The results of this study demonstrate that men and women show a rapid antidepressant response following scopolamine, but the mean reduction in depression ratings was larger in women than in men. Scopolamine produced improvement in depression severity by the first assessment following the first administration of the drug in both gender groups; thus, the rapidity of the antidepressant response was comparable, but by study end the magnitude of response was greater in females than in males. In addition, a larger proportion of women showed a response to scopolamine (71%) than did men (38%), and thus the greater improvement was driven partially by the larger proportion of women who responded to scopolamine.
The absence of significant differences in the antidepressant response magnitude between MDD and BD diagnostic subgroups, as well as the absence of differences between patients with and without comorbid anxiety disorder, indicates that no such underlying subgroup effects are driving gender-based differences. Moreover, there was no interaction between these diagnostic subtypes and gender, further supporting the conclusion that the observed effects are based on gender differences and are not spurious findings driven by other factors.
A robust antianxiety response was observed exclusively in females, with males showed no significant improvement in anxiety ratings associated with drug administration (although this effect in males might become significant with a larger sample size). Thus, women show scopolamine-induced improvement in both the depression severity and anxiety, whereas men show modest improvement in depression severity.
The cholinergic system has been implicated in depression for decades by a variety of types of evidence (Janowsky et al, 1972
; Janowsky and Overstreet, 1990
), and has resurfaced as a potential target for novel therapeutics (Furey and Drevets, 2006
; Janowsky et al, 1994
; Overstreet et al, 1996
). For example, in addition to the recent demonstration that this antimuscarinic agent has rapid antidepressant effects, several types of evidence suggest that muscarinic cholinergic receptor sensitivity is increased in the depressed phases of MDD and BD (Janowsky and Overstreet, 1990
; Janowsky et al, 1994
; Riemann et al, 1994b
). Compatible with the findings of the current study, functional sex differences have been reported in baseline and cholinergically stimulated plasma hormone measures between major depressives and matched controls that suggest that heightened cholinergic sensitivity exists in premenopausal female, but not in male, patients with MDD (Riemann et al, 1994a
; Rubin et al, 1999
). Moreover, both functional neuroimaging (Cannon et al, 2006
) and genetic (Comings et al, 2002
) studies have implicated type 2 muscarinic cholinergic (M2) receptors in affective disorders. Specifically, Cannon et al (2006)
reported that the distribution volume of the [18
F]FP-TZTP, a PET radioligand that is relatively selective for M2 receptors, was reduced in bipolar depressives relative to controls, although the sample size was too small to permit assessment of sex effects. In unipolar depression, Wang et al (2004)
showed associations between genetic variation in the CHRM2
gene and depression arising in families with an alcohol-dependent proband, whereas Comings et al (2002)
found that genetic variation in the 3′ region of the CHRM2
gene (A/T 1890) was associated with MDD specifically in females. Taken together, these findings highlight the relevance of the muscarinic cholinergic system in depression and also appear complementary to the current report, as gender differences have been associated with both the genetic variation in the CHRM2
gene in MDD and now with the likelihood of experiencing an antidepressant response to scopolamine.
Previously, we proposed that the antidepressant effects of scopolamine may be mediated via interactions involving N
-methyl--aspartate glutamatergic receptors (NMDARs). Elevated glutamatergic transmission has been associated with the pathophysiology of depression, and a variety of antidepressant treatments have been shown to result in reduced NMDAR function (for review, see Paul and Skolnick, 2003
). The NMDAR gene expression is enhanced by muscarinic receptor stimulation in at least some brain structures (Liu et al, 2004
), and thus the elevated muscarinic receptor sensitivity identified in mood disorders (Janowsky et al, 1994
) may contribute to an elevation in NMDAR transmission. Scopolamine administration reduces mRNA concentrations for NMDAR types 1A and 2A in rat brain (Liu et al, 2004
) and via this mechanism may reduce NMDAR function.
Although the underlying mechanism that explains gender differences remains unclear, there are indications that hormones may have an important role in modulating the interactions between NMDAR function and M2 receptor stimulation. Estrogen has been shown to modulate the functional state of the cholinergic system by increasing choline acetyltransferase (ChAT) activity and by increasing the release of Ach (Gibbs et al, 2004
; Pongrac et al, 2004
). Researchers have also demonstrated that estrogen enhances NMDAR function by increasing NMDAR binding, at least in some brain regions, possibly by increasing the density of dendritic spines that express NMDAR (McEwen et al, 2001
; Smith et al, 2009
; Woolley and McEwen, 1994
). Moreover, Daniel and Dohanich (2001
) demonstrated that the influence of estrogen on NMDA receptor function is mediated specifically via M2 receptors.
