Mechanisms of cocaine-induced decreases in immune cell function.

Cocaine has previously been shown to decrease mitogen-induced T lymphocyte proliferation in rats following intravenous administration. However, in this report, it is demonstrated that central administration of cocaine (1-50 microg) had no effect on lymphocyte proliferation responses. Similarly, the quaternary derivative, cocaine methiodide, also suppressed lymphocyte proliferation only when administered peripherally (6.5 mg/kg), and not centrally (1-20 microg). These results suggest that the effects of cocaine were mediated through a peripheral mechanism. Since significant elevations in plasma corticosterone were observed with all routes of administration of cocaine, the effects of cocaine did not appear to be due entirely to activation of the HPA axis. Instead, the peripheral administration of the local anesthetic, lidocaine (5 mg/kg) or the monoamine reuptake inhibitor, RTI-55 (2-5 mg/kg), produced significant suppressive effects on proliferation. suggesting that both of these peripheral activities of cocaine may be involved in the alteration of lymphocyte responses.

Specific serotonin reuptake inhibitor-induced decreases in lymphocyte activity require endogenous serotonin release.

OBJECTIVES: We have previously reported that acute administration of the specific serotonin reuptake inhibitor (SSRI), fluoxetine, resulted in a decrease in mitogen-induced blood lymphocyte proliferation. The present studies further examine the specificity of this response to serotonin reuptake systems and the potential role of endogenous serotonin in mediating these effects. METHODS: Male Sprague-Dawley rats were treated intraperitoneally with the SSRIs, fluoxetine (6-10 mg/kg) or sertraline (20 mg/kg), dopamine and norepinephrine reuptake inhibitors, GBR 12909 and desipramine, respectively (6 mg/kg) or the serotonin precursor, 5-hydoxytryptophan (5-HTP, 50 mg/kg) 2 h prior to sacrifice. The serotonin-depleting agents, p-chlorophenylalanine (PCPA, 2 x 200 mg/kg) or the serotonin-lesioning agent, p-chloroamphetamine (PCA, 2 x 10 mg/kg) were administered intraperitoneally 5-7 days prior to fluoxetine (10 mg/kg) administration. RESULTS: Unlike the SSRIs, which significantly suppressed lymphocyte proliferation responses, selective norepinephrine or dopamine reuptake inhibition had no effect on lymphocyte proliferation. Elevation of extracellular serotonin levels with the serotonin precursor, 5-HTP, resulted in a similar decrease in lymphocyte proliferation as that seen with SSRI administration. Conversely, decreases in endogenous serotonin following PCA or PCPA treatment prevented the fluoxetine-induced decreases in lymphocyte proliferation. CONCLUSIONS: These results suggest that decreases in mitogen-induced lymphocyte proliferation following acute fluoxetine administration were due to elevations in extracellular serotonin following reuptake inhibition.

Modulation of immune cell function following fluoxetine administration in rats.

Fluoxetine (FLX) and other specific serotonin uptake inhibitors (SSRIs) have become the drugs of choice for treating depression. However, only a limited number of studies have addressed the effects of FLX on immune cell function. Our lab has measured the effects of both acute and chronic FLX administration on two functions of cell-mediated immunity, mitogen-induced lymphocyte proliferation (MILP) and natural killer cell cytolytic activity (NKCA). In this article we report that acute FLX administration (10 mg/kg) resulted in a dose- and time-dependent decrease in MILP and NKCA. MILP was more sensitive than NKCA to FLX, requiring lower doses for inhibition; however, the effects were more transient. Following chronic FLX administration, these effects were no longer observed, suggesting that an apparent tolerance to these particular measures of cell-mediated immunity had developed. Finally, a single microinjection of FLX directly into the lateral ventricle produced similar suppressive effects on MILP and NKCA, suggesting that the immunomodulatory mechanism may have a central component.