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In vivo effects of cocaine on immune cell function
Journal of Neuroimmunology 83 Ž1998. 139–147
In vivo effects of cocaine on immune cell function Trisha Pellegrino ) , Barbara M. Bayer
1
Georgetown UniÕersity Medical Center, Department of Pharmacology, Washington, DC 20007, USA Received 7 March 1997; revised 20 October 1997; accepted 24 October 1997
Abstract Cocaine use has been shown to increase the risk of HIV infection in humans, and this increased risk cannot be explained by i.v. drug use alone. It is thought that this increased susceptibility may be a result of decreased immune responsiveness in cocaine addicts. Scientists are now using animal models to study the effects of cocaine on immune function in vivo under controlled conditions. Many facets of the immune system are being examined, which include immune cell number and distribution, cellular- and humoral-mediated immunity, cytokine production, and immunocompetence to challenges such as infection and tumor growth. The effects of cocaine on many of these functions are not yet clear. Often there are variations in the response of the immune system to cocaine. Potential confounding factors include variations in dose, duration of treatment, and route of administration of cocaine, as well as variations in assay protocols. In addition, there appear to be species differences in immune responses to cocaine. Although it is clear that more research is necessary to resolve the discrepancies, a sufficient number of trends are starting to emerge. This review will systematically evaluate the reported effects of cocaine on immune cell function in vivo. In addition, the possible mechanisms that may be contributing to the immune modulation observed with cocaine in vivo will be addressed. Further, data will be presented describing the effects of cocaine on the autonomic nervous system and the neuroendocrine system suggesting that inhibition of serotonin uptake may be an important component of the overall effects of cocaine on the immune system. q 1998 Elsevier Science B.V. Keywords: Cocaine; In vivo; Humoral immunity; Cellular immunity
1. Introduction Over the past decade, the increased susceptibility to infections among cocaine users has become more widely appreciated. In particular, the incidence of HIV seroprevalence has been shown to be significantly higher in cocaine addicts. Chaisson et al. Ž1989. reported a 26% increased incidence of HIV seroprevalence in cocaine addicts in San Francisco over other IV drug abusers. Similarly, a 16% increased incidence of HIV seroprevalence was observed in cocaine addicts in Baltimore Žover other IV drug abusers. ŽAnthony et al., 1991.. Collectively, these data suggest that the increased incidence of HIV infection may not be explained by intravenous drug use alone, and support the hypothesis that cocaine use may result in an increase in susceptibility to HIV infection. If so, it is imperative that the scientific basis underlying this association be fully
) 1
Corresponding author. Tel.: q1 202 6871616; fax: q1 202 6874226.
0165-5728r98r$19.00 q 1998 Elsevier Science B.V. All rights reserved. PII S 0 1 6 5 - 5 7 2 8 Ž 9 7 . 0 0 2 3 0 - 0
understood. To date, only a few laboratories have begun to address whether cocaine use may be associated with immune dysfunction which could ultimately contribute to a greater susceptibility to viral and bacterial infection. This review will address the existing information available on the in vivo effects of cocaine on various immune parameters and consequences to immunity. Possible mechanisms by which cocaine may influence immune cell activity will also be discussed.
2. Effects of cocaine on cell-mediated immunity
2.1. Immune cell populations and distribution The effects of cocaine on measures of cell-mediated immunity reported have examined possible alterations in immune cell number and distribution, mitogen-induced lymphocyte proliferation, and natural killer cell cytolytic activity, as summarized in Table 1. The most consistent
T. Pellegrino, B.M. Bayer r Journal of Neuroimmunology 83 (1998) 139–147
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Table 1 Effects of in vivo cocaine administration on cell-mediated immunity Species
Time course
Dose Žmgrkg.
Human
Acute Chronic Acute Chronic Acute Chronic Chronic Chronic Chronic
0.6 addicts 1–10 5 5–30 1 1–10 40 40
Rat Mouse
Murine AIDS
Proliferation
Cell number
Cytolytic activity
Cell number
Reference
≠
≠ ≠
Van Dyke et al., 1986 Ruiz et al., 1994 Bayer et al., 1995 Bayer et al., 1996 Ou et al., 1989 Francesco et al., 1991 Di Francesco et al., 1994 Lopez et al., 1992 Lopez and Watson, 1994
x x l
l l x x x x x
changes in any of the measures observed have been a reduction in the number or distribution of immune cells following cocaine administration. A significant dose-dependent decrease in the number of mouse thymocytes and white blood cells has been detected 96 h after acute administration of cocaine ŽOu et al., 1989.. Similarly, chronic treatment of mice with cocaine resulted in a slight, but significant, decrease in thymus weight and a decrease in CD8 q cells ŽLopez et al., 1992.. Chronic cocaine administration has also been shown to decrease CD8 q cells in the intestinal lamina propria of mice ŽLopez and Watson, 1994.. Although, Di Francesco et al. Ž1994. found that 7 days of cocaine administration also reduced circulating white blood cells in mice, no change in cell percentages or proportions between various subpopulations was observed. However, in the same study, after 30 consecutive days of cocaine administration, the decrease in cell number was no longer present, suggesting the possible development of an ‘apparent’ tolerance to the effects. The effects of cocaine on cell-mediated immunity in a murine AIDS ŽMAIDS. model have been investigated to more closely approximate the effect of cocaine-use on immune function during the course of HIV infection. MAIDS infection has been shown to result in decreased CD4 q lymphocyte counts in both the thymus and the intestinal lamina propria ŽLopez et al., 1992.. Chronic cocaine administration in infected mice appeared to exacerbate the effects of MAIDs resulting in a further decrease in CD4 q cells ŽLopez and Watson, 1994.. The implication of these results is that cocaine may have similar effects in HIV infected individuals. However, to date, there is little epidemiological evidence to support this hypothesis ŽKaslow et al., 1989.. 2.2. Natural killer cell (NK cell) cytolytic actiÕity NK cells are another type of lymphocyte involved in cell-mediated immunity. In contrast to the decrease in number of other lymphocyte subpopulations, cocaine administration has been shown to be accompanied by an increase in the number of circulating NK cells. This increase appears to be species independent, since it has been reported in both human cocaine addicts ŽVan Dyke et al.,
≠ ≠
1986 and Ruiz et al., 1994. and in mice ŽLopez et al., 1992.. In addition to increasing NK cell number in non-infectious models, NK cells have been shown to increase following chronic cocaine administration in infectious disease models, such as MAIDS ŽLopez and Watson, 1994.. Although consistent increases in NK cell number have been observed, the reported effects of cocaine on NK cell cytolytic activity have been unpredictable. For example, a significant increase in NK cell activity was found in the blood of human addicts ŽRuiz et al., 1994. and after acute intravenous cocaine administration to human subjects ŽVan Dyke et al., 1986.. However, in mice exposed to chronic cocaine, a significant decrease in NK cell cytolytic activity has been reported ŽFrancesco et al., 1991.. In contrast to these findings in humans and mice, Bayer et al. Ž1995. found no effect on NK cell cytolytic activity in rats after acute or chronic cocaine administration. At present, the reasons for the discrepancies among these studies, and the lack of relationship to the increase observed in NK cell number, are not clear. 2.3. T-lymphocyte proliferation Our laboratory has looked at the effects of acute and chronic cocaine administration in rats on mitogen-induced lymphocyte proliferation, another measure of cell-mediated immune function. Acute cocaine administration, intravenously Ži.v.., resulted in a decrease in mitogen-induced T-lymphocyte proliferation in a dose and time-dependent manner in rats ŽBayer et al., 1995.. However, following chronic i.v. administration of cocaine in rats, the immunosuppressive effects were no longer observed ŽBayer et al., 1996.. In addition, this ‘apparent’ tolerance was found to cross-over to morphine, which also had no suppressive effect on lymphocyte proliferation in rats chronically treated with cocaine. In contrast, acute morphine administration Ž10 mgrkg., to naive animals, resulted in a 70–80% suppression of blood lymphocyte responses ŽBayer et al., 1996.. These results suggested that perhaps morphine and cocaine may share a common mechanism of immunomodulation. In addition to species differences, the potential development of tolerance to some of the effects of cocaine
T. Pellegrino, B.M. Bayer r Journal of Neuroimmunology 83 (1998) 139–147
on selective immune parameters may be another reason for the discrepancies observed by various investigators. On a cautionary note, one should not assume that the ‘apparent’ tolerance to the suppression of mitogen-induced lymphocyte proliferation after chronic cocaine treatment indicates that the immune function of these animals is normal. Previous studies have indicated that ‘apparent’ tolerance to the inhibitory effects of morphine of lymphocyte proliferation renders the animal more susceptible to the immuno-suppressive effects of mild stressors ŽBayer et al., 1994.. Therefore, individual immune assays may not always be predictive of overall immune competence. It is possible that a compensatory mechanism has developed in animals treated chronically with cocaine, and therefore, when challenged through stress or infection, these animals may not be fully immunocompetent.
