The glial activation inhibitor AV411 reduces morphine-induced nucleus accumbens dopamine release

Abstract

Glial activation has recently been discovered to modulate several effects of morphine, including analgesia, tolerance, and dependence. The present studies extend this line of investigation by exploring whether glial activation may also affect extracellular levels of dopamine (DA) in the nucleus accumbens (NAc) shell, a neurochemical corollary of morphine-induced drug reward, during a challenge dose of morphine in experiments both with and without precipitated withdrawal. Morphine or vehicle was administered s.c. for 4 days (starting at 15 mg/kg/day up to 20 mg/kg/day), and the glial activation inhibitor AV411 (7.5 mg/kg) or vehicle was administered twice daily. A challenge dose of morphine (22.5 mg/kg) or saline was then given during dialysis. In the first experiment, naloxone (10 mg/kg) was administered 1h after morphine during dialysis in AV411- or vehicle-treated rats, and behavioral signs of somatic withdrawal were assessed during microdialysis. In the second experiment, using the same dosing regimen, sampling continued 3 h after morphine or saline in AV411- or vehicle-treated rats. NAc DA increased in vehicle-treated rats significantly more than in AV411-treated rats before naloxone treatment, and withdrawal symptoms were significantly reduced in AV411-treated rats. The decrease in morphine-induced NAc DA by AV411 was persistent, lasting 3+h post-morphine. These results indicate that glial activation contributes to the effects of morphine on NAc DA, which is associated with somatic signs of precipitated withdrawal.

Figure 1

Probe placements in the NAc shell in microdialysis experiments using plates adapted from Paxinos and Watson (1998). Not all probes can be seen due to overlapping placements.

Figure 2

Glial inhibition decreases morphine-induced NAc DA and naloxone-precipated withdrawal in morphine-dependent rats. Rats received escalating morphine for 5 days with concurrent AV411 or vehicle treatment and dialysis was performed on day 5. Naloxone (10 mg/kg) was injected 1 hr after morphine (22.5 mg/kg). A. Morphine-induced DA in the NAc shell was attenuated in AV411 treated rats compared to vehicle controls prior to naloxone. Data are means ± SEMs of 6 rats/group B. Somatic signs of naloxone-precipitated withdrawal were attenuated in AV411 treated rats compared to vehicle controls. Data are means ± SEMs of 6 rats/group. C. There was a significant correlation between peak DA and total behavioral score. * AV411 + morphine less than vehicle + morphine, p < .05. ** AV411 + morphine less than vehicle + morphine, p < .01.

Figure 3

Glial inhibition attenuates morphine-induced DA in the NAc shell for at least 3 hr. Rats received escalating morphine or saline control injections (there was no difference between saline AV411 and saline vehicle groups so they were pooled) for 5 days with concurrent AV411 or vehicle treatment. Dialysis was performed on day 5 with a challenge dose of morphine (22.5 mg/kg) or equivolume saline. Data are means ± SEMs of 5 or 6 rats/group. # Vehicle + morphine greater than saline, p < .05, * AV411 + morphine less than Vehicle + morphine, p < .05, @ AV411 + morphine greater than saline, p < .05.