OUTLINE OF THESIS PROJECT
The medial preoptic area (MPOA) is the most important integrative brain area for male sexual behavior. Stimulation of the MPOA enhances sexual behavior in the male rat. Neurotransmitters such as dopamine and glutatamate are responsible for stimulating this brain region and both have regulatory effects on the male’s sexual behavior. It has been shown that lesions of the MPOA impair the male’s behavior. Blocking dopamine and glutamate receptors in the MPOA produce a severe decline in copulation.
Glutatmate is the most common excitatory neurotransmitter in all species. There are two types of glutamate receptors, iontropic and metabotropic. Ionotropic recepetors open ion channels in the cell and are fast acting. Important ionotropic receptors include AMPA receptors, which are linked to sodium channels, and NMDA receptors, which are linked to calcium channels. Sodium entry through AMPA receptors is necessary for generating action potentials in neurons. When calcium enters the cell through NMDA receptors, it activates enzymes in the cell that can produce longer-term effects. Neural activity is dependent upon these receptors for various activities including communication between cells. Metabotropic receptors change the metabolic processes within a cell and usually function more slowly, but usually with longer effects. Metabotropic glutamate receptors can regulate neurotransmitter release from presynaptic axon terminals also act on the postsynaptic dendrites and can affect learning.
Previous data from Dr. Hull’s laboratory has shown that blocking NMDA receptors impaired copulation ability in the male rat. Also, inhibition of NMDA receptors blocked the facilitative effects of exposing sexually naïve males to a receptive female that was placed above the male’s cage (Vigdorchik et al, 2003). In addition to this study, further work has shown that increasing glutamate in the MPOA facilitates copulation in males (Dominguez, Gil, and & Hull, 2006). This study showed that enhanced extracellular glutamate resulted in more ejaculations, less time to reach ejaculation, and less time reinitiate sexual activity after reaching ejaculation.
This information leads to our current aim in research. It is our goal to test whether an metabotropic glutamate agonist at mGluR1 receptors will facilitate male rat sexual behavior. Using 20 Long Evans rats, we will perform intracranial surgery and cannulae implantation for microinjection procedures. The mGluR1 agonist will be purchased from Tocris Cookson and will be our primary drug for testing glutamate activity in the MPOA. Microinjections of two doses of the agonist or the vehicle will be administered and behavioral testing will measure the numbers and latencies of various sexual behaviors. Animals will be tested first while they are sexually naïve. They will then be given additional experiences with receptive females and will be retested as experienced animals. In the experienced animals, the order of drug doses will be counterbalanced. Statistical analysis (analysis of variance) will be used for both the naïve and experienced tests to determine the level of significance of the results. Histology will be used at the conclusion of the experiment to determine if the areas of microinjections were in the correct area of the brain, the MPOA.
We anticipate that the mGluR1 agonist will facilitate copulation in both naïve and experienced males; however, we expect the effect to be greater in the naïve animals. If there is sufficient time, we will also administer a mGluR1 antagonist in the MPOA of additional animals. We would expect the antagonist to inhibit copulation. These data will clarify whether metabotropic glutamate receptors, in addition to ionotropic receptors, in the MPOA contribute to the control of male sexual behavior.