The long-term goal of the proposed studies is to provide novel therapeutic approaches for the treatment of mood disorders that will work more rapidly and more effectively than the currently available medications. The introduction of selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (Prozac) has revolutionized psychiatry. In addition to their effectiveness in the treatment of depression, SSRIs also have proven effective for the treatment of several mood disorders for which the older medications were ineffective. These disorders include anxiety, obsessive compulsive disorder, aggression, eating disorders and premenstrual syndrome. However, a lag time of about 2-3 weeks exists from the onset of medication until the first signs of improvement appear. This delayed onset of therapeutic effects is a severe problem. Some of the suicides of depressed patients occur during this lag time. Therefore, there is a great need to find therapeutic approaches that will work more rapidly. Studies supporting the parent grant indicate that treatment with SSRIs produces a delayed-onset, homologous desensitization of post-synaptic serotoninlA( 5-HT1A) receptors in the hypothalamus. This desensitization is most likely mediated by increased levels of 5-HT in the synapse and the resulting over-activation of post-synaptic receptors. Studies in depressed patients indicate that the therapeutic effectiveness of SSRIs is dependent on maintaining high levels of 5-HT in the synaptic cleft. The 5-HT reuptake mechanism is the primary mechanism terminating the activation of post-synaptic receptors by 5-HT in the synaptic cleft. However, the release of 5-HT from the nerve terminals is highly regulated by inhibitory 5-HT1A autoreceptors on the soma and dendrites of the serotonergic cells in the raphe nuclei and by inhibitory 5-HT1B/1D autoreceptors on the serotonergic nerve terminals in forebrain regions. Thus, the overall hypothesis is that during SSRI therapy, the inhibitory influences of 5-HT autoreceptors must be overcome to allow SSRIs to increase the levels of 5-HT in the synaptic cleft. The proposed studies will use in vivo microdialysis approaches to investigate the time courses of changes in both 5-HT1A and 5-HT1B/1D autoreceptors, and thus determine whether these receptors contribute to the delay in onset of fluoxetine-induced increase in extracellular levels of 5-HT in several forebrain regions. In addition, the studies will investigate whether combining fluoxetine with selective 5-HT1A and/or 5-HT1B/1D antagonists will accelerate the fluoxetine-induced increase in extracellular levels of 5-HT. The results of the present studies will provide the scientific foundation for the use of specific autoreceptor antagonists as adjunctive therapy with SSRIs to produce a more rapid and effective therapy of mood disorders.
