaudal tissue damage was apparent around the knife cut. Even in these cases, reward degradation was rarely permanent. These results suggest that the majority of reward-relevant fibers probably do not arise in forebrain nuclei rostral to the stimulating electrode. A possible role of neurons endemic to the lateral hypothalamus in stimulation reward effects is discussed.     

'Cat P300' disappears after septal lesions

Endogenous responses were recorded from 9 awake cats with loud and soft clicks randomly presented as rare (P = 0.15) or frequent (P = 0.80) stimuli; a reinforced tone CS (P = 0.05) resulted in a conditioned eye blink response and focused the cat's attention on the auditory stimuli. Subsequent to 12 preoperative recording sessions the medial septal area was lesioned in 7 cats and similar but more rostral lesions were placed in 2 cats. Thereafter, 12 postoperative recording sessions were carried out, the animals were terminated, and the brains processed for AChE histochemistry and histology of the lesioned areas. Destruction of the medial septum and vertical limb of the diagonal band of Broca resulted in a transient postoperative 'cat P300' followed by reduction and disappearance of the response. The hippocampus of these animals was characterized by marked AChE depletion. In contrast, the animals with lesions rostral to the medial septal area showed no postoperative change in the P300 response and no depletion of hippocampal AChE. These data indicate an important role for the medial septal area as a modulator of 'cat P300' generation possibly through the cholinergic component of the septohippocampal projection system.     

Age-Related Vulnerability of Developing Cholinergic Basal Forebrain Neurons Following Excitotoxic Lesions of the Hippocampus

Previous studies have demonstrated that depleting the hippocampus of endogenous neurotrophins via excitotoxic lesions fails to alter the viability of adult cholinergic septal/diagonal band neurons. Since cholinergic basal forebrain neurons may be more vulnerable during development, we investigated whether excitotoxic lesions produced in neonatal animals alter the viability of these cells. Postnatal Day 7, 10, 14, and 28 rats pups received unilateral intrahippocampal injections of ibotenic acid and were sacrificed 4 weeks later. At 7, 10, and 14 days of age, significant reductions in the number of choline acetyltransferase (ChAT)- and p75 nerve growth factor receptor (NGFr)-immunoreactive neurons were observed within the medial septum ipsilateral to the hippocampal lesion. In contrast, rats receiving similar lesions on Day 28 failed to display a significant reduction in ChAT-immunoreactive medial septal neurons. The magnitude of ChAT-immunoreactive neuronal loss within the medial septum and the age at which the lesion was made were inversely correlated (r² = 0.887), indicating that cholinergic septal neurons become less vulnerable to target removal as the cells develop. Similar results were observed in the vertical limb of the diagonal band although a small but significant loss of ChAT-immunoreactive neurons was seen in this structure ipsilateral to the hippocampal lesion when lesions were performed on Postnatal Day 28. At all age groups, many remaining cholinergic septal/diagonal band neurons appeared dystrophic with stunted fiber outgrowth. The present study demonstrates that unlike adult rats, removal of hippocampal target neurons during development alters the viability and morphology of cholinergic neurons of the medial septum and diagonal band. This suggests that target neurons which synthesize endogenous neurotrophins are needed for normal development of cholinergic basal forebrain neurons, but may not be required for the normal maintenance of the adult cell.     

In vivo evidence for a hippocampal adrenergic neuronotrophic factor specifically released on septal deafferentation

