There are several reasons that might explain the small differences found when comparing L- dopa and placebo- modulated performance on our tasks. The simplest explanation is that saccadic decisions are unaffected by L-dopa at this dose. Otherwise, effects may have been lost due to individual variability in both the direction and the extent of performance difference due to the drug.
5.4.2.1
L-dopa has variable reaction time and dosage effects
The alteration in synaptic dopamine levels due to 100mg of levodopa may be insufficient to instigate changes in reward sensitivity, risk seeking, reaction time necessary to influence oculomotor task performance on our tasks. With larger doses, more marked effects may have seen. However, 100mg L-dopa was found to have the greatest effect (compared to either 25mg or 200mg) on paired associative stimulation induced plasticity, thought to reflect learning related processes (Thirugnanasambandam et al., 2011).
The lack of significant effects on saccadic reaction times in either the SRT task or the Lateral reward task may be due to the dose used (100mg). Previous studies demonstrating manual reaction time effects have used higher doses of L-dopa – e.g. 200mg (Rihet et al., 2002). There is also evidence that repeated doses in drug studies on healthy volunteers are more effective (Knecht et al., 2004). However, consistent with our findings, a previous study using 100mg found no effect upon ‘reflexive’ saccadic latencies (Duka and Lupp, 1997).
5.4.2.2
Patient and volunteer responses to L-dopa may differ
Extrapolation from patient studies is difficult. It is likely that the long term (tonic) drug effects reported (Cools et al., 2003, 2010) differ from the acute changes seen following administration of a single dose to a drug naive subject. There is evidence that suggests drug naïve PD patients are more susceptible to the cognitive effects of L-dopa than those with a stable response to L-dopa (Kulisevsky et al., 1998). There are possible differences in patients’ endogenous dopamine levels and dopamine receptor numbers/activity as a result of chronic drug administration. Previously reported effects of an L-dopa induced increase in saccadic latency (using the patients’ usual doses) in PD patients (Hood et al., 2007; Michell et al., 2006) may be due to these differences, or dose effects. Furthermore, in antisaccade tasks, L-dopa has been found to cause opposing effects in PD patients, who made fewer errors (Hood et al., 2007), and healthy volunteers, who made more errors (Duka and Lupp, 1997). Nevertheless, the trend in our results was for faster responses in the placebo rather than the L-dopa condition consistent with the patient studies,
and it is possible that with larger subject numbers, higher, or repeated dosing we might have replicated those findings.
5.4.2.3
There may be independent optimal levels of dopamine for both
individuals and tasks
Animal experiments have demonstrated large individual variation in both the direction and extent of drug effects. Experiments demonstrate the “law of initial value” wherein pharmacological manipulation of blood pressure and heart rate depended upon the baseline of the tested variable (Wilder, 1962). Similarly, the effects of dopaminergic drugs on cognition depend upon baseline levels of performance (Robbins and Sahakian, 1979; Kimberg et al., 1997; Mehta et al., 2000; Granon et al., 2000; Mehta et al., 2004). In other words, a dopaminergic drug may improve poor baseline performance in a given task, whereas good performance may be impaired. If this were the case in our study, we might expect analysis of poor performers in the training session to reveal different outcomes from those who performed better at baseline. A larger study would be required to demonstrate such differences. However, other animal and human experiments also demonstrate that simplistic ‘inverted-U-shape’ relationships between DA levels and performance are insufficient to explain or predict performance on cognitive tasks (Cools, 2006). Within a single subject, some functions will be enhanced and others impaired by the same drug dose. There is therefore task as well as an individual variation in the response to these drugs.
Recent research has shown that risk taking is associated with DAT1 polymorphisms when subjects perform the Balloon Analogue Risk Task (BART, see Chapter 3 (Mata et al., 2012)). It is also known that genetic variability can affect the response to L-dopa (Eisenegger et al., 2010): A high dose (300mg) of L-dopa was administered to a very large group (n=200) of healthy volunteers who had been genotyped for DRD4 polymorphism. Without considering D4 subtypes, L-dopa had no effect upon gambling propensity. However, division by genotype found increased gambling tendency in those carrying at least one copy of the 7-repeat allele. It is therefore possible that a genetically heterogeneous group might demonstrate opposing effects of the drug. There may also be underlying dopaminergically derived individual differences in the amount of effort people are willing to expend for rewards (Treadway et al., 2012). These effects might, when superimposed, cause regression to the mean.
5.4.2.4
Differential learning effects due to the order of drug/placebo
presentation
Analysis of variance demonstrated similar interactions of drug/placebo condition and session in SRT (interaction not significant) and Lateral Reward (interaction significant) tasks. There was also a non-significant interaction with regard to the number of errors in the Traffic Light task. Such interactions may indicate an enhanced training effect due to dopamine in the earlier session, or a chance ceiling effect due to the ‘placebo first’ group being faster to start with. A study using methylphenidate found that the drug enhanced performance on spatial tasks from the CANTAB battery (Robbins et al., 1994b) when taken in the first session but impaired
5.4.2.5
L-dopa modulates reward sensitivity
The lateral reward task is a measure of reward sensitivity. L-dopa administration non- significantly attenuated reward sensitivity. It is possible that this apparent difference is due to reaction time effects, in that L-dopa could be creating a ‘cap’ on the maximum saccade speed. Alternatively, excessive dopamine may impair an already optimal dopaminergic state, thereby reducing reward responsiveness. This may contrast with PD patients, in whom reward sensitivity might be optimised by exogenous dopamine administration. L-dopa withdrawal studies have demonstrated that the drug improves cognition in some patients, but causes deterioration in others (Gotham et al., 1988). Consistent with the inverted U-shape hypothesis, patients who were performing particularly poorly off the drug gained the most benefit from L- dopa, whereas those who performed well off drug were impaired by its administration. This finding has lead to the so-called “Dopamine overdose” hypothesis (Vaillancourt et al., 2013) . This suggests that the doses of L-dopa required to replace endogenous neurotransmitter in damaged brain areas lead to an overdose of other (intact) brain areas.
5.4.2.6
More potent dopaminergic modulation or alternate agents may
have greater impact upon oculomotor decisions.
It is possible that drugs with greater DA receptor subtype specificity might prove more effective in modulating response to our tasks. Many of the reported examples of drug effects on decision making in both healthy volunteers and PD patients have used DA agonists, D2 agonists in particular (Frank et al., 2004; Cools et al., 2007, 2009). This is consistent with the finding of a greater incidence of impulse control disorder in PD patients treated with DA agonists than those treated with L-dopa alone (Grosset et al., 2011). The relationship between specific pharmacological agents and task effects is complex; agents within the same class have been shown to have opposing effects. For example, bromocriptine has been shown to affect cognitive flexibility (in dual-tasking and Wisconsin card Sorting Task) but not simple delayed-response task (Kimberg et al., 1997; McDowell et al., 1998). Pergolide, on the other hand, modulated delayed-response tasks but did not affect set-shifting (Kimberg and D’Esposito, 2003).
Further experiments might consider the use of dopamine agonists, with greater DA receptor specificity and/or stimulant drugs that are more potent in acutely altering synaptic DA levels. The next chapter will discuss oculomotor experiments using a potent DA reuptake inhibitor, methylphenidate.