The effect of neurotoxic doses of methamphetamine on methamphetamine-conditioned place preference in rats.
BACKGROUND
Methamphetamine has been shown to produce neurotoxicity demonstrated by depletions of dopamine and serotonin in the striatum and nucleus accumbens.


OBJECTIVE
The current study examined the effects of neurotoxic doses of methamphetamine on the rewarding effect of subsequent administration of methamphetamine assessed by the conditioned place preference (CPP) procedure.


METHODS
Male and female rats were treated with a neurotoxic regimen of methamphetamine (4 x 10 mg/kg, s.c., once every 2 h) or saline, and concentrations of dopamine, 3,4-dihydroxyphenylacetic acid, serotonin, and 5-hydroxyindoleacetic acid were measured 15 days later in the striatum, nucleus accumbens, and prefrontal cortex (PFC). In another experiment, male rats were given methamphetamine neurotoxic treatment or saline and were then conditioned 7 days later with methamphetamine (0.1, 0.3, or 1.0 mg/kg, s.c.) or saline using a four-trial CPP procedure. Locomotor activity was also measured during the conditioning sessions to investigate whether or not the neurotoxic methamphetamine treatment altered locomotor activity following a subsequent methamphetamine challenge.


RESULTS
Males and females did not differ significantly in the amount of neurochemical depletion produced by methamphetamine in any brain region. Collapsed across sex, dopamine was significantly depleted in nucleus accumbens (25%) and striatum (51%); serotonin was significantly depleted in nucleus accumbens (35%), striatum (34%) and PFC (33%). The methamphetamine challenge dose dependently increased locomotor activity, but the increase was not affected by treatment with neurotoxic doses of methamphetamine. In contrast, treatment with neurotoxic doses of methamphetamine enhanced CPP at the intermediate conditioning dose (0.3 mg/kg).


CONCLUSIONS
These results indicate that the rewarding effect of methamphetamine is enhanced by prior treatment with neurotoxic doses of methamphetamine, suggesting either a compensatory hyperfunctioning of spared dopamine neurons or a loss of inhibitory control from serotonergic input.
Gehrke
B J
BJ
Department of Psychology, University of Kentucky, Lexington, KY 40506, USA.
Harrod
S B
SB
Cass
W A
WA
Bardo
M T
MT
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000494:pharmacology* / Q000633:toxicity*; D003216:Conditioning, Operant / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism; D005260:Female; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology* / Q000633:toxicity*; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000523:psychology*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D012201:Reward; D012701:Serotonin / Q000378:metabolism; D012727:Sex Characteristics
D000697:Central Nervous System Stimulants; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D008694:Methamphetamine; D006897:Hydroxyindoleacetic Acid; D004298:Dopamine