435
Recent ERP work supports this interpretation
(Shelley et al. 1994). Healthy subjects were re-
quired to detect a stimulus of a particular pitch
and duration from, one ear. Under clonidine, which
decreases NA firing, normal hierarchical process-
ing was disrupted and the hit-rate decreased. Im-
portant here is that while easy processing according
to stimulus locus was unaffected, further process-
ing according to the more difficult features of pitch
was specifically impaired — namely the middle-
PN elicited by irrelevant features (alone) increased.
This suggests that noise in the signal to noise com-
parison was not tuned out.
Dopamine (DA) activity (implicated in atten-
tion, motivation and motor organization alike) has
been described as promoting the likelihood of a
switch occurring between two inputs competing
for control of the output of a DA innervated re-
gion (Oades 1985). The argument was initially
made from Psychopharmacological modification
of operant discrimination, of animals’ escape strat-
egies from a water tank (Van den Bos et al. 1991)
and of food-search strategies on a holeboard. For
example, deviations from learned hole-visit se-
quences resulted from increased mesolimbic DA
stimulation as a result of direct ventral tegmental
treatment with neuroleptic (Oades et al. 1985) or
hippocampal damage. In the latter cases systemic
neuroleptic treatment resulted in mild improve-
ments (Oades and Isaacson 1978).
Recent ERP work supports the interpretation.
In the dichotic, paradigm used by Shelley and col-
leagues (above) the neuroleptic droperidol resulted
in a decreased hit rate and decreased PN in the
middle and late latency range (not stimulus-
specific). This suggests that subjects discriminated
the easiest aspect of the task (locus) and locked on
to the solution, leading to impaired comparisons
according to stimulus pitch and duration.
In mild Parkinsonism where DA is lacking (extra-
pyramidal motor system) L-DOPA treatment may
help discrimination performance. Reaction times
shorten. But it may induce an imbalance and even
hinder cognitive function if the task is simple and
one should Tock on’ to the solution. P3 latencies
lengthen (Prasher and Findley 1991). In contrast
if subjects are asked to detect a spot on a screen,
where the position varies on each trial (Fig. 6)
Fig. 6. Right: Possible location of 16 randomly presented visual
cues for delayed learning task. The display showed the fixa-
tion point (FP) but not the marked quadrants. Trial sequence:
FP 3 sec, cue <200 msec (10' eccentricity), time out (black-
screen) 0-8 sec, subject points to cue locus, inter-trial-interval
2.5 sec. Left: Mean errors (+sem) on delayed learning task
significantly decrease after 2.5 mg bromocriptine with re-
spect to placebo (t(7) 2.9 p < 0.02). (After Luciana et al.
1992 with permission of the author and publisher.)
and remember it for O or 8 s, then a good deal of
cognitive flexibility is required in the formation
and changing of working memory specifications
(Luciana et al. 1991). This delayed learning abil-
ity is known to depend on neuronal activity in lay-
ers V and VI of the prefrontal cortex and to be
influenced by DA receptors there. In this demand-
ing task the performance of women was improved
after treatment with bromocriptine, an agent with
D2 agonist properties.
A word of caution on the generalization of these
results to schizophrenic mechanisms should be
made. Ward et al. (1993) in a similar paradigm to
Shelley et al. (above, the same research group),
reported decreased PN in unmedicated schizo-
phrenics that related to the degree of psychopa-
thology shown. Does this show that the same effect
as the neuroleptic in healthy subjects can be
achieved by the biological concomitants of psy-
chosis or do both groups show decreased DA
activity? Our own experience with the З-tone dis-
crimination in medicated schizophrenics is differ-
ent. Firstly PN was present in psychotic patients,
secondly it was shifted parietally in paranoid sub-
jects. Does this imply that medication counteracted
the impairment or is the ‘PN’ reflecting different
processes in the two paradigms?
In the 80 years since acetylcholine was identi-
fied as a neurotransmitter a huge literature has built
up showing that its activity in the CNS is essential