Evidence from patients with Alzheimer's disease suggests that the basal forebrain cholinergic system is critical for normal mnemonic function. In support of this proposal, we have found that visual recognition memory in macaques is impaired following either excitotoxic lesions of this system or administration in normal monkeys of the muscarinic receptor antagonist scopolamine. Furthermore, our studies indicate that scopolamine affects other forms of memory besides recognition, such as object-reward association and spatial memory, though the latter to a lesser degree. In addition, we found that scopolamine affects primary as well as secondary memory, and memory storage, not retrieval. On a computer-automated memory test, we have shown that the cholinesterase inhibitors physostigmine, THA, and E2020 all produce significant, though small, improvements in performance. Conversely, the NMDA receptor antagonist MK-801 impairs recognition memory, and it does so to the same degree as scopolamine, although MK-801 also produces an increase in response bias, suggesting the two drugs act via different mechanisms. Using in vivo microdialysis in anesthetized monkeys, we have shown that THC increases acetylcholine release in the hippocampus on the first but not subsequent administrations, indicating that some form of acute tolerance had developed. Our microdialysis studies in awake monkeys indicate that acetylcholine levels increase when an animal is behaving compared to when it is sitting quietly. We are continuing to examine the neural mechanisms underlying the reinforcing properties of drugs of abuse such as cocaine. We previously showed that orally administered carbamazepine partially blocks cocaine self- administration in the monkey. We are now beginning to examine other longer-acting forms of carbamazepine for their ability to attenuate cocaine self-administration. We also have preliminary evidence showing that measurable levels of cocaine can be detected in reward- related brain structures such as the nucleus accumbens using in vivo dialysis and high performance liquid chromatography.
| Turchi, Janita; Saunders, Richard C; Mishkin, Mortimer (2005) Effects of cholinergic deafferentation of the rhinal cortex on visual recognition memory in monkeys. Proc Natl Acad Sci U S A 102:2158-61 |
