Effect of ketamine on cocaine-induced immunotoxicity in rats.
The abuse of cocaine (COC) with ketamine (KET) is currently popular among young drug abusers and has been associated with increased risk of human immunodeficiency virus (HIV) infection. The effect of subacute exposure to COC and KET alone and in combination on the immune system was assessed in adult male Sprague-Dawley (SD) rats. To simulate the route and mode of human exposure, rats were treated with COC alone (5 mg/kg, i.v.), KET alone (100 mg/kg, p.o.) or KET followed immediately by COC (same doses and routes of administration) once-a-day for 7 consecutive days. Rats were sacrificed 30 minutes following the last treatment. Total circulating leukocyte and lymphocyte counts were decreased with relative neutrophilia, whereas immunoglobulin M (IgM) antibody response to sheep erythrocytes (SRBCs) was increased in animals treated with COC. Moreover, treatment with COC alone increased serum interleukin-10 (IL-10) concentration; however, it did not affect serum interferon gamma (INF-gamma) concentration. Spleen histology showed hyperplasia of white pulp whereas thymus gland demonstrated mild cortical degeneration. On the other hand, KET treatment did not produce any significant change of any of these parameters. However, when coadministered with COC, significant reduction of bodyweight, spleen/bodyweight, and thymus/bodyweight ratios with degeneration of splenic white pulp and thymic cortex occurred. Moreover, the primary immunoglobulin response to SRBC and serum IL-10 concentration were decreased without significant change in serum IFN-gamma or circulating leukocytic counts. COC caused a significant increase in serum corticosterone concentration that KET effectively prevented. On the other hand, a significant increase in plasma and tissue concentrations of norcocaine (NC) resulted following KET and COC administration in combination. Daily SKF-525A pretreatment at a dose of 30 mg/kg, i.p., for 7 days 1 hour prior to KET and COC in combination effectively reversed the effects of this combination on body weight, organ/bodyweight ratios, histopathology, and serum IgM and IL-10 concentrations without affecting leukocytic counts. On the other hand, SKF-525A pretreatment did not change the immunomodulatory effects of COC compared to non-pretreated animals. The results suggest that COC-induced immunomodulation most likely occurred through neuroendocrinal mechanisms. On the other hand, enhanced oxidative metabolism of COC in the presence of KET-induced immunosuppression.
Rofael
H Z
HZ
Department of Pharmacology and Physiology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103-2714, USA.
Turkall
R M
RM
Abdel-Rahman
M S
MS
D000284:Administration, Oral; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003042:Cocaine / Q000493:pharmacokinetics / Q000633:toxicity*; D003345:Corticosterone / Q000097:blood / Q000276:immunology; D016207:Cytokines / Q000097:blood / Q000276:immunology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D013287:Illicit Drugs / Q000493:pharmacokinetics / Q000633:toxicity*; D007109:Immunity / Q000187:drug effects; D007075:Immunoglobulin M / Q000276:immunology; D008658:Inactivation, Metabolic / Q000276:immunology; D007275:Injections, Intravenous; D007649:Ketamine / Q000493:pharmacokinetics / Q000633:toxicity*; D007958:Leukocyte Count; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects; D008221:Lymphoid Tissue / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011335:Proadifen / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D016207:Cytokines; D004791:Enzyme Inhibitors; D013287:Illicit Drugs; D007075:Immunoglobulin M; D007649:Ketamine; D011335:Proadifen; D003042:Cocaine; D003345:Corticosterone