3. Effects on of cocaine humoral immunity 3.1. Plaque-forming actiÕity (PFA) Most of the data on the effects of cocaine on humoral immunity have been derived from investigations with mice, utilizing the plaque-forming assay to measure antibody production in animals immunized with sheep red blood cells ŽSRBC. ŽTable 2.. A decreased splenic PFA to SRBC was observed in mice treated acutely with low doses of cocaine at the time of immunization ŽOu et al., 1989.. Similarly, chronic administration of higher doses of cocaine after immunization also resulted in decreased PFA ŽWatson et al., 1983.. However, when mice were immunized with 2,4-dinitro-phenyl ligand ŽDNP., another T-cell dependent antigen, cocaine had no effect on PFA ŽHavas et al., 1987.. Therefore, the differential effects of cocaine in these two studies may be due to differences in the type of antigen ŽDNP vs. SRBC., or more likely due to inconsistencies in the timing of cocaine administration relative to the time of immunization with each antigen. 3.2. Antibody titer Another method, of assaying humoral immune function, is to determine the levels of antibody against an antigen in
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a preimmunized animal. No effect has been found with chronic cocaine administration on antibody production to the polysaccharide antigen SSS-III in normal, non-infected mice. Overall, the effects of chronic cocaine on antibody production in mice have been consistently marginal. Of the studies reported, no significant decrease in antibody production have been observed ŽTable 2.. This also seems to be the case with infectious mouse models. Following infection with a Friend Leukemia Virus ŽFLV., no further decrease in antibody titers to SRBC was observed following chronic cocaine administration ŽStarec et al., 1991.. However, in rats the effects of cocaine on humoral immunity may be dose-dependent. An increase in antibody titer to SSS-III was found in rats chronically-treated with low doses of cocaine, but a significant drop in antibody titer was observed after chronic treatment with higher doses of cocaine ŽBagasra and Forman, 1989.. Therefore, differences in the effects of cocaine on humoral immunity are emerging, but may be dependent on factors such as species, dose and duration of treatment. Again, further studies are necessary to determine the critical factors contributing to these differential responses following cocaine administration.
4. Effects of cocaine on cytokine production In addition to measures of cellular and humoral immunity, the effects of chronic cocaine treatment on cytokine production have also been examined. Since cytokines regulate a number of important immune cell functions, it is hypothesized that alterations in the expression of cytokines during cell activation may ultimately result in changes in immunity. To date, only two studies have addressed the possible effects of cocaine on cytokine production by immune cells and the results are summarized in Table 3. In both of these studies, the pattern of cytokine secretion from LPS and Con A stimulated mouse splenocytes was altered by chronic cocaine administration. Twenty-four hours after mitogen stimulation, decreases in the secretion of IL-4 and IL-10 were observed, which were accompanied by increases in TNF-a , IL-6, and IL-2. However, contrary to the increase at 24 h, at 72 h there was a
Table 2 Effects of in vivo cocaine administration on humoral immunity Species
Time course
Dose Žmgrkg.
Plaque-formation
Mouse
Acute Acute Chronic Chronic Chronic Chronic Chronic
5 5 Ž5 = . 2–60 30 50 1.25–2.5 5
x l l x
Murine FLV Rat
≠ ≠
Titer
Reference Ou et al., 1989 Havas et al., 1987
l x ≠ x
Watson et al., 1983 Starec et al., 1983 Bagasra and Forman, 1989
T. Pellegrino, B.M. Bayer r Journal of Neuroimmunology 83 (1998) 139–147
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Table 3 Effects of cocaine in vivo on splenocyte cytokine production Investigator
Species
Time course
Dose Žmgrkg.
TNF-a
g-IFN
Chen and Watson, 1991 Wang et al., 1994
Mouse
Chronic Chronic
x ≠
l
Chen and Watson, 1991
MAIDS model
20–40 10–40 a 10–40 b 20–40
x
x
a
Chronic
IL-2
IL-4
IL-5
IL-6
IL-10
≠
x
≠
≠ ≠
x ≠
b
24 h after mitogen stimulation; 72 h after mitogen stimulation.
decrease in TNF-a , which suggests that the incubation time after stimulation is an important factor in studies measuring cytokine expression ŽChen and Watson, 1991 and Wang et al., 1994.. No changes in g-IFN production was observed, except when mice were infected with murine AIDS. In infected mice treated chronically with cocaine, there was a significant decrease in g-IFN ŽChen and Watson, 1991.. Whether or not these changes in cytokine secretion are related to alterations in lymphocyte populations remain to be determined. However, unlike in vivo cocaine administration, in vitro cocaine administration results in a dose-dependent decrease in the secretion of all cytokines measured ŽWang et al., 1994.. The differential responses following in vivo and in vitro exposure to cocaine, suggest that these changes in cytokine secretion are not due entirely to direct effects of cocaine on immune cells. Therefore, indirect mechanisms of cocaine, such as alterations in hormone levels, may come into play.
