Dopamine in Male Sexual Behavior

1. Dopamine in Male Sexual Behavior Elaine M. Hull The Florida State University Psychology Department & Neuroscience Program

2. Neural circuits regulating sexual behavior NAc OB BST CTF MPOA VTA MeA Brain Stem

3. Neural circuits regulating sexual behavior NAc OB BST CTF MPOA VTA MeA Brain Stem

4. Neural circuits regulating sexual behavior NAc OB BST CTF MPOA VTA MeA Brain Stem

5. Neural circuits regulating sexual behavior NAc OB BST CTF MPOA VTA MeA Brain Stem

6. Neural circuits regulating sexual behavior NAc OB BST CTF MPOA VTA MeA Brain Stem

7. Our lab has focused on the medial preoptic area, which contains A14 periventricular DA neurons. It is the main integrative area for male sexual behavior in all vertebrate species.

8. Model for MPOA dopamine’s influence on male sexual behavior

9. Is dopamine released in the MPOA during copulation?

10. Gonadally intact males and T-treated castrates had increased extracellular DA during pre-exposure to a female and during copulation. Vehicle-treated 1-week castrates that copulated also showed DA increases, but those that did not copulate did not show the DA increase.

11. Whatelicits the MPOA DA release?

12. Large lesions of the amygdala abolished copulation, which was restored by apomorphine in the MPOA.

13. Smaller lesions of the MeA impaired, but did not abolish mating.

14. Basal DA levels in the MPOA were normal, but the DA response to the female was abolished.

15. Chemical stimulation of the MeA mimicked the MPOA DA response to a female.

17. Therefore, normal basal DA in the MPOA is sufficient for suboptimal copulation. The DA increase in response to a female facilitates mating and is mediated by input from the MeA. • But there are no DA neurons in the MeA. What elicits the DA increase?

18. Glutamatergic axons from the MeA and BNST to MPOA • Juan Dominguez, my former post-doc, showed that a few axons from the MeA, and numerous axons from the BNST, ended in the MPOA and contained glutamate.

19. Is glutamate released in the MPOA before and during mating?

20. Sexual activity increases glutamate in the MPOA of male rats. ** * Using 2 min microdialysis samples

21. ** Reverse dialysis of glutamate uptake inhibitors into the MPOA increased glutamate levels and facilitated mating. ** EJACULATION FREQUENCY EJACULATION LATENCY (sec) PEI (sec) * *

22. Therefore, glutamate is released in the MPOA during copulation, and it facilitates mating. • Does glutamate also affect MPOA DA levels?

23. Exogenous glutamate in the MPOA increased DA levels, but decreasedDOPAC and HVA DOPAC % CHANGE DA % CHANGE HVA % CHANGE Sample (6 min) Sample (6 min)

24. Nitric oxide has been reported to inhibit DA transport and increase DA levels in the striatum. • Could NO explain our results?

25. L-NAME blocked the glutamate-evoked DA release and the decreases in DOPAC and HVA. DOPAC % CHANGE DA % CHANGE HVA % CHANGE Sample (6 min) Sample (6 min) Metabolite levels were lower for animals receiving glutamate alone compared with those receiving glutamate+ L-NAME.

26. Exogenous glutamate in the MPOA increased DA levels, but inhibited metabolites: Role for NO? POSSIBLE EXPLANATIONS FOR THIS EFFECT: • Glutamate induces exocytocis of DA • Glutamate binds NMDA receptors, which allows for Ca2+ influx and induces NO production in NOS- containing cells. • Increased NO may inhibit DA uptake in neighboring terminals, prolonging DA’s effects & decreasing DA catabolism. • Increased NO might also increase extracellular DA by inducing vesicular leakage.

