The aim of the present study was to identify potential neural mechanisms underlying changes in motivated behaviors across the menstrual cycle. As hypothesized, we observed premenstrual increases in reward-related BOLD responses in the ventral striatum, a target region of the mesolimbic DA system. Notably, this premenstrual increase in ventral striatal activity was most pronounced in women who reported more premenstrual symptoms. Together, these findings support the notion that dysregulations of dopaminergic incentive processing circuits underlie premenstrual symptoms related to changes in motivated behaviors.
The observed increase of reward-related responses in the ventral striatum during the premenstrual phase can be explained by two possible neurobiological mechanisms. First, the observed findings may be caused by a delayed effect of changes in absolute levels of gonadal hormones across the menstrual cycle. In line with this notion, serum progesterone concentrations robustly predict negative symptom severity in women with PMS with a delay of ~3–4 days (Wang et al., 1996
). These patients moreover exhibit recurrent food cravings which are related to the steroid and mood state fluctuations across the menstrual cycle (Dye et al., 1995
; Dye and Blundell, 1997
). Furthermore, it has been shown that especially hedonic intake of palatable food is increased by administration of gonadal steroids, suggesting direct effects on reward seeking (Chen et al., 1996
; Reddy and Kulkarni, 1998
). Second, premenstrual increases in ventral striatal responsiveness may be caused by the ‘decline’ of gonadal hormone levels during the premenstrual phase. Because gonadal hormones are known to potentiate DA release (Di Paolo et al., 1985
; Bazzett and Becker, 1994
; Di Paolo, 1994
; Thompson and Moss, 1994
; Petitclerc et al., 1995
; Le Saux et al., 2006
; Larson and Carroll, 2007
), their decline in the premenstrual phase after a period of increased levels may prompt a down-regulation of endogenous DA activity and thus mimic a withdrawal state.
Previous studies have shown that dopaminergic withdrawal states are associated with enhanced cue-induced DA release, which is thought to attribute ‘incentive salience’, or motivational value, to drug or reward associated stimuli (Robinson and Berridge, 1993
). Notably, in humans, such withdrawal states appear to prompt changes in motivated behavior and its neural substrates that are analogous to the findings reported here, with enhanced ventral striatal responsiveness to food or drug cues (Kilts et al., 2001
; Rolls and McCabe, 2007
). Therefore, increased ventral striatal responsiveness in the premenstrual phase may result from a similar DA withdrawal state that is caused by the abrupt decline in gonadal hormone levels. To corroborate this notion, future research in humans should investigate whether the present findings generalize to other periods of gonadal hormone decline, such as postpartum or (peri) menopausal periods. Furthermore, effects of controlled hormone withdrawal can be investigated either through termination of hormone replacement therapy or hormonal contraception, or through pharmacological gonadal suppression using administration of gonadotropin-releasing hormone agonists such as leuprolide. Such studies may shed new light on potential gonadal hormone withdrawal effects both on neuronal and behavioral levels.
An important limitation of the present study is that the BOLD-fMRI signal in the ventral striatum cannot provide direct information about dopaminergic neurotransmission. However, a recent fMRI study has shown that BOLD responses during reward anticipation in the ventral striatum correlate positively with DA release (Schott et al., 2008
). It has been suggested that the ventral striatal BOLD signal reflects changes in postsynaptic D1-receptor agonism (Knutson and Gibbs, 2007
). Pharmacological fMRI studies have indeed shown that DA agonists induce ventral striatal BOLD responses (Breiter et al., 1997
; Vollm et al., 2004
). Although this suggests that the ventral striatal BOLD signal is related to DA function, our findings do not necessarily represent elevated DA release specifically. Moreover, conclusions regarding the specificity of our finding to reward anticipation are limited by the fact that our task only included trials with anticipated rewards and non-rewarding control trials.
In conclusion, the present study demonstrated enhanced reward-related neural responses in the ventral striatum during the premenstrual phase. These findings provide support for the notion that changes in functioning of mesolimbic incentive processing circuits may underlie premenstrual increases in normal and abnormal motivated behaviors such as food and drug cravings. These effects are likely caused by the sudden decrease in gonadal hormone levels during the premenstrual phase and may thus reflect a withdrawal-like state. The results of the present study may generalize to other periods of instability in the gonadal hormone milieu and may therefore provide novel insights into the pathophysiology of psychiatric disorders associated with gonadal hormonal fluctuations.