5. Consequences of in vivo cocaine administration Although tolerance may develop to some of the aforementioned immune parameters after chronic cocaine administration, this does not necessarily mean that the immune function of the animal is normal. It is possible that compensatory mechanisms may develop, which under stress or infection may result in inadequate immunocompetence. The best method of determining immunocompetence after chronic drug treatment is to look at the effects of that treatment in the intact animal. The measures of immuno-
competence following cocaine administration include delayed-type hypersensitivity ŽDTH., susceptibility to infection, and tumor growth and the results are summarized in Table 4. Chronic ingestion of coca alkaloids has been shown to result in a 20–53% decrease in the DTH response in mice ŽWatson et al., 1983.. In addition, a modest, but significant, decrease in the DTH response was found following chronic cocaine treatment with high doses Ž50 mgrkg. in mice previously infected with FLV ŽStarec et al., 1991.. This group also demonstrated an increased lethality to FLV in mice chronically treated with cocaine, particularly in the rate of death after infection. However, it should be noted that the doses of cocaine being used in these experiments were found to be toxic in normal, non-infected mice by Havas et al. Ž1987. ŽStarec et al., 1991.. Cocaine at low doses Ž0.05 mgrkg. was also found to be associated with an accelerated tumor growth in mice, suggesting a potential decrease in natural killer ŽNK. cell or cytotoxic T cell function ŽOu et al., 1989.. In contrast to low dose cocaine administration, chronic administration of high doses of cocaine have no effect on tumor growth or death rate ŽHavas et al., 1987.. In addition, there is no change in death rate in mice that had been infected with Streptococcus pneumonia ŽHavas et al., 1987.. The susceptibility to secondary parasitic infections common in HIV patients, was measured in mice previously infected with the murine AIDS virus. An increased number of Cryptosporidium were found on the villi of mice infected with the MAIDS virus and chronically treated with cocaine. However, this cocaine treatment did not result in any significant increase in the number of oocysts in the feces or the number of mice testing positive for Cryp-
Table 4 Immune consequences of in vivo cocaine Species
Time course
Dose Žmgrkg.
Infectivity
Human
Chronic Chronic Chronic Chronic Chronic Chronic Chronic
addicts addicts addicts 0.05–5 2–60 50 40
≠ ≠ ≠
Mouse
l l
Tumor growth
≠ l ≠
DTH
x
Investigator Donahue et al., 1986 Chaisson et al., 1989 Anthony et al., 1991 Ou et al., 1989 Havas et al., 1987 Starec et al., 1991 Darban et al., 1993
T. Pellegrino, B.M. Bayer r Journal of Neuroimmunology 83 (1998) 139–147
tosporidium in both non-infected mice and mice infected with murine AIDS ŽDarban et al., 1993.. Therefore, the consequences of cocaine administration on immunity are still not well defined. Although collectively these studies suggest cocaine may suppress overall immunity, variations in dose, duration and frequency of cocaine administration, and animal models used in these studies make it difficult to reach a definitive conclusion.
6. Pharmacological mechanisms of cocaine Considering the current available information, the effects of cocaine on immune function do not appear to be due to a direct action of cocaine on immune cells. Although very high doses of cocaine in vitro will decrease immune cell function, there is little or no effect at doses which would be expected in vivo ŽJavaid et al., 1978; Welch, 1983; Martinez and Watson, 1990; Lou et al., 1992; Berkeley et al., 1994.. Instead, cocaine has several well-known pharmacologi-cal mechanisms which could contribute to the effects on the immune response ŽFig. 1.. These multiple pharmacological properties may also contribute to the varied immune effects due to cocaine with different doses. At low doses Ž0.2–1 mgrkg., cocaine acts primarily as an inhibitor of all three monoamine uptake pumps—serotonin, dopamine, and norepinephrine ŽSzabo et al., 1995.. It is inhibition of monoamine uptake, particularly dopamine, that is thought to be involved in the reinforcing properties of cocaine ŽJohanson and Fischman, 1989.. At higher doses Ž) 1 mgrkg., cocaine also demonstrates cholinergic antagonist properties ŽSharkey et al., 1988 and Szabo et al., 1995.. Finally, at even higher doses ŽG 5 mgrkg., cocaine also has local anesthetic activity ŽSzabo et al., 1995.. It is not yet clear which of these actions may be the most prominent in producing the immunomodulatory effects of cocaine. Furthermore, a combination of these actions may be required to modify immune responses. Therefore, the selection of the dose is an important consideration when attempting to evaluate the mechanismŽs. by which cocaine administration in vivo may be influencing the immune system.
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7. Physiological mechanisms by which cocaine influences the immune system The pharmacological actions of cocaine ultimately lead to a number of physiological effects, each of which have independently been shown to be involved in the regulation of immune responses. Through its primary effects on several monoamine systems, cocaine has a cascade of secondary physiological effects. Studies have only just begun to address the potential physiological mechanisms which could be involved in the immunomodulatory effects and include the changes induced by cocaine on autonomic nervous system activity, neuroendocrine hormone secretion, as well as changes in plasma monoamine concentrations ŽFig. 2.. 7.1. Autonomic nerÕous system The autonomic nervous system is one of the primary ways by which the central nervous system is thought to regulate immune function. Overall, cocaine increases autonomic nervous system activity resulting in an increase in sympathetic tone and an elevation of plasma catecholamines ŽChiueh and Kopin, 1978; Kiristy-Roy et al., 1990; Tella et al., 1993.. There are a number of ways in which increased autonomic nervous activity may alter immune cell activity, as reviewed by Madden et al., 1995. First, an increase in sympathetic nervous activity leads to an increase in catecholamines both in the plasma, as well as in innervated tissues. The primary and secondary lymphoid tissues are highly innervated by the sympathetic nervous system, which could act as a direct neurological link between the central nervous system and immune cells ŽMadden et al., 1995.. Adrenergic agonists have long been found to directly suppress immune cell function in vitro. Therefore, elevation of catecholamines in the immune cell environment may contribute to a decrease in immune competence after cocaine administration. 7.2. Neuroendocrine system Another primary mechanism by which the central nervous system is thought to modulate immune function is
Fig. 1. Pharmacological effects of cocaine. ŽDoses were derived from Sharkey et al., 1988, Ritz et al., 1990, and Szabo et al., 1995..
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Fig. 2. Physiological effects of cocaine in vivo.