27. MPOA dopamine release during copulationdepends on nitric oxide L-NAME blocked mating-induced DA release in the MPOA.

28. Microinjection of L-NAME into the MPOA impaired copulation in sexually naïve (A) and experienced (B) males. B A

29. Sexually Experienced Males • Show increased preference for being with a receptive female.

30. Sexually Experienced Males • Increased preference for being with a receptive female. • Require less time and stimulation to achieve ejaculation.

31. Sexually Experienced Males • Increased preference for being with a receptive female. • Require less time and stimulation to achieve ejaculation. • Require less time to resume copulation after ejaculating.

32. Sexually Experienced Males • Increased preference for being with a receptive female. • Require less time and stimulation to achieve ejaculation. • Require less time to resume copulation after ejaculating. • Are more resistant to sexual impairments due to castration, brain damage, or stress.

33. Sexually Experienced Males • Increased preference for being with a receptive female • Require less time and stimulation to achieve ejaculation • Require less time to resume copulation after ejaculating • Are more resistant to sexual impairments due to castration, brain damage, or stress Is the MPOA implicated?

34. First Experience Repeated Experience Sexually experienced males had more Fos-ir in the MPOA resulting from mating to one ejaculation, than did naïve males that mated for the first time. Stronger Activation of the MPOA in Sexually Experienced Males

35. Does NOS in the MPOA contribute to exposure-induced enhancement of mating? L-NAME administration before each of seven non-copulatory exposures to an estrous female blocked exposure-induced enhancements on the drug-free test day. (Preliminary data suggest that a D1 antagonist has similar effects.)

36. NOS NMDAR1 % NOS w/NR1 Percentage Overlay NNS NS ES ENS Total NOS # Cells NNS NS ES ENS Sexual experience increases NOS-ir in the MPOA of male rats * * * Nearly all cells containing NOS also contained NMDA receptors. Sexual experience increased the number of NOS-ir cells in MPOA.

37. Sexual experience increases NOS protein concentration in the MPOA of male rats Sexually Experienced and Not Mated (EC) Sexually Experienced and Mated (EM) Sexually Naïve and Not Mated (NC) Sexually Naïve and Mated (NM) * MEAN DENSITY (PIXELS) * * NC NM EC EM

38. A major means of activating NOS is via NMDA glutamate receptors.Does an NMDA antagonist in the MPOA also impair sexual sensitization?

39. Blocking NMDA receptors in the MPOA impaired sexual sensitization. • Microinjecting MK-801 before each noncopulatory exposures to an estrous female impaired exposure-induced enhancements of: • number of mounts *

40. Blocking NMDA receptors in the MPOA impaired sexual sensitization. • Microinjecting MK-801 prior to repeated noncopulatory exposures to an estrous female impaired experience-induced enhancements on: • number of mounts • number of intromissions *

41. Blocking NMDA receptors in the MPOA impaired sexual sensitization. • Microinjecting MK-801 prior to repeated noncopulatory exposures to an estrous female impaired experience-induced enhancements on: • number of mounts • number of intromissions • number of ejaculations *

42. What intracellular messenger mediates NO’s effects?

43. Cyclic GMP mediates NO’s facilitation of DA release in the MPOA Inhibition of guanylyl cyclase blocked effects of the NO donor (sodium nitroprusside).

44. Cyclic GMP mediates NO’s facilitation of DA release in the MPOA Inhibition of NOS did not affect facilitation by cGMP analog, because cGMP is downstream of NOS.

45. Sexual stimulation NMDAr NOS Summary Glutamate Dopamine

46. Sexual stimulation NMDAr NOS NO Summary Glutamate Dopamine

47. Sexual stimulation NMDAr NOS NO Summary Glutamate Dopamine (Higher NOS w/ experience)

48. Postscript: Orexin/hypocretin increases mesolimbic DA activity and facilitates copulation

49. Copulation increased Fos-ir in orexin-containing neurons of perifornical LH. Double-labeled cells in Non-copulating males Double-labeled cells in copulating males

50. Castration decreased orexin-containing cells; E2 restored them.