Effects of subchronic methamphetamine exposure on basal dopamine and stress-induced dopamine release in the nucleus accumbens shell of rats.
BACKGROUND
Subchronic administration of stimulants reduces basal dopamine (DA) concentrations and blocks stress-induced DA release in the nucleus accumbens (NA) of rats during withdrawal. However, no studies have attempted to relate early withdrawal from chronic drug exposure to stress reactivity and changes in DA transmission.


OBJECTIVE
The effects of subchronic low-dose methamphetamine (METH) administration on regional changes in dopamine transporter (DAT) and norepinephrine transporter (NET) immunoreactivity and function during early withdrawal were examined. The effects of subchronic METH on stress responsivity measured by DA release in the nucleus accumbens shell (NA SHELL) and core (NA CORE) during acute restraint stress were also examined.


METHODS
Male rats received single injections of METH (2.0 mg/kg i.p.) or saline (SAL) for 10 days and then were killed 24 h after the last injection. DAT and NET protein in NA, striatum (STR), medial prefrontal cortex (mPFC), and hippocampus were assayed by Western blot analysis. Experiment 2 measured basal extracellular DA concentrations and restraint-stress-induced DA release in vivo in the NA SHELL and CORE of SAL- and METH-pretreated rats after 24-h withdrawal. Experiment 3 examined the in vivo regulation of extracellular DA in the NA SHELL and/or CORE after local administration of GBR12909 (50 microM) or nisoxetine (100 microM; NA SHELL).


RESULTS
Subchronic METH increased DAT but not NET immunoreactivity in the NA compared to the STR and mPFC. METH reduced basal extracellular DA and blocked restraint-stress-induced DA release in the NA SHELL. DA uptake blockade increased extracellular DA more in the NA SHELL of METH rats, whereas NE uptake blockade increased basal DA concentrations to a similar extent in METH and SAL rats.


CONCLUSIONS
These results suggest that subchronic METH exposure selectively increases NA DAT and consequently reduces basal and stress-induced DA release in the NA SHELL during early withdrawal.
Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Room L-613, 715 Albany Street, Boston, MA 02118, USA.
Susan L
SL
Broom
Bryan K
BK
Yamamoto
D019969:Amphetamine-Related Disorders / Q000503:physiopathology*; D000818:Animals; D001143:Arousal / Q000187:drug effects / Q000502:physiology; D001931:Brain Mapping; D003342:Corpus Striatum / Q000187:drug effects / Q000503:physiopathology; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000503:physiopathology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013315:Stress, Psychological / Q000150:complications*; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology
D050483:Dopamine Plasma Membrane Transport Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; C493226:Slc6a2 protein, rat; D008694:Methamphetamine; D004298:Dopamine