Neurochemical and behavioral differences between d-methamphetamine and d-amphetamine in rats.
BACKGROUND
Methamphetamine (METH) and amphetamine (AMPH) are both abused psychostimulants. Although METH is generally accepted to be more addictive and potent than its analogue AMPH, there are no known neurobiological differences in action between the two drugs that may account for such differences.


OBJECTIVE
METH and AMPH were compared to determine potential mechanisms for such differences between the two drugs in order to provide new targets for the treatment of METH addiction.


METHODS
Using in vivo microdialysis on rats, dopamine (DA), DA metabolites, and glutamate (GLU) release in the nucleus accumbens (NAC) and prefrontal cortex (PFC) were measured after administration of 2 mg/kg, IP, of METH or AMPH. Based on the neurochemical differences between METH and AMPH, a locomotor activity study was designed to assess differences in locomotor activation for a range of doses (1-4 mg/kg, IP) of METH and AMPH and after pretreatment with intra-accumbens GLU antagonists.


RESULTS
METH and AMPH raised NAC DA levels to a similar degree. In the PFC, both METH and AMPH raised DA levels, but METH was less effective than AMPH. In the NAC, AMPH raised GLU levels but METH did not. In the PFC, METH raised GLU levels but AMPH did not. The locomotor activity dose response curve for METH had a lower peak than that of AMPH. This difference was blocked by pretreatment with either the GLU NMDA antagonist AP5 or the GLU AMPA antagonist DNQX locally in the NAC.


CONCLUSIONS
This study reveals several previously unknown neurochemical and behavioral differences between METH and AMPH. Based on these results, it is suggested that new pharmacotherapeutic agents that produce augmentations of NAC GLU or PFC DA activity, or perhaps inhibition of PFC GLU activity, may someday be useful for the treatment of METH addiction.
Shoblock
James R
JR
Center for Neuropharmacology and Neuroscience, Albany Medical College, 47 New Scotland Avenue (MC-136), Albany, NY 12208, USA. ShobloJ@mail.amc.edu
Sullivan
Eric B
EB
Maisonneuve
Isabelle M
IM
Glick
Stanley D
SD
D015102:3,4-Dihydroxyphenylacetic Acid / Q000032:analysis / Q000378:metabolism; D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D018698:Glutamic Acid / Q000032:analysis; D006719:Homovanillic Acid / Q000032:analysis; D008694:Methamphetamine / Q000494:pharmacology*; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000697:Central Nervous System Stimulants; D018691:Excitatory Amino Acid Antagonists; D011810:Quinoxalines; D015102:3,4-Dihydroxyphenylacetic Acid; D018698:Glutamic Acid; D008694:Methamphetamine; C056723:FG 9041; C056639:2-amino-5-phosphopentanoic acid; D000661:Amphetamine; D014633:Valine; D006719:Homovanillic Acid