, a selective inhibitor of type 4 cyclic AMP phosphodiesterase (PDE4), completely reversed the amnesic effects of MK-801 on working and reference memory (F[4,64] ϭ 11.10; p Ͻ .0001 and F[4,64] N-methyl-D-aspartate (NMDA) receptors are widely distributed in the brain; their density is highest in the hippocampal CA1 subregion (Monaghan and Cotman 1985; Monyeret al. 1994;Boyer et al. 1998). It has been shown that NMDA receptors in this area are very important in the regulation of synaptic plasticity and the process of learning and memory, especially long-term memory (Kesner and Dakis 1995;Morris et al. 1986;Nguyen and Kandel 1996;Kawabe et al. 1998). Meanwhile, NMDA elicits an increase in cAMP in the hippocampal CA1 area that is antagonized by the competitive antagonist DL-2-amino-5-phosphonovaleric acid (AP5) or removal of extracellular Ca 2 ϩ (Chetkovich et al. 1991). Antagonism of NMDA receptors not only blocks NMDA-induced increases in cAMP, but also impairs learning and memory (Morris et al. 1986;Nguyen and Kandel 1996;Kawabe et al. 1998;Chetkovich et al. 1991;Meehan 1996). These results indicate that cAMP is involved in the NMDA receptor antagonist-induced impairment of learning and memory.Rolipram, a selective inhibitor of type 4 cAMP-specific phosphodiesterase (PDE4), produces an increase in brain cAMP levels via the inhibition of its degradation Rolipram Antagonizes MK-801-Induced Memory Deficits 199 (Schneider 1984;Ilien et al. 1982). Behavioral studies show that rolipram inhibits locomotor activity and rearing induced by methaphetamine and produces biphasic effects on schedule-controlled behavior, increasing response rate at lower doses and decreasing response rate at higher doses (Iyo et al. 1995;O'Donnell and Frith 1999). It elicits a morphine-withdrawal-like behavioral syndrome characterized by head twitches, forepaw shaking, grooming and hypoactivity, which are related to a high level of cAMP (Wachtel 1982;Wachtel 1983). Rolipram also exhibits antidepressant-like effects in animal models and in patients with depressive disorders (O'Donnell and Frith 1999;Hebenstreit et al. 1989;O'Donnell 1993).Recently, rolipram has been shown to reverse the impairment of either working memory or reference memory induced by the muscarinic receptor antagonist scopolamine (Egawa et al. 1997;Imanishi et al. 1997;Zhang and O'Donnell 2000). Furthermore, PDE4 has been shown to be involved in NMDA receptor-mediated signal transduction mechanisms. Chronic treatment with rolipram up-regulates NMDA receptors in the rat hippocampus ; rolipram also attenuates the expression of the heat shock protein HSP-70 induced by the NMDA receptor antagonist MK-801 (Hashimoto et al. 1997). Thus, although there is no direct evidence linking the effect of rolipram to NMDA receptors, the results described above suggest that rolipram will reverse the amnesic effect of the NMDA receptor antagonist MK-801. Such a finding would suggest an important role for PDE4 and cAMP in signal transduction mechanisms for NMDA receptors that are involved in ...

The novel PDE4 inhibitors MEM1018 and MEM1091 enhance memory in a manner generally similar to rolipram. PDE4D may be the primary target for the PDE4 inhibitors in the mediation of memory.

Understanding the neurobiological mechanisms that regulate how the brain perceives the intoxicating effects of alcohol is highly relevant to understanding the development and maintenance of alcohol addiction. The basis for the subjective effects of intoxication can be studied in drug discrimination procedures in which animals are trained to differentiate the presence of internal stimulus effects of a given dose of ethanol (EtOH) from its absence. Research on the discriminative stimulus effects of psychoactive drugs has shown that these effects are mediated by specific receptor systems. In the case of alcohol, action mediated through ionotropic glutamate, gamma-aminobutyric acid, and serotonergic receptors concurrently produce complex, or multiple, basis for the discriminative stimulus effects of EtOH. These receptor systems may contribute differentially to the discriminative stimulus effects of EtOH based on the EtOH dose, species differences, physiological states, and genetic composition of the individual. An understanding of the receptor mechanisms that mediate the discriminative stimulus effects of EtOH can be used to develop medications aimed at decreasing the subjective effects associated with repeated intoxication. The goal of this symposium was to present an overview of recent findings that highlight the neurobiological mechanisms of EtOH's subjective effects and to suggest the relevance of these discoveries to both basic and clinical alcohol research.