product is required for this regulated release.
), tyramine increas-
es initial cocaine responsiveness in
Exposure of tyramine-fed
flies to 35
of cocaine induced behaviors normally seen
in control flies exposed to 75
g (Fig. 4).
Thus, although long-term increase of tyra-
mine levels can affect initial cocaine respon-
siveness, it is not sufficient for sensitization
in flies lacking normal
A unifying feature of most genes that
regulate circadian rhythmicity in
and vertebrates is the PAS dimerization do-
main, common to a subset of basic helix-
loop-helix transcription factors (
Within the circadian cycle, CLOCK/CYCLE
whereas PER/TIM heterodimers inhibit the
activity of CLOCK/CYCLE (
find that mutations in
share the same cocaine phenotype: a deficien-
cy in the ability to sensitize after one or more
drug exposures. This similarity leads us to
suspect that as in circadian behaviors, these
genes are functioning in a common pathway.
In contrast to the above mentioned genes,
mutant showed normal cocaine re-
sponses. The implication of this finding is two-
fold. First, there must be an as yet unidentified
PER binding partner that is specifically in-
volved in regulation of drug responsiveness.
Second, drug responsiveness is likely regulated
expression in a set of cells distinct from
those involved in circadian function. In
mutants, PER levels are constitutively low (
); if the same TIM-containing cells were
involved in circadian and cocaine responses,
flies should not sensitize.
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