through the release of neuroendocrine hormones. Of these neuroendocrine hormones, the hypothalamic–pituitary– adrenal axis ŽHPA axis. has been the most widely studied in relation to immune function. Cortical steroids have long been reported to have immunosuppressive properties, as reviewed by Parrillo and Fauci, 1979. Decreases in immune function in rodents after elevation of plasma corticosterone are thought to be due to immune cell death and redistribution in lymphoid tissue compartments. However, Stanulis et al. Ž1996. recently reported that the enhanced antibody response observed following acute cocaine in mice is due to increases in plasma corticosterone levels. Cocaine administration has been found to result in activation of the HPA axis, which leads to elevation in plasma corticosterone levels in rodents, and cortisol levels in humans ŽSaphier et al., 1993; Bayer et al., 1995; Baumann et al., 1995.. Elevations of corticosterone in rats have been shown to be transient and dose-dependent following i.v. administration of cocaine ŽRivier and Vale, 1987; Bayer et al., 1995.. In addition, i.v. cocaine administration to cocaine addicts results in elevations of cortisol levels ŽBaumann et al., 1995.. These effects have been shown to be centrally mediated since administration of cocaine directly into the third ventricle of rats results in a dose-dependent increase in plasma corticosterone levels ŽSaphier et al., 1993.. Doses of cocaine Ž1 mgrkg. which were not accompanied by increases of corticosterone were also found not to produce suppression of blood lymphocyte proliferation to mitogens, suggesting a possible role of increased steroids in the immunosuppressive effects of cocaine. The changes in the HPA axis after cocaine administration are also most likely due to increases in monoamine neurotransmission. Several of the monoamine pathways have been implicated in these effects. For example, activation of serotonin receptors results in elevated corticosterone and b-endorphin secretion in rats ŽKoenig et al., 1987.. Serotonin appears to be involved in the elevation of
ACTH and corticosterone after cocaine administration in rats ŽLevy et al., 1991.. Consistent with these observations, our laboratory has also found increases in corticosterone levels after acute administration of selective serotonin uptake inhibitors ŽPellegrino and Bayer, 1996.. However, other monoamines may also be involved in the neuroendocrine changes seen with cocaine, since elevation of corticosterone after cocaine has been shown to be blocked by dopaminergic and adrenergic antagonists ŽSarnyai et al., 1993.. In addition, selective inhibition of dopamine uptake has been shown to lead to activation of the HPA axis ŽBorowsky and Kuhn, 1993.. Utilizing selective antagonists, it was demonstrated that acute cocaine activates the HPA axis through inhibition of both dopamine as well as serotonin uptake ŽLevy et al., 1994.. Therefore, it appears that the monoamine pathways, particularly serotonergic and dopaminergic pathways, are important mediators of the neuroendocrine changes seen with cocaine. In addition to cortical steroids, cocaine administration has also been shown to modulate the release of opioid peptides, prolactin, and vasopressin ŽFig. 2.. Madden and Felten Ž1995. thoroughly reviewed, the effects of cortical steroids and other neuroendocrine hormones on the imTable 5 Effects of specific monoamine uptake inhibitors of mitogen-induced lymphocyte proliferation ŽPellegrino and Bayer, 1996. Treatment a
Specificity
Saline Fluoxetine Desipramine GBR 12909
Serotonin Norepinephrine Dopamine
a
3
H-Thymidineb Žcpm"SEM.
41,234"6397 13,632"1537 c 48,332"8910 54,458"7694
n 11 10 13 14
Drugs were administered at doses of 10 mgrkg, i.p., and animals were sacrificed two hours later. b Maximal response after stimulation with 0.2, 0.4, and 0.6 m g Concanavalin Arculture of whole blood lymphocytes diluted 1:10 with RPMI-1640 media. c Denotes significant difference from saline, p- 0.01, determined by one-way ANOVA.
T. Pellegrino, B.M. Bayer r Journal of Neuroimmunology 83 (1998) 139–147
mune system in vivo and in vitro. Cocaine administration results in a modulation in the release of these other neuroendocrine hormones ŽFig. 2.. Therefore, the combined alteration of these hormones may contribute to the overall effects of cocaine on the immune system. Furthermore, tolerance does not develop to the neuroendocrine effects of cocaine ŽLevy et al., 1994.. Therefore, prolonged cocaine exposure results in persistent alterations in neuroendocrine hormone levels. The consequence of these changes induced by cocaine on the ability to mount an immune response remain to be determined.
8. Monoamine involvement in cocaine mediated immunomodula-tion The physiological changes described in autonomic and neuroendocrine system activity observed with cocaine, are most likely mediated through the activation of central monoamine pathways. Cocaine primarily inhibits reuptake and thus increases monoamine neurotransmission. Our laboratory has measured the effects of specific monoamine uptake inhibitors on lymphocyte proliferation ŽPellegrino and Bayer, 1996.. Specific uptake inhibitors of norepinephrine and dopamine had no significant effect on mitogen-induced lymphocyte proliferation ŽTable 5.. Only the serotonin uptake inhibitor, fluoxetine, was able to mimic the suppression seen with cocaine on mitogen-induced lymphocyte proliferation ŽPellegrino and Bayer, 1996.. This suggests that the inhibitory effects of cocaine on lymphocyte proliferation may be predominantly due to serotonin uptake inhibition, rather than norepinephrine or dopamine. Our laboratory has been accumulating data suggesting that sero-tonin may be the primary monoamine involved in the immune effects seen with cocaine ŽPellegrino and Bayer, 1996.. Serotonin has been shown to modulate immune function in vitro ŽAune et al., 1994; Hellstrand and Hermodsson, 1987; Nordlind et al., 1992.. In vivo, serotonin receptors have been shown to activate the HPA axis and the sympathetic nervous system, which as previously described, can decrease immune cell function ŽKoenig et al., 1987; Levy et al., 1991; Levy et al., 1994; Li et al., 1994; Levy et al., 1995.. Therefore, the inhibition of serotonin uptake may be an important component of the effects of cocaine on immune function. However, the contribution of the various monoamines on overall immune function has not been well characterized.
9. Conclusions From the existing data, it is clear that more studies are necessary to further characterize the differential effects of
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cocaine on immune cell function. Although the data in humans suggest that cocaine-use increases susceptibility to infection, the reasons for this are still not clear. The differences among the studies with reference to dose, route of administration, duration and frequency of treatment, animal model and assay protocols make comparisons tentative at best. Furthermore, when utilizing chronic cocaine paradigms and measuring one specific immune parameter, the possible development of compensatory mechanisms in the intact animal must be taken into consideration. An animal which has developed an ‘apparent’ tolerance to the effects of cocaine after chronic administration, may not be immune competent when challenged by stress, other drugs of abuse, or infection. Patterns are emerging that indicate cocaine suppresses a number of measures of cell-mediated and humoral-mediated immunity. Infectious disease models also suggest a overall decrease in immunocompetence. However, too few studies have been carried out to reach definitive conclusions. Although cocaine has many mechanisms which may contribute to immune effects observed, further studies are required to determine the underlying mechanisms involved in producing these effects. Because of the multiplicity of actions of cocaine on so many systems, this will require a careful characterization of the individual contributions of each of these mechanisms on immune function. These types of studies will require careful dose considerations, as well as the use of other more specific pharmacological agents. The increasing epidemic of cocaine use in America necessitates further investigation of its effects on immunocompetence and the mechanism by which cocaine is modulating the immune response. If the mechanism of immunosuppression can be established, then interventions might be taken to curb the rapidly rising incidence of HIV and other infectious diseases in this population. In addition, the effects of cocaine on immune function, can help us to better understand endogenous regulation of the immune system and how these systems can be regulated pharmacologically.
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T. Pellegrino, B.M. Bayer r Journal of Neuroimmunology 83 (1998) 139–147 Szabo, B., Obergfell, A., Starke, K., 1995. Involvement of monoamine inhibition and local anesthesia in the cardiovascular response to cocaine in conscious rabbits. J. Pharmacol. Exp. Ther. 273, 128–137. Tella, S.R., Schindler, C.W., Goldberg, S.R., 1993. Cocaine: cardiovascular effects in relation to inhibition of peripheral neuronal monoamine uptake and central stimulation of the sympathoadrenal system. J. Pharmacol. Exp. Ther. 267, 153–162. Van Dyke, C., Stesin, A., Jones, R., Chonthrapal, A., Seaman, W., 1986. Cocaine increases natural killer cell activity. J. Clin. Invest. 77, 1387–1390.