Denervation of the hippocampal formation in adult rats through lesions of the septohippocampal pathway was found to induce a trophic growth response in intracortical grafts of sympathetic superior cervical ganglia, and to stimulate regeneration of the intrinsic locus coeruleus adrenergic neurons following chemically induced axotomy. The grafted sympathetic adrenergic neurons grew very poorly into the adjacent hippocampus in animals with the septohippocampal pathways intact. A lesion of the ipsilateral fimbria-fornix or the medial septum-diagonal band area caused a massive stimulation of axonal growth from the transplanted ganglionic neurons into the denervated hippocampus. This increase was more than 100-fold by 1 month after lesion and about 10-fold by 3 months after lesion. Fluorescence histochemistry revealed that the lesion-induced ingrowth occurred primarily into those areas of the dentate gyrus and hippocampus which were denervated of their septal cholinergic afferents. In addition, the septal and fimbria-fornix lesions induced a marked increase in size and noradrenaline fluorescence of the grafted sympathetic neurons, without any clear-cut effects on the numbers of surviving neurons in the graft.This lesion-induced trophic growth response (increases in axonal outgrowth, cell body size and noradrenaline content) was specific for lesions of the septal (probably primarily cholinergic) innervation of the hippocampus. Thus, extensive denervations induced by lesions of the commissural or perforant path afferents, as well as selective lesions of the intrinsic adrenergic afferents from the locus coeruleus, had no clear-cut effects.The intrinsic central adrenergic neurons were also found to be responsive to the lesion-induced growth-stimulating mechanism. Thus, lesions of the fimbria-fornix or the medial septum-diagonal band area had a marked stimulatory effect on the regeneration of the locus coeruleus noradrenergic neurons after selective chemical axotomy (induced by 5,7-dihydroxytryptamine; 5,7-DHT). Thus, the adrenergic reinnervation of the initially denervated hippocampus was significantly accelerated by 3 weeks after the fimbria-fornix or septal lesions, and the increase persisted for at least 8–10 months after transplantation.These results provide evidence for an adrenergic neuronotrophic factor whose production in the hippocampus normally is under the control of non-adrenergic (probably cholinergic) afferents originating in the septal-diagonal band area. The actions of this putative factor on sympathetic adrenergic neurons resemble those induced by nerve growth factor (NGF). Interestingly, however, the results obtained after 5,7-DHT-induced axotomy indicate that central and peripheral adrenergic neurons are equally responsive, and thus that the putative central adrenergic neuronotrophic factor may play a normal physiological role in the regulation of axonal growth and regeneration within the central nervous system.     

Colchicine-induced deafferentation of the hippocampus selectively disrupts cholinergic rhythmical slow wave activity

It has been proposed that hippocampal rhythmical slow wave activity (RSA or theta-rhythm) induced by sensory stimulation (atropine-sensitive theta) is generated by the cholinergic septo-hippocampal system. Although ablations of the septum or its projections to the hippocampus disrupt hippocampal RSA, such non-selective lesions damage both cholinergic and non-cholinergic septo-hippocampal inputs. The present study assesses the effects of a selective septal neurotoxic lesion on hippocampal electrical activity. Colchicine, which has been reported to be selectively toxic to cholinergic neurons in the medial septum, was injected into the right lateral ventricle, and electrodes were implanted bilaterally into the dorsal hippocampus of female Sprague-Dawley rats. Hippocampal electrical activity was recorded 10-14 days later from the ipsilateral (colchicine-treated) and contralateral (control) hemispheres during locomotor activity or immobility. RSA ranging from 6.3 to 8.7 Hz was evoked in both hippocampi during mobility. Following i.p. administration of an anesthetic dose of urethane, hippocampal RSA at a frequency of 4 Hz could be elicited in the control hemisphere (n = 12) of all animals by pinching the tail. RSA was absent in 6 of 9 animals in the colchicine-treated hemisphere. RSA from control and treated hemispheres persisting after urethane administration was abolished by 5 mg/kg of scopolamine, thus verifying its cholinergic nature. A decrease in the number of choline acetyltransferase (ChAT)-immunoreactive neurons in the medial septum and a depletion of acetylcholinesterase (AChE)-staining in the hippocampus were evident in the hemisphere ipsilateral to colchicine administration. These data support the septal pacemaker hypothesis of hippocampal theta-rhythm and further demonstrate the neurotoxic effect of colchicine on septo-hippocampal cholinergic neurons by the induction of a functional alteration. The selective disruption of cholinergic neurons in the medial septum by colchicine provides a means to dissociate the contribution of septal cholinergic and non-cholinergic components to hippocampal electrical activity.     

Aversive stimulus attenuates impairment of acquisition in a delayed match to position T-maze task caused by a selective lesion of septo-hippocampal cholinergic projections

Infusion of 192 IgG-saporin (SAP) into the medial septum (MS) of rats selectively destroys cholinergic neurons projecting to the hippocampus and impairs acquisition of a delayed matching to position (DMP) T-maze task. The present study evaluated whether introduction of a mild aversive stimulus 30 min prior to training would attenuate the deficit in DMP acquisition caused by the SAP lesions. Male Sprague-Dawley rats received medial septal infusions of either artificial cerebrospinal fluid or SAP (0.22 microg in 1.0 microl). Fourteen days later, all animals were trained to perform the DMP task. Half of the SAP-treated animals and controls received an intraperitoneal injection of saline each day, 30 min prior to training. Results show that intraperitoneal saline attenuated the impairment in DMP acquisition in SAP lesioned rats. These results suggest that a mild aversive stimulus can attenuate cognitive deficits caused by medial septal cholinergic lesions.