Basal and morphine-evoked dopaminergic neurotransmission in the nucleus accumbens of MOR- and DOR-knockout mice.
Conventional and no net flux microdialysis were used to quantify basal and morphine-induced extracellular dopamine (DA) levels and the basal extraction fraction, which provides an estimate of the rate of DA uptake, in the nucleus accumbens (NAc) of wild-type mice and those with a constitutive deletion of mu (MOR)- or delta (DOR)-opioid receptors. Locomotor activity was assessed in these same animals. No difference between genotypes in basal dialysate DA levels was seen. No net flux studies revealed significant decreases in the DA extraction fraction in both MOR- and DOR-knockout mice, indicating decreased basal DA uptake in both genotypes. Extracellular DA, however, was unchanged. Because extracellular neurotransmitter levels are determined by the dynamics of both release and uptake, these findings provide suggestive evidence that basal DA release is decreased in mutant mice. Systemic administration of morphine significantly increased locomotor activity and dialysate DA levels in wild-type mice. MOR-knockout mice failed to exhibit a behavioural response to morphine. The ability of morphine to increase DA levels, however, was reduced but not prevented. No alteration in the effects of morphine was observed in DOR-knockout mice. These data provide genetic evidence for the existence of tonically active MOR and DOR systems that modulate basal DA neurotransmission in the NAc. Furthermore, they demonstrate that in contrast to the locomotor-activating effects of morphine, a small component of morphine-evoked DA release occurs independently of MOR activation.
Chefer
Vladimir I
VI
Integrative Neuroscience Section, DHHS/NIH/NIDA/IRP/BNRB/INS, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA. vchefer@intra.nih.gov
Kieffer
Brigitte L
BL
Shippenberg
Toni S
TS
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D019540:Area Under Curve; D001522:Behavior, Animal / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005110:Extracellular Space / Q000378:metabolism; D005838:Genotype; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017551:Microdialysis / Q000379:methods; D009020:Morphine / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000235:genetics / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
D000701:Analgesics, Opioid; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D009020:Morphine; D004298:Dopamine