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Volume 17, Number 21, Issue of November 1, 1997 pp. 8596-8612
Copyright ©1997 Society for Neuroscience

Systemic Morphine-Induced Fos Protein in the Rat Striatum and Nucleus Accumbens Is Regulated by µ Opioid Receptors in the Substantia Nigra and Ventral Tegmental Area

Received April 4, 1997; revised Aug. 6, 1997; accepted Aug. 21, 1997.

Bruno Bontempi and Frank R. Sharp

Department of Neurology (V127), University of California at San Francisco and Department of Veterans Affairs Medical Center, San Francisco, California 94121

To characterize how systemic morphine induces Fos protein in dorsomedial striatum and nucleus accumbens (NAc), we examined the role of receptors in striatum, substantia nigra (SN), and ventral tegmental area (VTA). Morphine injected into medial SN or into VTA of awake rats induced Fos in neurons in ipsilateral dorsomedial striatum and NAc. Morphine injected into lateral SN induced Fos in dorsolateral striatum and globus pallidus. The morphine infusions produced contralateral turning that was most prominent after lateral SN injections. Intranigral injections of [D-Ala², N-Me-Phe⁴, Gly-ol⁵]-enkephalin (DAMGO), a µ opioid receptor agonist, and of bicuculline, a GABA_A receptor antagonist, induced Fos in ipsilateral striatum. Fos induction in dorsomedial striatum produced by systemic administration of morphine was blocked by (1) SN and VTA injections of the µ₁ opioid antagonist naloxonazine and (2) striatal injections of either MK 801, an NMDA glutamate receptor antagonist, or SCH 23390, a D₁ dopamine receptor antagonist.

Fos induction in dorsomedial striatum and NAc after systemic administration of morphine seems to be mediated by dopamine neurons in medial SN and VTA that project to medial striatum and NAc, respectively. Systemic morphine is proposed to act on µ opioid receptors located on GABAergic interneurons in medial SN and VTA. Inhibition of these GABA interneurons disinhibits medial SN and VTA dopamine neurons, producing dopamine release in medial striatum and NAc. This activates D₁ dopamine receptors and coupled with the coactivation of NMDA receptors possibly from cortical glutamate input induces Fos in striatal and NAc neurons. The modulation of target gene expression by Fos could influence addictive behavioral responses to opiates.

Key words: morphine; immediate early genes; Fos; drug addiction; rotational behavior; striatum; substantia nigra; ventral tegmental area; nucleus accumbens; Parkinson's disease

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