1. ¹Neuroscience Doctoral Program, University of Michigan, Ann Arbor, MI, USA
2. ²Mental Health Research Institute, University of Michigan, Ann Arbor, MI, USA
3. ³NIDDK, NIH, DHHS, Bethesda, MD, USA
4. ⁴Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA

Correspondence: JH Woods, Department of Pharmacology, University of Michigan Medical School, 1301 MSRB III, Ann Arbor, MI 48109-0632, USA. Tel: +1 (734) 764 9133; Fax: +1 (734) 764 7118; E-mail: jhwoods@umich.edu

Received 23 April 2003; Revised 23 September 2003; Accepted 6 October 2003; Published online 26 November 2003.

Abstract

-Opioid receptor agonists have antidepressant-like effects in behavioral models of depression. Chronic administration of classical antidepressants upregulates mRNA expression of brain-derived neurotrophic factor (BDNF) and its high-affinity tyrosine kinase receptor, TrkB in the frontal cortex and hippocampus of rats. Increases in BDNF and TrkB levels are thought to be important for the therapeutic effects of these drugs. Therefore, we examined the ability of the -opioid receptor agonist (+)BW373U86 to regulate BDNF and TrkB mRNA expression in frontal cortex, hippocampus, as well as, basolateral amygdala, endopiriform nucleus, and primary olfactory cortex. At 3 h after a single administration of (+)BW373U86 animals were killed and BDNF and TrkB mRNA levels were examined by in situ hybridization. BDNF mRNA levels produced by (+)BW373U86 were compared to acute administration of the antidepressants desipramine and bupropion. A behaviorally antidepressant dose of 10 mg/kg (+)BW373U86 increased BDNF mRNA expression in all regions examined; a smaller dose of (+)BW373U86 (1 mg/kg) significantly increased BDNF mRNA expression only in frontal cortex. The -opioid receptor antagonist naltrindole blocked (+)BW373U86-mediated increases in BDNF mRNA expression. In addition, tolerance developed to increased BDNF mRNA expression with repeated injection, except in frontal cortex. Midazolam was administered to some animals to prevent the convulsions produced by (+)BW373U86, but midazolam did not block -opioid receptor-mediated increases in BDNF mRNA expression in frontal cortex, hippocampus, or amygdala. Unlike desipramine and bupropion, (+)BW373U86 upregulated BDNF mRNA expression acutely (within 3 h after a single administration). These data support the concept that -opioid receptor agonists may have antidepressant potential, and could be good targets for the development of faster-acting antidepressants.