Mechanisms of cocaine-induced decreases in immune cell function
Introduction
Cocaine abuse has been associated with an increased incidence of HIV seroprevalence in cocaine addicts over other intravenous drug abusers [1], [2], [3], [4]. In addition, cocaine users have a higher incidence of hepatitis C infection than other intravenous drug users [5]. This increased susceptibility to HIV and hepatitis C cannot, therefore, be explained by intravenous drug use alone. There are indications that cocaine users engage in risky sexual behaviours that could increase their risk of exposure [3], [6], [7], [8], [9]. However, another possibility is that cocaine decreases cellular-mediated immune function in cocaine addicts, thus increasing their susceptibility to viral infections. Many investigators have examined the effects of cocaine in vivo on various measures of cellular-mediated immunity in both human and rodent models (reviewed in Ref. [10]). However, differential effects have been observed in these studies, in almost every immune parameter measured [10]. For example, human studies have shown little change in lymphocyte function and number in some cocaine addicts [11], whereas the same group has shown decreases in CD4+ T cells and increases in NK cell number in a different group of addicts [12]. These discrepancies in both human and animal studies appear to be the result of multi-drug use, differences in dose, route of administration, timing, duration, species, and assay protocols [10]. One possible reason for the incongruity between these studies is that cocaine has multiple mechanisms of action both physiologically and pharmacologically that could effect immune cell function.
Pharmacologically, cocaine binds to monoamine reuptake pumps, preventing removal of serotonin, dopamine, and norepinephrine from the synapse [13]. Cocaine also acts as a muscarinic cholinergic antagonist [13], [14] and as a local anesthetic [13]. The multiplicity of pharmacological actions may contribute to the varied immune response to cocaine, particularly when doses are varied. The different pharmacological actions of cocaine result in physiological changes, which have been shown to alter immune responses. Cocaine has been previously shown to activate the HPA axis, resulting in an increase in plasma corticosterone [15], [16], [17], [18], [19], [20]. The hypothalamic–pituitary–adrenal (HPA) axis is one of the primary mechanisms by which the central nervous system modulates immune cell function [21], [22]. Therefore, activation of the HPA axis or other physiological systems could be involved in cocaine-induced modulation of immunological responses.
In addition to central modulatory pathways, cocaine could modulate immune cell function through actions on peripheral receptors. All of the receptors which cocaine binds are found in peripheral tissues [23]. Blockade of monoamine reuptake leads to alterations in peripheral monoamine neurotransmission. In addition, changes in monoamine levels or hemodynamics could lead indirectly to neuroendocrine hormone release and changes autonomic nervous system activity [24], [25]. Therefore, there are many physiological mechanisms by which cocaine could alter immune cell function through actions on either central or peripheral receptors. Determining the location of the receptors involved in the immunomodulatory response to cocaine could help to decipher the physiological mechanism by which cocaine is modulating lymphocyte activity.
Cocaine has been previously shown by our laboratory to decrease mitogen-induced T-lymphocyte proliferation in rat whole blood [16]. These effects were found to be maximal at 2 h following an intravenous (i.v.) dose of cocaine hydrochloride (5 mg/kg) [16]. These effects were dose-dependent, transient, and were accompanied by a transient increase in plasma corticosterone [16]. The mechanism by which these effects on immune cell function occur following cocaine administration has yet to be determined. These studies will attempt to separate both the pharmacological and physiological mechanism of action of cocaine on lymphocyte proliferation following acute intravenous administration. Central versus peripheral effects will be dissociated by utilizing a quaternary derivative of cocaine, cocaine methiodide, as well as by utilizing central administration of these agents directly into the third ventricle of the brain. Changes in plasma corticosterone levels will be monitored to determine if the changes in HPA axis activity correlate with the changes in lymphocyte proliferation following drug administration. The distinct pharmacological properties will be examined by utilizing agents with selective local anesthetic or monoamine uptake inhibitory activity. Lidocaine, a local anesthetic, which is devoid of monoamine uptake properties [26], will be utilized to examine the potential role of local anesthesthia in the immunomodulatory effects of cocaine. RTI-55, a potent monoamine uptake inhibitor devoid of local anesthetic properties [27], will be utilized to determine if monoamine uptake inhibition is involved in the immunomodulatory effects of cocaine.
Section snippets
Animals
Virus-free male Sprague–Dawley rats weighing 200–250 g upon receipt were purchased from Taconic Laboratories (Germantown, NY). Animals were housed three per cage, in polypropylene cages with microisolator tops. Animals were allowed to acclimate for 1 week after receipt prior to any surgical manipulations. Animals were maintained at 23±1°C on a 12-h light–dark cycle (6 a.m. on, 6 p.m. off) with food and water ad lib.
Jugular cannulation
Cannulae were prepared and implanted using methods previously described by our
Inhibition of mitogen-induced blood lymphocyte proliferation following peripherally administered cocaine and cocaine methiodide
Animals were implanted with an indwelling cannula into the right jugular vein and allowed to recover for 1 week. Concanvalin A (con A) stimulated blood lymphocyte proliferative responses were determined 2 h following the intravenous administration of either saline (1 ml), cocaine (5 mg/kg) or cocaine methiodide (6.5 mg/kg). In all experiments, responses of treated animals were compared to responses of similarly injected saline controls. As previously reported, peripheral administration of
Discussion
Cocaine acts on several receptor subtypes both in the central nervous system and in the periphery [13], [14]. The data presented here support the hypothesis that cocaine was acting through peripheral receptors to decrease lymphocyte proliferation. The first observation that supported this hypothesis was that systemic cocaine methiodide, which should not cross the blood–brain barrier [29], [30], [31], decreased lymphocyte proliferation in a similar manner as that observed with systemic cocaine.
Acknowledgments
These studies were funded by the National Institute of Health, NIDA Grant #DA05849 and NIMH fellowship #MH11589.
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