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Wang, Y., Huang, D.S., Watson, R.R., 1994. In vivo and in vitro cocaine modulation on production of cytokines in C57BLr6 mice. Life Sci. 54, 401–411. Welch, W.D., 1983. Effect of cocaine on non-specific human cellular host defenses. Res. Commun. Subst. Abuse 4, 1–9. Watson, E.S., Murphy, J.C., ElSolhy, H.N., ElSolhy, M.A., Turner, C.E., 1983. Effects of the administration of coca alkaloids on the primary immune responses of mice: interaction with tetrahydro-cannabinol and ethanol. Toxicol. Appl. Pharmacol. 71, 1–13.
In vivo effects of cocaine on immune cell function Trisha Pellegrino ) , Barbara M. Bayer
1
Georgetown UniÕersity Medical Center, Department of Pharmacology, Washington, DC 20007, USA Received 7 March 1997; revised 20 October 1997; accepted 24 October 1997
Abstract Cocaine use has been shown to increase the risk of HIV infection in humans, and this increased risk cannot be explained by i.v. drug use alone. It is thought that this increased susceptibility may be a result of decreased immune responsiveness in cocaine addicts. Scientists are now using animal models to study the effects of cocaine on immune function in vivo under controlled conditions. Many facets of the immune system are being examined, which include immune cell number and distribution, cellular- and humoral-mediated immunity, cytokine production, and immunocompetence to challenges such as infection and tumor growth. The effects of cocaine on many of these functions are not yet clear. Often there are variations in the response of the immune system to cocaine. Potential confounding factors include variations in dose, duration of treatment, and route of administration of cocaine, as well as variations in assay protocols. In addition, there appear to be species differences in immune responses to cocaine. Although it is clear that more research is necessary to resolve the discrepancies, a sufficient number of trends are starting to emerge. This review will systematically evaluate the reported effects of cocaine on immune cell function in vivo. In addition, the possible mechanisms that may be contributing to the immune modulation observed with cocaine in vivo will be addressed. Further, data will be presented describing the effects of cocaine on the autonomic nervous system and the neuroendocrine system suggesting that inhibition of serotonin uptake may be an important component of the overall effects of cocaine on the immune system. q 1998 Elsevier Science B.V. Keywords: Cocaine; In vivo; Humoral immunity; Cellular immunity
1. Introduction Over the past decade, the increased susceptibility to infections among cocaine users has become more widely appreciated. In particular, the incidence of HIV seroprevalence has been shown to be significantly higher in cocaine addicts. Chaisson et al. Ž1989. reported a 26% increased incidence of HIV seroprevalence in cocaine addicts in San Francisco over other IV drug abusers. Similarly, a 16% increased incidence of HIV seroprevalence was observed in cocaine addicts in Baltimore Žover other IV drug abusers. ŽAnthony et al., 1991.. Collectively, these data suggest that the increased incidence of HIV infection may not be explained by intravenous drug use alone, and support the hypothesis that cocaine use may result in an increase in susceptibility to HIV infection. If so, it is imperative that the scientific basis underlying this association be fully
) 1
Corresponding author. Tel.: q1 202 6871616; fax: q1 202 6874226.
0165-5728r98r$19.00 q 1998 Elsevier Science B.V. All rights reserved. PII S 0 1 6 5 - 5 7 2 8 Ž 9 7 . 0 0 2 3 0 - 0
understood. To date, only a few laboratories have begun to address whether cocaine use may be associated with immune dysfunction which could ultimately contribute to a greater susceptibility to viral and bacterial infection. This review will address the existing information available on the in vivo effects of cocaine on various immune parameters and consequences to immunity. Possible mechanisms by which cocaine may influence immune cell activity will also be discussed.
2. Effects of cocaine on cell-mediated immunity
2.1. Immune cell populations and distribution The effects of cocaine on measures of cell-mediated immunity reported have examined possible alterations in immune cell number and distribution, mitogen-induced lymphocyte proliferation, and natural killer cell cytolytic activity, as summarized in Table 1. The most consistent
T. Pellegrino, B.M. Bayer r Journal of Neuroimmunology 83 (1998) 139–147
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Table 1 Effects of in vivo cocaine administration on cell-mediated immunity Species
Time course
Dose Žmgrkg.
Human
Acute Chronic Acute Chronic Acute Chronic Chronic Chronic Chronic
0.6 addicts 1–10 5 5–30 1 1–10 40 40
Rat Mouse
Murine AIDS
Proliferation
Cell number
Cytolytic activity
Cell number
Reference
≠
≠ ≠
Van Dyke et al., 1986 Ruiz et al., 1994 Bayer et al., 1995 Bayer et al., 1996 Ou et al., 1989 Francesco et al., 1991 Di Francesco et al., 1994 Lopez et al., 1992 Lopez and Watson, 1994
x x l
l l x x x x x
changes in any of the measures observed have been a reduction in the number or distribution of immune cells following cocaine administration. A significant dose-dependent decrease in the number of mouse thymocytes and white blood cells has been detected 96 h after acute administration of cocaine ŽOu et al., 1989.. Similarly, chronic treatment of mice with cocaine resulted in a slight, but significant, decrease in thymus weight and a decrease in CD8 q cells ŽLopez et al., 1992.. Chronic cocaine administration has also been shown to decrease CD8 q cells in the intestinal lamina propria of mice ŽLopez and Watson, 1994.. Although, Di Francesco et al. Ž1994. found that 7 days of cocaine administration also reduced circulating white blood cells in mice, no change in cell percentages or proportions between various subpopulations was observed. However, in the same study, after 30 consecutive days of cocaine administration, the decrease in cell number was no longer present, suggesting the possible development of an ‘apparent’ tolerance to the effects. The effects of cocaine on cell-mediated immunity in a murine AIDS ŽMAIDS. model have been investigated to more closely approximate the effect of cocaine-use on immune function during the course of HIV infection. MAIDS infection has been shown to result in decreased CD4 q lymphocyte counts in both the thymus and the intestinal lamina propria ŽLopez et al., 1992.. Chronic cocaine administration in infected mice appeared to exacerbate the effects of MAIDs resulting in a further decrease in CD4 q cells ŽLopez and Watson, 1994.. The implication of these results is that cocaine may have similar effects in HIV infected individuals. However, to date, there is little epidemiological evidence to support this hypothesis ŽKaslow et al., 1989.. 2.2. Natural killer cell (NK cell) cytolytic actiÕity NK cells are another type of lymphocyte involved in cell-mediated immunity. In contrast to the decrease in number of other lymphocyte subpopulations, cocaine administration has been shown to be accompanied by an increase in the number of circulating NK cells. This increase appears to be species independent, since it has been reported in both human cocaine addicts ŽVan Dyke et al.,
≠ ≠
