Consistent with our hypothesis, we demonstrate that DA depletion improves punishment-based reversal learning, while leaving reward-based reversal learning unaffected. However, this effect was gender-specific so that effects were only observed in female subjects, who are known to exhibit higher baseline DA levels than do male subjects.
These findings extend a growing body of research implicating DA in punishment as well as reward processing (Frank 2005
; Seymour et al. 2007
; Cohen and Frank 2009
; Cools et al. 2009
; Robinson et al. 2010
). More specifically, prior work has shown that increases in DA impair punishment-based reversal in patients with Parkinson's disease and healthy volunteers with low DA synthesis capacity (Cools et al. 2006a
). Thus, low levels of DA seem beneficial for learning from punishment. This concurs with recent theoretical modelling in which increases in DA impair punishment-based learning by blocking the effects of punishment-associated DA dips on cortico-striatal action suppression (Frank 2005
; Frank et al. 2007a
). The present data reveal the opposite side of the same coin, i.e., that decreases in DA can improve punishment-based learning (here, we do not distinguish between receipt of punishment and reward omission). Recent fMRI work with this task adopted in this study suggests that such a shift in responses may occur either via modulation of a valence non-specific Pavlovian signal within the anterior ventral striatum or a reward-specific instrumental-like signal within the posterior dorsal striatum (Robinson et al. 2010
It is worth noting that, following the unexpected outcome, the same stimulus was always highlighted in this task. This meant that punishment-based reversal required primarily the breaking of a prepotent stimulus–reward link, as well as the formation of a new stimulus–punishment link. Conversely, reward-based reversal required primarily the breaking of a prepotent stimulus–punishment link and the formation of a new stimulus-reward link. We hypothesise that the effect of ATPD on punishment-based reversal likely reflected the breaking of the old prepotent stimulus–reward link rather than the formation of a new stimulus–punishment link, based on two observations. First, we observed no effect of ATPD on the punishment non-reversal trials (although we cannot be sure that the non-reversal trials were sufficiently sensitive to detect punishment-related learning, given that the task contingencies were deterministic and learning likely occurred on an approximately single trial basis). Second, there is precedence for the importance of dopamine in the breaking of prepotent stimulus–reward links. Specifically, injection of d
-amphetamine in the NAc of rats potentiates behavioural control by stimuli formerly associated with reward (i.e., conditioned reinforcement) in a DA-dependent way (Robbins et al. 1989
). The observation that this d
-amphetamine induced potentiation of control by previously rewarded stimuli was abolished by lesions of the ventral striatum (the nucleus accumbens) (Parkinson et al. 2002
) strengthens the hypothesis that the striatum might play a role in the effects shown here. Evidence for this hypothesis comes from a series of recent studies (Cools et al. 2007
; Dodds et al. 2008
; Clatworthy et al. 2009
) showing that effects of DA-enhancing drugs (LDOPA in PD and methylphenidate in healthy volunteers) are accompanied by modulations of BOLD signals in the ventral striatum during punishment-based reversal learning. Furthermore, Goto and Grace (2005
) have revealed that increases in tonic DA release in the ventral striatum and administration of a DA (D2) receptor agonist in the ventral striatum disrupted PFC-evoked responses in the ventral striatum and impaired behavioural reversal learning in rats. Thus, the DA-enhancing drugs in these studies may have induced aberrant potentiation of control by previously rewarded stimuli and disrupted input to the striatum, signalling the need for a switch. By analogy, DA depletion in the present study may have attenuated potentiation of control by previously rewarded stimuli and may have enhanced input to the striatum, signalling the need for a switch.
The present findings suggest, however, that this effect may depend on gender. This is consistent with the previously observed gender disparity in DA synthesis capacity. Female subjects have been shown to have increased DA synthesis relative to males (Laakso et al. 2002
), and punishment processing is shown to be impaired in individuals with high baseline DA synthesis (Cools et al. 2009
). As such, the improvement in punishment processing following DA reduction in females may be driven by a greater ATPD-induced deviation from this putatively higher baseline DA synthesis rate in females relative to males (although future work in which we directly measure DA synthesis [rather than levels of amino acid precursors] across genders under both conditions is necessary to test this hypothesis more thoroughly).
