Galactosylated dopamine enters into the brain, blocks the mesocorticolimbic system and modulates activity and scanning time in Naples high excitability rats

Pathological conditions, such as Parkinson’s disease
and attention deficit hyperactivity disorder, have been
linked to alterations of specific dopamine (DA) pathways.
However, since exogenous DA does not cross the blood–
brain barrier, DA levels can be modulated e.g. by DA precursors
or DA reuptake blockers. Hereby histochemical, analytical
and behavioral evidence shows that a galactosylated
form of DA (GAL-DA) carries DA into the brain, thus modulating
activity and nonselective attention in rats. To this aim
adult male rats of the Naples high-excitability (NHE) and
random bred controls (NRB) lines were given a single i.p.
injection of GAL-DA (10 or 100 mg/kg). Three hours later the
behavior was videotaped and analyzed for horizontal activity,
orienting frequency and scanning duration. The dose of 100
mg/kg of GAL-DA reduced by 25% the horizontal activity in
NHE rats, mainly in the first part of the testing period. No
effect was observed on orienting frequency or on scanning
duration. However, GAL-DA 100 mg/kg was associated with
longer rearing episodes in the second part of the testing
period in NHE rats.
In parallel experiments histochemistry with a galactosespecific
lectin showed 10% increase in galactose residues
into the striatum between 0.5 and 3.0 h. To quantify the level of
GAL-DA, its metabolite DA-succinate and DA in the prefrontal
cortex, neostriatum, and cerebellum, rats were killed 2.0 h after
the injection of prodrug. Mass high performance liquid chromatography
(HPLC) was used for analysis of GAL-DA and DA
succinate whereas electrochemical HPLC for DA. Both HPLC
techniques demonstrate that GAL-DA carries and releases DA
into the brain. Specifically 100 mg/kg of GAL-DA increased DA
level in the striatum in the NHE rats only. Moreover, DA in the
mesencephalon (MES) was correlated positively with striataland prefrontal cortex DA in NHE rats. In contrast DA in the MES
was negatively correlated with striatal DA in NRB. GAL-DA disrupted
these correlations in both rat lines. Thus, this new DA
prodrug may modify DA neurotransmission and might have a
potential clinical application.