1986 and Ruiz et al., 1994. and in mice ŽLopez et al., 1992.. In addition to increasing NK cell number in non-infectious models, NK cells have been shown to increase following chronic cocaine administration in infectious disease models, such as MAIDS ŽLopez and Watson, 1994.. Although consistent increases in NK cell number have been observed, the reported effects of cocaine on NK cell cytolytic activity have been unpredictable. For example, a significant increase in NK cell activity was found in the blood of human addicts ŽRuiz et al., 1994. and after acute intravenous cocaine administration to human subjects ŽVan Dyke et al., 1986.. However, in mice exposed to chronic cocaine, a significant decrease in NK cell cytolytic activity has been reported ŽFrancesco et al., 1991.. In contrast to these findings in humans and mice, Bayer et al. Ž1995. found no effect on NK cell cytolytic activity in rats after acute or chronic cocaine administration. At present, the reasons for the discrepancies among these studies, and the lack of relationship to the increase observed in NK cell number, are not clear. 2.3. T-lymphocyte proliferation Our laboratory has looked at the effects of acute and chronic cocaine administration in rats on mitogen-induced lymphocyte proliferation, another measure of cell-mediated immune function. Acute cocaine administration, intravenously Ži.v.., resulted in a decrease in mitogen-induced T-lymphocyte proliferation in a dose and time-dependent manner in rats ŽBayer et al., 1995.. However, following chronic i.v. administration of cocaine in rats, the immunosuppressive effects were no longer observed ŽBayer et al., 1996.. In addition, this ‘apparent’ tolerance was found to cross-over to morphine, which also had no suppressive effect on lymphocyte proliferation in rats chronically treated with cocaine. In contrast, acute morphine administration Ž10 mgrkg., to naive animals, resulted in a 70–80% suppression of blood lymphocyte responses ŽBayer et al., 1996.. These results suggested that perhaps morphine and cocaine may share a common mechanism of immunomodulation. In addition to species differences, the potential development of tolerance to some of the effects of cocaine
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on selective immune parameters may be another reason for the discrepancies observed by various investigators. On a cautionary note, one should not assume that the ‘apparent’ tolerance to the suppression of mitogen-induced lymphocyte proliferation after chronic cocaine treatment indicates that the immune function of these animals is normal. Previous studies have indicated that ‘apparent’ tolerance to the inhibitory effects of morphine of lymphocyte proliferation renders the animal more susceptible to the immuno-suppressive effects of mild stressors ŽBayer et al., 1994.. Therefore, individual immune assays may not always be predictive of overall immune competence. It is possible that a compensatory mechanism has developed in animals treated chronically with cocaine, and therefore, when challenged through stress or infection, these animals may not be fully immunocompetent.
3. Effects on of cocaine humoral immunity 3.1. Plaque-forming actiÕity (PFA) Most of the data on the effects of cocaine on humoral immunity have been derived from investigations with mice, utilizing the plaque-forming assay to measure antibody production in animals immunized with sheep red blood cells ŽSRBC. ŽTable 2.. A decreased splenic PFA to SRBC was observed in mice treated acutely with low doses of cocaine at the time of immunization ŽOu et al., 1989.. Similarly, chronic administration of higher doses of cocaine after immunization also resulted in decreased PFA ŽWatson et al., 1983.. However, when mice were immunized with 2,4-dinitro-phenyl ligand ŽDNP., another T-cell dependent antigen, cocaine had no effect on PFA ŽHavas et al., 1987.. Therefore, the differential effects of cocaine in these two studies may be due to differences in the type of antigen ŽDNP vs. SRBC., or more likely due to inconsistencies in the timing of cocaine administration relative to the time of immunization with each antigen. 3.2. Antibody titer Another method, of assaying humoral immune function, is to determine the levels of antibody against an antigen in
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a preimmunized animal. No effect has been found with chronic cocaine administration on antibody production to the polysaccharide antigen SSS-III in normal, non-infected mice. Overall, the effects of chronic cocaine on antibody production in mice have been consistently marginal. Of the studies reported, no significant decrease in antibody production have been observed ŽTable 2.. This also seems to be the case with infectious mouse models. Following infection with a Friend Leukemia Virus ŽFLV., no further decrease in antibody titers to SRBC was observed following chronic cocaine administration ŽStarec et al., 1991.. However, in rats the effects of cocaine on humoral immunity may be dose-dependent. An increase in antibody titer to SSS-III was found in rats chronically-treated with low doses of cocaine, but a significant drop in antibody titer was observed after chronic treatment with higher doses of cocaine ŽBagasra and Forman, 1989.. Therefore, differences in the effects of cocaine on humoral immunity are emerging, but may be dependent on factors such as species, dose and duration of treatment. Again, further studies are necessary to determine the critical factors contributing to these differential responses following cocaine administration.
4. Effects of cocaine on cytokine production In addition to measures of cellular and humoral immunity, the effects of chronic cocaine treatment on cytokine production have also been examined. Since cytokines regulate a number of important immune cell functions, it is hypothesized that alterations in the expression of cytokines during cell activation may ultimately result in changes in immunity. To date, only two studies have addressed the possible effects of cocaine on cytokine production by immune cells and the results are summarized in Table 3. In both of these studies, the pattern of cytokine secretion from LPS and Con A stimulated mouse splenocytes was altered by chronic cocaine administration. Twenty-four hours after mitogen stimulation, decreases in the secretion of IL-4 and IL-10 were observed, which were accompanied by increases in TNF-a , IL-6, and IL-2. However, contrary to the increase at 24 h, at 72 h there was a
Table 2 Effects of in vivo cocaine administration on humoral immunity Species
Time course
Dose Žmgrkg.
Plaque-formation
Mouse
Acute Acute Chronic Chronic Chronic Chronic Chronic
5 5 Ž5 = . 2–60 30 50 1.25–2.5 5
x l l x
Murine FLV Rat
≠ ≠
Titer
Reference Ou et al., 1989 Havas et al., 1987
l x ≠ x
Watson et al., 1983 Starec et al., 1983 Bagasra and Forman, 1989
T. Pellegrino, B.M. Bayer r Journal of Neuroimmunology 83 (1998) 139–147
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Table 3 Effects of cocaine in vivo on splenocyte cytokine production Investigator
Species
Time course
Dose Žmgrkg.
TNF-a
g-IFN
Chen and Watson, 1991 Wang et al., 1994
Mouse
Chronic Chronic
x ≠
l
Chen and Watson, 1991
MAIDS model
20–40 10–40 a 10–40 b 20–40
x
x
a
Chronic
IL-2
IL-4
IL-5
IL-6
IL-10
≠
x
≠
≠ ≠
x ≠
b
24 h after mitogen stimulation; 72 h after mitogen stimulation.
decrease in TNF-a , which suggests that the incubation time after stimulation is an important factor in studies measuring cytokine expression ŽChen and Watson, 1991 and Wang et al., 1994.. No changes in g-IFN production was observed, except when mice were infected with murine AIDS. In infected mice treated chronically with cocaine, there was a significant decrease in g-IFN ŽChen and Watson, 1991.. Whether or not these changes in cytokine secretion are related to alterations in lymphocyte populations remain to be determined. However, unlike in vivo cocaine administration, in vitro cocaine administration results in a dose-dependent decrease in the secretion of all cytokines measured ŽWang et al., 1994.. The differential responses following in vivo and in vitro exposure to cocaine, suggest that these changes in cytokine secretion are not due entirely to direct effects of cocaine on immune cells. Therefore, indirect mechanisms of cocaine, such as alterations in hormone levels, may come into play.
