Effect of Ketamine on Cocaine-Induced Immunotoxicity in Rats

Abstract

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.

The rapid antidepressant effect of ketamine in rats is associated with down-regulation of pro-inflammatory cytokines in the hippocampus

“…It has been widely acknowledged that ketamine down-regulates inflammatory responses, and it has been recommended for use in surgery of sepsis patients due to its anti-inflammatory effects ( 15-17 ). Previous studies in both animals and humans have shown that ketamine produces immunomodulatory effects and facilitates 5-HT production in the hippocampus, partly contributing to the beneficial effect of ketamine on depressive symptoms, which is consistent with our data ( 17 , 29 ). Our previous clinical study also suggested that serum IL-6 is a predictive biomarker for the antidepressant effect of ketamine in treatment-resistant patients ( 30 ).…”

Intravenous haloperidol and cocaine alter the distribution of T CD3+CD4+, non‐T/NK and NKT cells in rats

“…In our study, intravenous infusions of haloperidol and cocaine resulted in an increased concentration of plasma corticosterone, accompanied by pronounced lymphopenia. Similar effects were observed in rats receiving a high dose of exogenous corticosterone or a single intravenous injection of cocaine (5 mg/kg) 47,48 . Surprisingly, in our study, haloperidol prevented the decrease in numbers of NKT cells caused by cocaine infusions.…”

“…Similar effects were observed in rats receiving a high dose of exogenous corticosterone or a single intravenous injection of cocaine (5 mg/kg). 47,48 Surprisingly, in our study, haloperidol prevented the decrease in numbers of NKT cells caused by cocaine infusions. This result suggests that blocking D2-like DA receptors allows NKT cells to escape cocaine-induced lymphopenia.…”

Drugs of Abuse, Immune Modulation, and AIDS

“…This substance, commonly used to tranquilize animals, is currently popular among young cocaine users. Rofael et al (2003) examined the effect of subacute exposure to cocaine and ketamine alone and in combination on the immune system in rats. Treatment with cocaine alone resulted in an increase in immunoglobulin M (IgM) antibody response to sheep erythrocytes and in serum levels of the anti-inflammatory cytokine IL-10.…”