Drugs used in the treatment of attention-deficit/hyperactivity disorder affect postsynaptic firing rate and oscillation without preferential dopamine autoreceptor action.
BACKGROUND
Current theories propose that low doses of catecholaminergic stimulants reduce symptoms in patients with attention-deficit/hyperactivity disorder by acting on autoreceptors to reduce catecholaminergic transmission; few data are available that directly address this hypothesis.


METHODS
We investigated the autoreceptor and postsynaptic receptor actions of systemically administered stimulants on dopaminergic systems in rats with single-unit recording in the substantia nigra pars compacta and globus pallidus, respectively.


RESULTS
Dose-response curves for rate indicated that the potencies of the indirect-acting agonists methylphenidate and D-amphetamine at dopaminergic autoreceptors were not greater than at postsynaptic receptors; in fact, D-amphetamine was more potent postsynaptically. In addition to effects on firing rate, spectral/wavelet analyses indicated that these drugs had prominent effects on postsynaptic multisecond oscillations. These oscillations were shifted by stimulants from baseline periods of approximately 30 sec to periods of 5-10 sec. Effects on pattern were found at doses as low as 1.0 mg/kg (methylphenidate) and 0.2 mg/kg (D-amphetamine). At this latter dose, D-amphetamine had little effect presynaptically.


CONCLUSIONS
These and prior results demonstrate that there is no autoreceptor-preferring dose range of catecholaminergic stimulants; these drugs at low doses are unlikely to reduce motor activity by this mechanism. Nonetheless, they might affect attentive and cognitive processes by modulating multisecond temporal patterns of central activity.
Experimental Therapeutics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-1406, USA.
D N
DN
Ruskin
D A
DA
Bergstrom
A
A
Shenker
L E
LE
Freeman
D
D
Baek
J R
JR
Walters
D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy*; D017660:Autoreceptors / Q000187:drug effects*; D002395:Catecholamines / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D003913:Dextroamphetamine / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects*; D005917:Globus Pallidus / Q000187:drug effects; D008297:Male; D008774:Methylphenidate / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D009474:Neurons / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D017660:Autoreceptors; D002395:Catecholamines; D000697:Central Nervous System Stimulants; D008774:Methylphenidate; D003913:Dextroamphetamine; D004298:Dopamine