5. Consequences of in vivo cocaine administration Although tolerance may develop to some of the aforementioned immune parameters after chronic cocaine administration, this does not necessarily mean that the immune function of the animal is normal. It is possible that compensatory mechanisms may develop, which under stress or infection may result in inadequate immunocompetence. The best method of determining immunocompetence after chronic drug treatment is to look at the effects of that treatment in the intact animal. The measures of immuno-
competence following cocaine administration include delayed-type hypersensitivity ŽDTH., susceptibility to infection, and tumor growth and the results are summarized in Table 4. Chronic ingestion of coca alkaloids has been shown to result in a 20–53% decrease in the DTH response in mice ŽWatson et al., 1983.. In addition, a modest, but significant, decrease in the DTH response was found following chronic cocaine treatment with high doses Ž50 mgrkg. in mice previously infected with FLV ŽStarec et al., 1991.. This group also demonstrated an increased lethality to FLV in mice chronically treated with cocaine, particularly in the rate of death after infection. However, it should be noted that the doses of cocaine being used in these experiments were found to be toxic in normal, non-infected mice by Havas et al. Ž1987. ŽStarec et al., 1991.. Cocaine at low doses Ž0.05 mgrkg. was also found to be associated with an accelerated tumor growth in mice, suggesting a potential decrease in natural killer ŽNK. cell or cytotoxic T cell function ŽOu et al., 1989.. In contrast to low dose cocaine administration, chronic administration of high doses of cocaine have no effect on tumor growth or death rate ŽHavas et al., 1987.. In addition, there is no change in death rate in mice that had been infected with Streptococcus pneumonia ŽHavas et al., 1987.. The susceptibility to secondary parasitic infections common in HIV patients, was measured in mice previously infected with the murine AIDS virus. An increased number of Cryptosporidium were found on the villi of mice infected with the MAIDS virus and chronically treated with cocaine. However, this cocaine treatment did not result in any significant increase in the number of oocysts in the feces or the number of mice testing positive for Cryp-
Table 4 Immune consequences of in vivo cocaine Species
Time course
Dose Žmgrkg.
Infectivity
Human
Chronic Chronic Chronic Chronic Chronic Chronic Chronic
addicts addicts addicts 0.05–5 2–60 50 40
≠ ≠ ≠
Mouse
l l
Tumor growth
≠ l ≠
DTH
x
Investigator Donahue et al., 1986 Chaisson et al., 1989 Anthony et al., 1991 Ou et al., 1989 Havas et al., 1987 Starec et al., 1991 Darban et al., 1993
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tosporidium in both non-infected mice and mice infected with murine AIDS ŽDarban et al., 1993.. Therefore, the consequences of cocaine administration on immunity are still not well defined. Although collectively these studies suggest cocaine may suppress overall immunity, variations in dose, duration and frequency of cocaine administration, and animal models used in these studies make it difficult to reach a definitive conclusion.
6. Pharmacological mechanisms of cocaine Considering the current available information, the effects of cocaine on immune function do not appear to be due to a direct action of cocaine on immune cells. Although very high doses of cocaine in vitro will decrease immune cell function, there is little or no effect at doses which would be expected in vivo ŽJavaid et al., 1978; Welch, 1983; Martinez and Watson, 1990; Lou et al., 1992; Berkeley et al., 1994.. Instead, cocaine has several well-known pharmacologi-cal mechanisms which could contribute to the effects on the immune response ŽFig. 1.. These multiple pharmacological properties may also contribute to the varied immune effects due to cocaine with different doses. At low doses Ž0.2–1 mgrkg., cocaine acts primarily as an inhibitor of all three monoamine uptake pumps—serotonin, dopamine, and norepinephrine ŽSzabo et al., 1995.. It is inhibition of monoamine uptake, particularly dopamine, that is thought to be involved in the reinforcing properties of cocaine ŽJohanson and Fischman, 1989.. At higher doses Ž) 1 mgrkg., cocaine also demonstrates cholinergic antagonist properties ŽSharkey et al., 1988 and Szabo et al., 1995.. Finally, at even higher doses ŽG 5 mgrkg., cocaine also has local anesthetic activity ŽSzabo et al., 1995.. It is not yet clear which of these actions may be the most prominent in producing the immunomodulatory effects of cocaine. Furthermore, a combination of these actions may be required to modify immune responses. Therefore, the selection of the dose is an important consideration when attempting to evaluate the mechanismŽs. by which cocaine administration in vivo may be influencing the immune system.
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7. Physiological mechanisms by which cocaine influences the immune system The pharmacological actions of cocaine ultimately lead to a number of physiological effects, each of which have independently been shown to be involved in the regulation of immune responses. Through its primary effects on several monoamine systems, cocaine has a cascade of secondary physiological effects. Studies have only just begun to address the potential physiological mechanisms which could be involved in the immunomodulatory effects and include the changes induced by cocaine on autonomic nervous system activity, neuroendocrine hormone secretion, as well as changes in plasma monoamine concentrations ŽFig. 2.. 7.1. Autonomic nerÕous system The autonomic nervous system is one of the primary ways by which the central nervous system is thought to regulate immune function. Overall, cocaine increases autonomic nervous system activity resulting in an increase in sympathetic tone and an elevation of plasma catecholamines ŽChiueh and Kopin, 1978; Kiristy-Roy et al., 1990; Tella et al., 1993.. There are a number of ways in which increased autonomic nervous activity may alter immune cell activity, as reviewed by Madden et al., 1995. First, an increase in sympathetic nervous activity leads to an increase in catecholamines both in the plasma, as well as in innervated tissues. The primary and secondary lymphoid tissues are highly innervated by the sympathetic nervous system, which could act as a direct neurological link between the central nervous system and immune cells ŽMadden et al., 1995.. Adrenergic agonists have long been found to directly suppress immune cell function in vitro. Therefore, elevation of catecholamines in the immune cell environment may contribute to a decrease in immune competence after cocaine administration. 7.2. Neuroendocrine system Another primary mechanism by which the central nervous system is thought to modulate immune function is
Fig. 1. Pharmacological effects of cocaine. ŽDoses were derived from Sharkey et al., 1988, Ritz et al., 1990, and Szabo et al., 1995..