Intriguingly, the effect that we see here is distinct from the effects of reducing serotonin on the same task. Acute tryptophan depletion (ATD), which is similar in principle to ATPD, reduces the serotonin precursor tryptophan and has been used to reduce serotonin in subjects completing this task. ATD influenced performance on non-reversal punishment trials, rather than on punishment reversal trials seen in these findings (Cools et al. 2008
) (although, note that we do replicate the increased unexpected (non-reversal) punishment errors). It also should be noted, however, that although gender effects were not seen in the prior ATD study, the sample size in that study was not large enough to enable such analysis. Other studies within our lab have in fact shown gender-specific effects of ATD on cognitive processing (Robinson et al. 2009
; Robinson and Sahakian 2009
), but additional research with the present task would be required to determine the effects of gender on serotonin manipulation of this task.
The gender biases in the response to neurotransmitter precursor depletion are particularly interesting in the light of the gender biases in the susceptibility to affective disorders. Females are, for instance, much more likely to become depressed than males (Nolen-Hoeksema et al. 1999
) but tend to experience a more benign form of PD with a later onset than males (Haaxma et al. 2007
). The gender-specific effects of depletion may be driven by, for example, differential baseline levels of neurotransmitters, differential rates of precursor absorption or differential rates neurotransmitter production, and this, may in turn, influence susceptibility to affective disorders. Indeed, susceptibility to affective biases following precursor depletion may provide a means of predicting susceptibility to affective disorders, although future work is clearly necessary to clarify this.
It should be noted that the affective bias that we see here was found in the absence of any effects on mood. This is consistent with a number of prior ATPD (and ATD) studies in healthy individuals (Booij et al. 2003
), and it is now thought that the link between monoamines and mood state is indirect (Ruhe et al. 2007
). As such, the affective biases seen here may represent alterations in ‘emotional’ processing (the short-term affective response to distinct stimuli) rather than alterations in ‘mood’ states (long-term changes in affective state with diverse, unclear causes; Robinson and Sahakian 2009
). It should also be noted that whilst the BAL drink did not cause depletion, it is still a somewhat artificial situation compared with normal food consumption. As such, caution should be exercised when comparing the BAL condition to “healthy” performance. As a further caveat, it should be noted that we did not have the facility for more comprehensive screening methods that are sometimes used (e.g., a urine drug screen). However, we would point out that the mean BDI score (3; Table ) puts the sample firmly within the lowest category (cut off 13) of depressive symptoms (“minimal depression”). Crucially, this was also equivalent across males and females (as, indeed were all the trait measures taken). Indeed, given that over 50% of the sample had an education level higher than BA, there is a possibility that this is a hyper
performing sample. Again, care should be exercised when extrapolating these findings to the population as a whole.
One advantage of the ATPD method is that it should promote a global reduction in DA rather than focusing upon a specific subtype (i.e., D1 or D2), but it is, nevertheless, an imperfect technique. Previous research has shown effects to be modest on some aspects of cognition (Booij et al. 2003
; Roiser et al. 2005
) and, given that noradrenaline (NA) is synthesised from DA, it may also influence NA levels. However, as highlighted by Roiser et al. (2005
), a number of lines of evidence suggest that this is not the case. Firstly, ATPD attenuates d
-amphetamine-induced DA efflux (Leyton et al. 2003
; McTavish et al. 1999a
; McTavish et al. 1999b
) but has no effect upon NA response to amphetamine or idazoxan; secondly, ATPD also only influences the DA-mediated subjective effects of d
-amphetamine (e.g., the ‘buzz’) and not influence the NA-associated effects (e.g., hunger) (McTavish et al. 1999c
; although see Leyton et al. 2005
); and thirdly, ATPD has no effect on melatonin levels (which are controlled by NA) but does influence prolactin levels (which are controlled by DA) (Sheehan et al. 1996
; Harmer et al. 2001
). It should be noted as a limitation that the venipuncture method of blood sample collection used in this study causes short-term stress (influencing prolactin levels) and is therefore unreliable as means of assessing prolactin levels. Future research should use cannulation to adequately assay prolactin.
In sum, this study strengthens previous observations that DA plays an important role in punishment processing but suggests that it may be dependent upon gender. It is conceivable that this disproportionate sensitivity to DA depletion of females is due to increased levels of baseline DA in females relative to males, although further work is necessary to clarify this. However, these findings further cement the role of DA in punishment processing and underline the importance of gender in the neuropharmacology of cognitive processing. Such gender differences may shed light on the gender biases in susceptibility to and severity of psychiatric diseases like Parkinson's disease or depression.