The effects of the selective estrogen receptor modulator, raloxifene, on dopamine-induced locomotion depends on sex steroid background — ASN Events
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  3. The effects of the selective estrogen receptor modulator, raloxifene, on dopamine-induced locomotion depends on sex steroid background

The effects of the selective estrogen receptor modulator, raloxifene, on dopamine-induced locomotion depends on sex steroid background (#202)

Tertia D Purves-Tyson 1 2 3 , Kathryn Allen 1 3 4 , Danny Boerrigter 1 3 , Cyndi Shannon Weickert 1 3 4 , Vanezha Djunaidi 1 2 3
  1. Schizophrenia Research Laboratory, Neuroscience Research Australia, Sydney, Australia
  2. School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
  3. Schizophrenia Research Institute, Sydney, NSW, Australia
  4. School of Psychiatry, University of New South Wales, Sydney, NSW, Australia

Schizophrenia is a debilitating mental illness that often involves psychosis. Psychosis is attributed to increased dopamine in the striatum. Psychosis in women with schizophrenia is attenuated at times of high estrogen. Schizophrenia is more prevalent in men and men have a worse course of disease, attributed, in part, to less estrogen protective effects. The SERM, raloxifene, has been shown to attenuate psychosis in postmenopausal women with schizophrenia1. Raloxifene is potentially useful in men as it does not have feminizing side effects. Little is known about how raloxifene acts in the male brain. We have shown that testosterone in male rats induces dopamine pathway molecules leading to a potential hyperdopaminergia2,3. In this study we tested two hypotheses a) that adolescent testosterone increases subcortical hyperdopaminergia and b) that this testosterone-induced hyperdopaminergia would be reversed by raloxifene. Male rats were gonadectomised (Gdx) or sham operated (Intact) immediately prior to the adolescent testosterone surge and given continuous testosterone (T) or vehicle replacement. Two weeks later, rats were given daily raloxifene (R) or vehicle injections for a further 4 weeks, with ongoing testosterone replacement. The treatment groups were: Intact; Gdx; Gdx+T; Intact+R; Gdx+R and Gdx+T+R. Three days prior to sacrifice rats underwent amphetamine-induced locomotion tests to measure extent of striatal dopamine release. The Gdx group exhibited less locomotion than the Gdx+T group. Raloxifene (Intact+R) treatment appeared to attenuate locomotion in Intact rats. The Gdx+T+R group exhibited amphetamine-induced locomotion greater than the Gdx+T group. These data support the hypothesis that testosterone increases subcortical dopamine but does not support the hypothesis that raloxifene will prevent this. Rather, raloxifene potentiated testosterone-induced hyperdopaminergia. This highlights the importance of determining the effect of raloxifene in the male brain. Further studies will include analysis of molecular changes in the dopamine pathway that may underlie behavioural responses.

  1. Kulkarni, J, C Gurvich, SJ Lee, H Gilbert, E Gavrilidis, A de Castella, . . . SR Davis, Piloting the effective therapeutic dose of adjunctive selective estrogen receptor modulator treatment in postmenopausal women with schizophrenia. Psychoneuroendocrinology, 2010. 35(8): 1142-7.
  2. Purves-Tyson, TD, DJ Handelsman, KL Double, SJ Owens, S Bustamante, CS Weickert, Testosterone regulation of sex steroid-related mRNAs and dopamine-related mRNAs in adolescent male rat substantia nigra. BMC Neurosci, 2012. 13: 95.
  3. Purves-Tyson, TD, SJ Owens, KL Double, R Desai, DJ Handelsman, CS Weickert, Testosterone induces molecular changes in dopamine signaling pathway molecules in the adolescent male rat nigrostriatal pathway. PLoS One, 2014. 9(3): e91151.