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Fig. 2. Physiological effects of cocaine in vivo.
through the release of neuroendocrine hormones. Of these neuroendocrine hormones, the hypothalamic–pituitary– adrenal axis ŽHPA axis. has been the most widely studied in relation to immune function. Cortical steroids have long been reported to have immunosuppressive properties, as reviewed by Parrillo and Fauci, 1979. Decreases in immune function in rodents after elevation of plasma corticosterone are thought to be due to immune cell death and redistribution in lymphoid tissue compartments. However, Stanulis et al. Ž1996. recently reported that the enhanced antibody response observed following acute cocaine in mice is due to increases in plasma corticosterone levels. Cocaine administration has been found to result in activation of the HPA axis, which leads to elevation in plasma corticosterone levels in rodents, and cortisol levels in humans ŽSaphier et al., 1993; Bayer et al., 1995; Baumann et al., 1995.. Elevations of corticosterone in rats have been shown to be transient and dose-dependent following i.v. administration of cocaine ŽRivier and Vale, 1987; Bayer et al., 1995.. In addition, i.v. cocaine administration to cocaine addicts results in elevations of cortisol levels ŽBaumann et al., 1995.. These effects have been shown to be centrally mediated since administration of cocaine directly into the third ventricle of rats results in a dose-dependent increase in plasma corticosterone levels ŽSaphier et al., 1993.. Doses of cocaine Ž1 mgrkg. which were not accompanied by increases of corticosterone were also found not to produce suppression of blood lymphocyte proliferation to mitogens, suggesting a possible role of increased steroids in the immunosuppressive effects of cocaine. The changes in the HPA axis after cocaine administration are also most likely due to increases in monoamine neurotransmission. Several of the monoamine pathways have been implicated in these effects. For example, activation of serotonin receptors results in elevated corticosterone and b-endorphin secretion in rats ŽKoenig et al., 1987.. Serotonin appears to be involved in the elevation of
ACTH and corticosterone after cocaine administration in rats ŽLevy et al., 1991.. Consistent with these observations, our laboratory has also found increases in corticosterone levels after acute administration of selective serotonin uptake inhibitors ŽPellegrino and Bayer, 1996.. However, other monoamines may also be involved in the neuroendocrine changes seen with cocaine, since elevation of corticosterone after cocaine has been shown to be blocked by dopaminergic and adrenergic antagonists ŽSarnyai et al., 1993.. In addition, selective inhibition of dopamine uptake has been shown to lead to activation of the HPA axis ŽBorowsky and Kuhn, 1993.. Utilizing selective antagonists, it was demonstrated that acute cocaine activates the HPA axis through inhibition of both dopamine as well as serotonin uptake ŽLevy et al., 1994.. Therefore, it appears that the monoamine pathways, particularly serotonergic and dopaminergic pathways, are important mediators of the neuroendocrine changes seen with cocaine. In addition to cortical steroids, cocaine administration has also been shown to modulate the release of opioid peptides, prolactin, and vasopressin ŽFig. 2.. Madden and Felten Ž1995. thoroughly reviewed, the effects of cortical steroids and other neuroendocrine hormones on the imTable 5 Effects of specific monoamine uptake inhibitors of mitogen-induced lymphocyte proliferation ŽPellegrino and Bayer, 1996. Treatment a
Specificity
Saline Fluoxetine Desipramine GBR 12909
Serotonin Norepinephrine Dopamine
a
3
H-Thymidineb Žcpm"SEM.
41,234"6397 13,632"1537 c 48,332"8910 54,458"7694
n 11 10 13 14
Drugs were administered at doses of 10 mgrkg, i.p., and animals were sacrificed two hours later. b Maximal response after stimulation with 0.2, 0.4, and 0.6 m g Concanavalin Arculture of whole blood lymphocytes diluted 1:10 with RPMI-1640 media. c Denotes significant difference from saline, p- 0.01, determined by one-way ANOVA.
T. Pellegrino, B.M. Bayer r Journal of Neuroimmunology 83 (1998) 139–147
mune system in vivo and in vitro. Cocaine administration results in a modulation in the release of these other neuroendocrine hormones ŽFig. 2.. Therefore, the combined alteration of these hormones may contribute to the overall effects of cocaine on the immune system. Furthermore, tolerance does not develop to the neuroendocrine effects of cocaine ŽLevy et al., 1994.. Therefore, prolonged cocaine exposure results in persistent alterations in neuroendocrine hormone levels. The consequence of these changes induced by cocaine on the ability to mount an immune response remain to be determined.
8. Monoamine involvement in cocaine mediated immunomodula-tion The physiological changes described in autonomic and neuroendocrine system activity observed with cocaine, are most likely mediated through the activation of central monoamine pathways. Cocaine primarily inhibits reuptake and thus increases monoamine neurotransmission. Our laboratory has measured the effects of specific monoamine uptake inhibitors on lymphocyte proliferation ŽPellegrino and Bayer, 1996.. Specific uptake inhibitors of norepinephrine and dopamine had no significant effect on mitogen-induced lymphocyte proliferation ŽTable 5.. Only the serotonin uptake inhibitor, fluoxetine, was able to mimic the suppression seen with cocaine on mitogen-induced lymphocyte proliferation ŽPellegrino and Bayer, 1996.. This suggests that the inhibitory effects of cocaine on lymphocyte proliferation may be predominantly due to serotonin uptake inhibition, rather than norepinephrine or dopamine. Our laboratory has been accumulating data suggesting that sero-tonin may be the primary monoamine involved in the immune effects seen with cocaine ŽPellegrino and Bayer, 1996.. Serotonin has been shown to modulate immune function in vitro ŽAune et al., 1994; Hellstrand and Hermodsson, 1987; Nordlind et al., 1992.. In vivo, serotonin receptors have been shown to activate the HPA axis and the sympathetic nervous system, which as previously described, can decrease immune cell function ŽKoenig et al., 1987; Levy et al., 1991; Levy et al., 1994; Li et al., 1994; Levy et al., 1995.. Therefore, the inhibition of serotonin uptake may be an important component of the effects of cocaine on immune function. However, the contribution of the various monoamines on overall immune function has not been well characterized.
9. Conclusions From the existing data, it is clear that more studies are necessary to further characterize the differential effects of
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cocaine on immune cell function. Although the data in humans suggest that cocaine-use increases susceptibility to infection, the reasons for this are still not clear. The differences among the studies with reference to dose, route of administration, duration and frequency of treatment, animal model and assay protocols make comparisons tentative at best. Furthermore, when utilizing chronic cocaine paradigms and measuring one specific immune parameter, the possible development of compensatory mechanisms in the intact animal must be taken into consideration. An animal which has developed an ‘apparent’ tolerance to the effects of cocaine after chronic administration, may not be immune competent when challenged by stress, other drugs of abuse, or infection. Patterns are emerging that indicate cocaine suppresses a number of measures of cell-mediated and humoral-mediated immunity. Infectious disease models also suggest a overall decrease in immunocompetence. However, too few studies have been carried out to reach definitive conclusions. Although cocaine has many mechanisms which may contribute to immune effects observed, further studies are required to determine the underlying mechanisms involved in producing these effects. Because of the multiplicity of actions of cocaine on so many systems, this will require a careful characterization of the individual contributions of each of these mechanisms on immune function. These types of studies will require careful dose considerations, as well as the use of other more specific pharmacological agents. The increasing epidemic of cocaine use in America necessitates further investigation of its effects on immunocompetence and the mechanism by which cocaine is modulating the immune response. If the mechanism of immunosuppression can be established, then interventions might be taken to curb the rapidly rising incidence of HIV and other infectious diseases in this population. In addition, the effects of cocaine on immune function, can help us to better understand endogenous regulation of the immune system and how these systems can be regulated pharmacologically.
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