Immunomodulation by cocaine and ketamine in postnatal rats
Introduction
The impact of fetal and neonatal COC exposure is a major public health concern. It is estimated that approximately 25% of regular users of COC are females 18–34 years of age, women in their prime childbearing years (National Institute on Drug Abuse, 1992). It is estimated that 4.5% of newborns in US (approximately 158,400 infants) are prenatally exposed to COC each year (Gomby and Shiono, 1991). To complicate matters, multiple drug use is not uncommon in pregnant women. A study that examined the drug use patterns of pregnant women in two inner-city sites found that women who used COC were much more likely to have used a combination of drugs than any single drug (Bendersky et al., 1996).
Concomitant use of COC with KET is currently popular among drug abusers (Dillmann, 1998, Jansen and Darracot-Cankovic, 2001), and their combination is known as “CK” (Jansen and Darracot-Cankovic, 2001). The abuse of COC with KET among pregnant women is high; random urine toxicology studies performed by Knisely et al. (1991) have demonstrated COC with KET abuse in 10–25% of pregnant women. The combined use of COC and KET by women of childbearing age raises concerns regarding the hazardous potential of these two agents to the fetus.
In addition to potential in utero exposure, it is known that nursing infants of COC-abusing mothers have become intoxicated from COC that distributed into breast milk (Chasnoff et al., 1987). COC concentration in the breast milk of rat can be sevenfold more than COC concentration in the blood (Wiggins et al., 1989). The partitioning of COC into the breast milk of human has been estimated to be even higher (Dickson et al., 1994). Since KET is also distributed into breast milk (Oye et al., 1993), co-exposure to COC and KET is a possible scenario for the nursing infant of a drug-abusing mother.
COC has been shown to have a variety of immunomodulatory effects in rats following prenatal (Sobrian et al., 1989, Bohn et al., 1997) and postnatal (Barat and Turkall, 1996, Figliomeni and Turkall, 1997) exposure. COC metabolism to NC and other reactive oxygen species (ROS), mediated by the cytochrome P-450 enzyme system, has been suggested to play a role in these effects (Jeong et al., 1995a, Jeong et al., 1995b, Jeong et al., 1996). Increased NC levels have been shown to suppress the IgM response to SRBC (Jeong et al., 1995b, Kump et al., 1996). On the other hand, COC's immunomodulatory effects may occur indirectly through neuroendocrine stimulation of the hypothalamic-pituitary-adrenal (HPA) axis resulting in an increase in plasma corticosterone concentration (Watzl and Watson, 1990, Torres and Rivier, 1992, Stanulis et al., 1997a). Recently, it has been reported that corticosterone or increased ROS production may disturb Th1/Th2-related cytokine balance affecting the T-dependent antibody response against SRBC (Stanulis et al., 1997a, Stanulis et al., 1997b, Kump et al., 1998, Malmberg et al., 2001).
KET appears to suppress the production of the proinflammatory cytokines: tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and IFN-γ in adult mice and human (Takenaka et al., 1994, Roytblat et al., 1998, Hill et al., 1998). However, the significance and the clinical applications of such effects are unclear. Moreover, KET has been shown to be a cytochrome P-450 inducer (Marietta et al., 1977). Previously, we have demonstrated that KET pretreatment resulted in increased production of plasma NC when rats were administered COC (Rofael and Abdel-Rahman, 2002a). In addition, Torres et al. (1994) reported that KET completely reversed the potent stimulatory effects of COC on adrenocorticotropin hormone (ACTH) secretion. This later effect is presumably mediated via the antagonist properties of KET on N-methyl-d-aspartate (NMDA) receptors that have been found to play a significant role in activation of the HPA axis (Huber et al., 2001).
While the incidence of co-abuse of COC and KET is growing, no studies have assessed the role, if any, that KET abused with COC may play on the immune system. For these reasons, the effect of daily exposure to COC or KET alone and in combination was assessed in the neonatal rat from birth to 21 days. Maturation of immunocompetence occurs during this period in rats; in humans this period extends from birth up to 1 year (Dietert et al., 2000). Possible mechanisms of COC-mediated immunomodulation and the impact of KET co-exposure were investigated.
Section snippets
Animals
Mature SD rats (200–250 g) were obtained from Taconic Farms (Germantown, NY) and quarantined for 1 week prior to use. Animals were maintained on a 12-h light/dark cycle with constant temperature (23–25 °C) and humidity (50–55%), and access to water and Purina Rodent Chow ad libitum. The handling of all animals was in accordance with the National Institute of Health (NIH) Guidelines for the Care and Use of Laboratory Animals. The use of animals for this experiment was approved by the
Effect of sub-chronic administration of COC and/or KET on neonatal growth rate and lymphoid organ/body weight ratios
COC and KET alone or in combination, administered daily for the first 21 days of life, had no effect on weight gain of male pups versus saline control (data not shown). However, a significant increase in spleen to body weight ratio was observed only following treatment with COC alone compared to saline controls (Table 1). Thymus/body weight ratio was not statistically different for any of the treatment regimens relative to saline controls.
