Abstract
σ-1 Receptors are endoplasmic reticulum (ER) chaperones that are implicated in the neuroplasticity associated with psychostimulant abuse. We immunocytochemically examined the distribution of σ-1 receptors in the brain of drug-naive rats and then examined the dynamics of σ-1 receptors and other ER chaperones in specific brain subregions of rats that self-administered methamphetamine, received methamphetamine passively, or received only saline injections. σ-1 Receptors were found to be expressed in moderate to high levels in the olfactory bulb, striatum, nucleus accumbens shell, olfactory tubercle, amygdala, hippocampus, red nucleus, ventral tegmental area, substantia nigra, and locus ceruleus. Methamphetamine, whether self-administered or passively received, significantly elevated ER chaperones including the σ-1 receptor, BiP, and calreticulin in the ventral tegmental area and substantia nigra. In the olfactory bulb, however, only the σ-1 receptor chaperone was increased, and this increase occurred only in rats that actively self-administered methamphetamine. Consistent with an increase in σ-1 receptors, extracellular signal-regulated kinase was found to be activated and protein kinase A attenuated in the olfactory bulb of methamphetamine self-administering rats. σ-1 Receptors in the olfactory bulb were found to be colocalized with dopamine D1 receptors. These results indicate that methamphetamine induces ER stress in the ventral tegmental area and substantia nigra in rats whether the drug is received actively or passively. However, the changes seen only in rats that actively self-administered methamphetamine suggest that D1 and σ-1 receptors in the olfactory bulb might play an important role in the motivational conditioning/learning aspects of methamphetamine self-administration in the rat.
Footnotes
This research was supported by the Intramural Research Program of the National Institutes of Health National Institute on Drug Abuse.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.159244.
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ABBREVIATIONS:
- ER
- endoplasmic reticulum
- CHO
- Chinese hamster ovary
- ERK
- extracellular signal-regulated kinase
- PKA
- protein kinase A
- PBS
- phosphate-buffered saline
- D1R
- dopamine D1 receptor
- RT-PCR
- reverse transcription-polymerase chain reaction
- ANOVA
- analysis of variance
- ATF4
- activating transcription factor 4
- AOL
- anterior olfactory nucleus, lateral part
- VTA
- ventral tegmental area.
- Received July 23, 2009.
- Accepted November 23, 2009.
- U.S. Government work not protected by U.S. copyright
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