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The ventral subiculum (vSUB), a hippocampal efferent target implicated in learning and stress coping, receives cholinergic input and sends glutamatergic output to the bed nucleus of the stria terminalis (BNST). This study examined the roles of vSUB muscarinic activation and its interaction with BNST N-methyl-D-aspartate and noradrenergic receptors in formation of aversive memory. Male Wistar rats with cannulae implanted into the vSUB or BNST were trained on a step-through inhibitory avoidance task. Shortly after training, they received cholinergic drugs infused into the vSUB and/or glutamatergic or noradrenergic drugs infused into the BNST. Results of the 1-day retention tests showed that intra-vSUB infusion of oxotremorine (0.01 microg) or scopolamine (0.3 or 3.0 microg) enhanced or impaired retention, respectively. Both effects were dose- and time-dependent, and 0.001 microg oxotremorine attenuated the amnesia induced by 3.0 microg scopolamine. The oxotremorine-induced memory enhancement was blocked by intra-BNST infusion of DL-2-amino-5-phosphonovaleric acid or propranolol at a dose not affecting retention; the amnesia induced by scopolamine was blunted by intra-BNST infusion of glutamate or norepinephrine at a dose with a negligible effect on retention. These data suggest that in an inhibitory avoidance task muscarinic activation of the vSUB modulated memory formation by interacting with the BNST glutamatergic and noradrenergic functions.

Previous studies have reported that drugs affecting neuromodulatory systems within the basolateral amygdala (BLA), including drugs affecting muscarinic cholinergic receptors, modulate the consolidation of many kinds of training, including contextual fear conditioning (CFC). The present experiments investigated the involvement of muscarinic cholinergic influences within the BLA in modulating the consolidation of CFC extinction memory. Male Sprague Dawley rats implanted with unilateral cannula aimed at the BLA were trained on a CFC task, using footshock stimulation, and 24 and 48 h later were given extinction training by replacing them in the apparatus without footshock. Following each extinction session they received intra-BLA infusions of the cholinergic agonist oxotremorine (10 ng). Immediate post-extinction BLA infusions significantly enhanced extinction but infusions administered 180 min after extinction training did not influence extinction. Thus the oxotremorine effects were time-dependent and not attributable to non-specific effects on retention performance. These findings provide evidence that, as previously found with original CFC learning, cholinergic activation within the BLA modulates the consolidation of CFC extinction.

Growing evidence suggests that processes of synaptic plasticity, such as long-term potentiation (LTP) occurring in one synaptic population, can be modulated by consolidating afferents from other brain structures. We have previously shown that an early-LTP lasting less than 4 h (E-LTP) in the dentate gyrus can be prolonged by stimulating the basolateral amygdala, the septum or the locus coeruleus within a specific time window. Pharmacological experiments have suggested that noradregeneric (NE) and/or cholinergic systems might be involved in these effects. We have therefore investigated whether the direct intraventricular application of agonists for NE- or muscarinic receptors is able to modulate synaptic plasticity. E-LTP was induced at the dentate gyrus of freely moving rats using a mild tetanization protocol that induces only an E-LTP. NE or oxotremorine (OXO) were applied icv 10 min after the tetanus. Results show that low doses of NE (1.5 and 5 nM) effectively prolong LTP. A higher dose (50 nM) was not effective. None of the OXO doses employed (5, 25, and 50 nM) showed similar effects. These results stress the importance of transmitter-specific modulatory influences on the time course of synaptic plasticity, in particular NE whose application mimics the reinforcing effect of directly stimulating limbic structures on LTP.

Four cholinesterase inhibitors have been approved by the US Food and Drug Administration for treating behavioral symptoms of Alzheimer's disease. Here we review our experiences with two cholinesterase inhibitors (metrifonate and galanthamine) and a muscarinic acetylcholine receptor agonist (CI-1017) in behavioral pharmacological and brain slice experiments in aging and young rabbits. Aging rabbits are impaired in their ability to acquire the hippocampus-dependent trace eyeblink conditioning task, as compared to young controls. A large proportion of aging animals cannot reach behavioral criterion in this task. Those that do learn, do so more slowly. In addition, the post-burst afterhyperpolarization and spike frequency accommodation is increased in hippocampal pyramidal neurons from aging animals, i.e., cellular excitability is reduced as compared to those from young animals. Metrifonate, galanthamine, and CI-1017 reduced the learning deficits observed in aging rabbits so that they learned almost as quickly as young controls. These cholinergic compounds also enhanced the postsynaptic excitability of hippocampal pyramidal neurons in vitro. Therefore, we propose that the amelioration of learning impairment with the cholinergic compounds may in part be due to the enhanced excitability of hippocampal pyramidal neurons. The potential relevance of our studies to further understanding the cellular and behavioral changes that occur with normal aging and Alzheimer's Disease is discussed.

The present experiments were aimed at determining whether acetylcholine (ACh) plays a role in encoding and retrieval of spatial information using a modified Hebb-Williams maze. In addition, the present experiments tested two computational models of hippocampal function during encoding and retrieval using a maze sensitive to hippocampal disruption. Thirty male, Long-Evans rats served as subjects. Chronic cannulae were implanted bilaterally into the CA3 (n=26) and CA1 (n=5) subregions of the hippocampus. Rats were tested using a modified Hebb-Williams maze. In the first experiment, rats were injected with either saline or scopolamine hydrobromide 10 min before testing for each day. The number of errors made per day per group was used as the measure of learning. Encoding was assessed by the average number of errors made on the first five trials of Day 1 compared to the last five trials of Day 1, whereas the average number of errors made on the first five trials of Day 2 compared to the last five trials of Day I was used to assess retrieval. No deficit was found for the saline group. The scopolamine group showed a deficit in encoding, but not retrieval. In the second experiment, rats were injected with either saline or physostigmine 10 min before testing each day. In contrast to the scopolamine groups, the physostigmine group showed a deficit in retrieval, but not encoding. To test whether the retrieval deficit was due to a disruption in storage or gaining access to the information two groups of rats received either saline on Day 1 and physostigmine on Day 2 or physostigmine on Day 1 and saline on Day 2. In addition, one group received physostigmine immediately after testing on Day 1. Data indicate that physostigmine causes a disruption of retrieval by means of a disruption in consolidation process. In conclusion, the cholinergic antagonist, scopolamine, disrupts encoding in both CA3 and CA1 subregions of the hippocampus. Furthermore, the cholinesterase inhibitor, physostigmine, boosts ACh action during a time when cholinergic levels need to decline for proper consolidation.