Effects on white blood cell counts
Treatment with COC alone resulted in a significant
Discussion
In this investigation, two frequently abused illicit substances were administered alone or in combination to an immunologically immature rodent model. No changes in the growth rate of postnatal male rat pups occurred as a result of any treatment. This suggests that gross toxicity and malnutrition could be ruled out as a possible cause for other differences observed in the treatment groups. The current data are consistent with that of other investigators (Barat and Turkall, 1996, Figliomeni and
References (65)
- et al.
Immunologic effects of cocaine in prenatally exposed rats and mice
Toxicol. Lett.
(1997) - et al.
Evidence for N-methyl-d-aspartate receptor mediation of cocaine induced corticosterone release and cocaine conditioned stimulant effects
Behav. Brain Res.
(1995) - et al.
Differential effects of short-term or prolonged cocaine exposure on peripheral blood cells in mice
Life Sci.
(1994) - et al.
Developmental immunotoxicity of cocaine and ethanol in postnatal Lewis rats
Immunopharmacology
(1997) - et al.
The role of NMDA receptors in neonatal cocaine-induced neurotoxicity
Pharmacol. Biochem. Behav.
(2001) - et al.
Role of metabolism in cocaine-induced immunosuppression in splenocyte cultures from B6C3F1 female mice
Immunopharmacology
(1995) - et al.
Sensitivity of the SRBC PFC assay versus ELISA for detection of immunosuppression by TCDD and TCDD-like congeners
Toxicology
(2000) - et al.
Possible incorporation of an immunotoxicological functional assay for assessing humoral immunity for hazard identification purposes in rats on standard toxicology study
Toxicology
(1995) - et al.
Development of attesting battery to assess chemical-induced immunotoxicity: National Toxicology Program's guidelines for immunotoxicity evaluation in mice
Fundam. Appl. Toxicol.
(1988) - et al.
Characterization of ketamine induction of hepatic microsomal drug metabolism
Biochem. Pharmacol.
(1977)
The role of neuroendocrine immune interactions in the initiation of humoral immunity in chickens
Domest. Anim. Endocrinol.
Rat immunoglobulins in serum and secretions: purification of rat IgM, IgA and IgG and their quantitation in serum, colostrum, milk and saliva
Immunochemistry
Alterations in interleukin-4 and antibody production following pheromone exposure: role of glucocorticoids
J. Neuroimmunol.
Effects of cocaine on the immune system of balb/c mice
Clin. Immunol. Immunopathol.
The role of ketamine on plasma cocaine pharmacokinetics in rat
Toxicol. Lett.
Modulation of T-helper cell populations: potential mechanisms of respiratory hypersensitivity and immune suppression
TAAP
Disruption of Th1/Th2 cytokine balance by cocaine is mediated by corticosterone
Immunopharmacology
Comparison of ELISA and plaque-forming cell assays for measuring the humoral immune response to SRBC in rats and mice treated with benzo[a]pyrene or cyclophosphamide
Fundam. Appl. Toxicol.
Differential effects of intermittent or continuous exposure to cocaine on the hypothalamic-pituitary-adrenal axis and c-fos expression
Brain Res.
A ketamine mixture anesthetic inhibits neuroendocrine and behavioral consequences of cocaine administration
Brain Res.
Immunomodulation by cocaine—a neuroendocrine mediated response
Life Sci.
Teratogenic effect of ketamine and cocaine in CF-1 mice
Teratology
Effect of sub-chronic cocaine and lidocaine exposure on the lymphoid tissues in neonatal rats
Toxicol. Lett.
Characteristics of pregnant substance abusers in two cities in the northeast
Am. J. Drug Alcohol Abuse
Characterization of glucocorticoid-induced change in lymphocyte circulation in the rat
Clin. Res.
Corticosteroids inhibits IL-12 production in human monocytes and enhances their capacity to induce IL-4 synthesis in CD4+ lymphocytes
J. Immunol.
Effects of sex and gonadectomy on cocaine metabolism in the rat
J. Pharmacol. Exp. Ther.
Cocaine intoxication in a breast-fed infant
Pediatrics
Contrasting effects of glucocorticoids on the capacity of T cells to produce the growth factor interleukin 2 and interleukin 4
Eur. J. Immunol.
Corticosteroids enhance the capacity of macrophages to induce Th2 cytokine synthesis in CD4+ lymphocytes by inhibiting IL-12 production
J. Immunol.
Cocaine-induced peroxidative stress in rat liver: antioxidant enzymes and mitochondria
J. Pharmacol. Exp. Ther.
The routine analysis of breast milk for drugs of abuse in a clinical toxicology laboratory
J. Forensic Sci.
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