The interactions among M2 receptors, NMDA receptors, and estrogen may indicate a direction for further study to evaluate the role of the cholinergic system in mood disorders, and the gender-based differences in the prevalence of depression. A variety of types of evidence have suggested that the cholinergic muscarinic receptors are hypersensitive in mood disorders, although the extent to which this finding extends to specific muscarinic subtypes has yet to be established. Nevertheless, if the muscarinic supersensitivity includes M2 receptors, this would be expected to increase NMDA receptor function (either via modulating gene expression and/or by increasing NMDA receptor density), consistent with the current understanding that increased glutamatergic activity is associated with depression. Thus, the reduction of NMDA receptor activity following the antagonism of M2 receptors with scopolamine conceivably could account for the antidepressant effects observed (Liu et al, 2004
). More interesting in the context of the current paper is the role of estrogen in this complex interaction. Estrogen enhances the interaction between M2 and NMDA receptors to boost further NMDA receptor activity, a mechanism that may contribute to the increased prevalence of depression in women, as well as the greater antidepressant response to scopolamine in women than men. By blocking M2 receptors with scopolamine, the influence of estrogen on NMDA receptors presumably would be diminished, which should further reduce NMDAR activity. Although the relation between NMDA receptors and M2 receptors would also apply to mood disorders in men, the influence of estrogen would be substantially smaller and thus the magnitude of change would be reduced.
The muscarinic cholinergic system interacts with other neurotransmitter systems implicated in the pathophysiology of depression that are also influenced by gonadal steroids, and that may alternatively or additionally contribute to sex differences in the antidepressant response to scopolamine. Interactions between the muscarinic cholinergic and serotonergic systems are hypothesized to contribute to the pathogenesis of major depression (Overstreet et al, 1996
). Multiple aspects of serotonergic system function are influenced by testosterone, progesterone, and/or estrogen, and these interactions are hypothesized to underlie sex differences in the clinical epidemiology and course of mood disorders (Benmansour et al, 2009
; Gupta et al, 2007
; Rubinow et al, 1998
; Sell et al, 2008
; Zhang et al, 2006
). Such interactions conceivably may influence cholinergic–serotonergic interactions in a way that modulates antidepressant responses to scopolamine.
Similarly, catecholaminergic neurotransmitter systems have been implicated in the pathophysiology of mood disorders, and testosterone, progesterone, and/or estrogen have been shown to modulate catecholamine synthesis, release, degradation, and/or transport (Alonso-Solis et al, 1996
; Lester et al, 2010
; Thompson and Certain, 2005
; Zhang et al, 2006
). The muscarinic cholinergic system interacts with catecholaminergic neurotransmitter function such that alterations in the balance between systems may have major roles in the pathophysiology of mood disorders (Janowsky et al, 1972
; Lester et al, 2010
; Sarter et al, 1999
). For example, reduced dopaminergic receptor transmission is hypothesized to underlie the impairment of reward seeking and motivated behavior in depression (reviewed in Drevets et al, 2008
). Increased muscarinic receptor sensitivity in depression would be expected to result in reduced striatal dopaminergic release (Hartvig et al, 2002
). In addition, ovarian steroids exert an antidopaminergic effect at both the pituitary and striatal levels, whereas androgens can reverse these effects (Alonso-Solis et al, 1996
; Dluzen and Ramirez, 1989
; Labrie et al, 1980
). Thus, females conceivably may develop more prominently reduced dopaminergic transmission in association with muscarinic receptor supersensitivity than males. If so, then conversely females would be expected to show enhanced improvement in response to muscarinic antagonist administration than males. In summary, although the mechanisms underlying sex differences in the antidepressant response to scopolamine remain unclear, the prominent influence that gonadal steroids exert on a variety of neurobiological systems suggests that these mechanisms involve complex interactions involving multiple neurotransmitter systems.
Several features of the sample selection limit the generalizability of the current findings. First, the sample was relatively small for the male participants. Second, both elderly and pediatric subjects, and current nicotine users, were excluded from participation in the study, and thus the findings may not generalize to such cases. Smokers were excluded from participation because of concern regarding possible functional interactions between the muscarinic and nicotinic cholinergic receptor systems that could potentially influence the antidepressant effect of scopolamine. Finally, we used a single regimen for the administration of scopolamine.
The finding that males show a reduced antidepressant response to three pulses of scopolamine at 4
μg/kg i.v. may highlight the need to determine if males would experience added benefit from increasing the number of administrations or by using a larger dose of scopolamine. The dose used in this study varied based on body weight, but was the same for males and females. Future studies should focus on the evaluation of slightly higher doses of scopolamine in men.