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 mglkg 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 galactose-specific 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 striatal and 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.
Ruocco
L A
LA
Department of Experimental Medicine, Faculty of Medicine, II University of Naples, Naples, Italy.
Viggiano
D
D
Viggiano
A
A
Abignente
E
E
Rimoli
M G
MG
Melisi
D
D
Curcio
A
A
Nieddu
M
M
Boatto
G
G
Carboni
E
E
Gironi Carnevale
U A
UA
Sadile
A G
AG
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D001923:Brain Chemistry; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D004298:Dopamine / Q000378:metabolism* / Q000494:pharmacology*; D005690:Galactose / Q000378:metabolism* / Q000494:pharmacology; D007091:Image Processing, Computer-Assisted; D008297:Male; D011355:Prodrugs / Q000378:metabolism*; D051381:Rats
D011355:Prodrugs; D004298:Dopamine; D005690:Galactose