Evidence for the nucleus accumbens as a neural substrate of heroin-induced immune alterations

Abstract

Administration of opioid drugs such as heroin produces several immunosuppressive effects, including decreases in natural killer (NK) cell activity, lymphocyte proliferative responses, and nitric oxide production. Interestingly, opioids have been shown to alter many immune parameters indirectly by modulating the immunoregulatory actions of the central nervous system. Recently, it has been demonstrated that morphine inhibits NK cell activity through a neural pathway that requires the activation of dopamine D(1) receptors in the nucleus accumbens shell. The present study examined whether the nucleus accumbens also mediates the effects of heroin, a more commonly abused opioid, on several parameters of immune status in Lewis rats. The results showed that bilateral administration of the dopamine D(1) receptor antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH-23390; 0.015 and 0.15 microg/side) into the nucleus accumbens shell blocked decreases in splenic NK activity produced by heroin (3 mg/kg s.c.) but did not attenuate the suppression of splenocyte proliferative responses to concanavalin-A or lipopolysaccharide (LPS). A subsequent experiment was performed to evaluate the effect of D(1) receptor antagonism on LPS-induced expression of inducible nitric-oxide synthase (iNOS) in vivo. These results showed that intra-accumbens SCH-23390 administration prevented heroin-induced reductions of iNOS mRNA expression in spleen, liver, and lung tissues and attenuated the suppression of nitric oxide levels in plasma. Collectively, these findings indicate that nucleus accumbens dopamine D(1) receptors are critically involved in heroin-induced immune alterations.

Fig. 1.

Effects of heroin dose on splenic immune measures. Data from the cytotoxicity assay are expressed as lytic units (mean ± S.E.). Data from proliferation assays are expressed as disintegrations per minute (mean ± S.E.). *, p < 0.05; ***, p < 0.001 compared with saline-treated control group.

Fig. 2.

Effect of D₁ receptor antagonism in the nucleus accumbens on heroin-induced suppression of NK cell activity. Rats received bilateral microinjections of saline or SCH-23390 into the nucleus accumbens shell before a subcutaneous injection of heroin. Data are expressed as lytic units (mean ± S.E.). ***, p < 0.001 compared with the saline-treated control group that received an equivalent dose of SCH-23390.

Fig. 3.

Effect of D₁ receptor antagonism in the nucleus accumbens on heroin-induced decreases in splenocyte mitogenic responses. Rats received bilateral microinjections of SCH-23390 into the nucleus accumbens shell before a subcutaneous injection of saline or heroin. Data are expressed as disintegrations per minute (mean ± S.E.). **, p < 0.01 compared with the saline group that received the same dose of SCH-23390.

Fig. 4.

Effect of D₁ receptor antagonism in the nucleus accumbens on heroin-induced reductions of iNOS mRNA expression. Rats received microinjections of SCH-23390 into the nucleus accumbens shell before subcutaneous injections of saline or heroin in conjunction with LPS administration. Data are expressed as the ratio of iNOS mRNA expression to expression of the housekeeping gene cyclophilin (mean ± S.E.). *, p < 0.05; **, p < 0.01; ***, p < 0.001 compared with the saline group that received an equivalent dose of SCH-23390.

Fig. 5.

Effect of D₁ receptor antagonism in the nucleus accumbens on heroin-induced reductions of plasma nitrite/nitrate. Data are expressed as the plasma nitrite/nitrate concentration in micromolar (mean ± S.E.). *, p < 0.05; **, p < 0.01; ***, p < 0.001 compared with the saline group that received an equivalent dose of SCH-23390.