Differences in the cellular mechanism underlying the effects of amphetamine on prepulse inhibition in apomorphine-susceptible and apomorphine-unsusceptible rats.
BACKGROUND
Amphetamine is often used to mimic certain aspects of schizophrenia in laboratory animals, such as a decreased prepulse inhibition.


METHODS
Apomorphine-susceptible and apomorphine-unsusceptible rats represent a well-characterized animal model for individual differences in the sensitivity to dopaminergic drugs. Moreover, apomorphine-susceptible rats show a wide variety of schizophrenia-like abnormalities. The differential response to administration of amphetamine (1-4 mg/kg, i.p.) was investigated in these two rat lines using the prepulse inhibition paradigm. Because amphetamine promotes dopamine release, the cellular mechanism underlying the line-specific effects of amphetamine was investigated by administration of alpha-methyl-para-tyrosine (aMpT) and reserpine, substances that are known to deplete the cytosolic dopamine pool and the vesicular dopamine pool, respectively, the former being primarily implicated in mediating the effects of amphetamine.


RESULTS
All doses of amphetamine decreased prepulse inhibition in apomorphine-susceptible rats, whereas only the highest doses (2 and 4 mg/kg, i.p.) of amphetamine decreased prepulse inhibition in apomorphine-unsusceptible rats. Alpha-methyl-para-tyrosine, but not reserpine, blocked the amphetamine-induced disruption in prepulse inhibition in apomorphine-unsusceptible rats, whereas both substances alone had no effect in apomorphine-susceptible rats. However, the combination of alpha-methyl-para-tyrosine and reserpine did block the amphetamine-induced effects in the latter rat line.


CONCLUSIONS
The present study suggests that apomorphine-susceptible rats are more sensitive to systemic administration of amphetamine than apomorphine-unsusceptible rats. In addition, the data show that the cellular mechanism underlying the effects of amphetamine differs between apomorphine-susceptible and apomorphine-unsusceptible rats. Whereas the effects of amphetamine on prepulse inhibition in apomorphine-unsusceptible rats just require the alpha-methyl-para-tyrosine sensitive dopamine pool, the effects in apomorphine-susceptible rats require both the alpha-methyl-para-tyrosine sensitive and the reserpine sensitive dopamine pool. Because apomorphine-susceptible rats share many features with schizophrenic patients, these data open the perspective that in these patients amphetamine may induce dopamine release from both types of dopamine pool. This might provide an explanation for the increased dopamine release after this psychostimulant drug in patients vs controls.
van der Elst
Martine C J
MC
Molecular Neurobiology Section, Department of Cognitive Neurosciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Wunderink
Yvette S
YS
Ellenbroek
Bart A
BA
Cools
Alexander R
AR
D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007266:Inhibition, Psychological; D007274:Injections, Intraperitoneal; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D013216:Reflex, Startle / Q000187:drug effects*; D017330:Remoxipride / Q000494:pharmacology; D012110:Reserpine / Q000494:pharmacology; D012565:Schizophrenic Psychology; D019805:alpha-Methyltyrosine / Q000494:pharmacology
D000697:Central Nervous System Stimulants; D018491:Dopamine Agonists; D004791:Enzyme Inhibitors; D017330:Remoxipride; D019805:alpha-Methyltyrosine; D012110:Reserpine; D000661:Amphetamine; D001058:Apomorphine; D004298:Dopamine