INCREASED LOCUS-COERULEUS GLUTAMATE LEVELS ARE ASSOCIATED WITH NALOXONE-PRECIPITATED WITHDRAWAL FROM BUTORPHANOL IN THE RAT

Extracellular fluid levels of glutamate were measured in the locus coe ruleus during butorphanol (a mixed agonist at mu-, delta-, and kappa-o pioid receptors) withdrawal by using microdialysis in conscious butorp hanol-dependent Sprague-Dawley rats. Guide cannulae were implanted chr onically and rats were given intracerebroventricular (i.c.v.) infusion s of butorphanol (26 nmol/l mu l/hr) or saline (1 mu l/hr) for 3 days. Microdialysis probes (2 mm tip) were inserted into the locus coeruleu s 24 hr before precipitation of withdrawal by i.c.v. injection of nalo xone (48 nmol/5 mu l). A separate series of rats was rendered dependen t by peripheral injection of butorphanol (20 mg/kg, s.c., b.i.d.) for 5 days and naloxone (5 mg/kg, i.p.) was given to precipitate withdrawa l. Single injections of butorphanol (26 nmol/5 mu l, i.c.v.) had no ef fect on the extracellular fluid levels of glutamate, compared to rats injected with vehicle. Behavioral evidence of withdrawal was detected following naloxone challenge in butorphanol-dependent rats (both i.c.v . and s.c. models), but not in non-dependent, vehicle-treated rats. Si gnificant increases (P<0.05) in levels of glutamate were noted after n aloxone-precipitated withdrawal only in the butorphanol group. The glu tamate levels in the locus coeruleus increased from 8.37 +/- 2.01 befo re, to 21.93 +/- 4.58 mu M in the first 15 min sample following i.c.v. injections of 48 nmol/5 mu l naloxone and from 10.84 +/- 1.74 before, to 26.01 +/- 6.19 mu M in the 15-30 min sample following i.p. injecti ons of 5 mg/kg naloxone in the butorphanol-dependent rats, respectivel y. These results provide direct evidence to support the role of excita tory amino acids within the locus coeruleus in butorphanol withdrawal.