Subchronic ketamine alters behaviour, metabolic indices and brain morphology in adolescent rats: Involvement of oxidative stress, glutamate toxicity and caspase-3-mediated apoptosis.

Ketamine is a dissociative anaesthetic agent whose recreational use amongst adolescents and young adults is reaching epidemic proportions in a number of countries. While animal studies have examined the long-term detrimental effects of early-life ketamine exposure, there is a paucity of information on the immediate effects of ketamine following subchronic administration in the adolescence period. Adolescent rats were assigned into four groups of 10 animals each, administered intraperitoneal (i.p) injections of vehicle or one of three doses of ketamine (7.5, 15 or 30 mg/kg daily) for 8 weeks, and then exposed to behavioural paradigms. Rats were then euthanised after an overnight fast, and blood taken was used for measurement of metabolic indices. The brains were dissected out and either homogenised for estimation of neurochemical parameters, or processed for histological and immunohistochemical studies. Results showed that subchronic administration of ketamine was associated with a lesser weight gain inspite of an increase in food intake across the treatment groups. There was a dose-dependent increase in open-field novelty-induced behaviours, a decline in spatial working-memory, and an anxiolytic effect in the elevated-plus maze. There was associated derangement of serum triglyceride, and increase in brain glutamate levels, acetylcholinesterase activity, plasma/brain oxidative stress parameters, caspase-3 activity and biochemical indices of hepatic and renal function. Ketamine administration was also associated with neurodegenerative changes in the cerebral cortex, hippocampus, cerebellum and the pons. In conclusion, subchronic administration of ketamine to adolescent rats was associated with dose-related memory loss, oxidative stress and possibly caspase-3 mediated neurodegenerative changes.

Influence of a Nigerian honey on CYP3A4 biotransformation of quinine in healthy volunteers.

WHAT IS KNOWN AND OBJECTIVES: Some studies, howbeit with conflicting reports, have suggested that consumption of honey has a potential to modulate drug metabolizing enzymes which may result in a honey-drug interaction. Numerous studies have established that honey varies in composition, influenced by the dominant floral, processing and environmental factors. Thus, variation in honey composition may be a contributing factor to the controversial results obtained. No previous drug interaction study has been carried out with any honey from Africa. CYP 3A4 is an important enzyme in drug metabolism studies as it is involved in the metabolism of over 50% of drugs in clinical use and quinine remains very relevant in malaria treatment in the tropics, and we therefore determined whether there is potential drug interaction between a Nigerian honey and quinine, a drug whose metabolism to 3-hydroxyquinine is mediated majorly by CYP3A4. METHODS: In a three-phase randomized crossover study with a washout period of 2 weeks between each treatment phase, ten (10) healthy volunteers received quinine sulphate tablet (600 mg single dose) alone (phase 1) or after administration of 10 ml of honey (Phase 2) and 20 mL of honey (Phase 3) twice daily for seven (7) days. Blood samples were collected at the 16th hour post-quinine administration in each phase, and quinine and its major metabolite, 3-hydroxyquinine, were analysed using a validated HPLC method. RESULTS: After scheduled doses of honey, the mean metabolic ratios of quinine (3-hydroxyquinine/quinine) increased by 24·4% (with 10 mL of honey) and reduced by 23·9% (with 20 mL of honey) when compared to baseline. These magnitudes of alteration in the mean metabolic ratios were not significant (P > 0·05; Friedman test). The geometric mean (95% CI) for the metabolic ratio of quinine before and after honey intake at the two dose levels studied was 0·82 (0·54, 1·23) and 1·29 (0·96, 1·72), respectively, and were also not significant (P = 0·296 and 0·081 respectively; Student's t-test). WHAT IS NEW AND CONCLUSION: This is a pioneer study on the effect of Nigerian/African honey on quinine metabolism. The findings indicated that low and high doses of honey did not significantly affect metabolism of quinine to 3-hydroxyquinine. This suggests that CYP3A4 activity is not significantly altered following low or high dose of honey, as CYP3A4 has been reported to be responsible for the conversion of quinine to 3-hydroxyquinine. In conclusion, the outcome of this study suggests that there may be no potential significant metabolic interaction between Nigerian honey and quinine administration.

Functional reactivity of the dopaminergic system following acute and chronic ketamine treatments.

This study examined the effects of acute (15 mg/kg, i.p.) and chronic subanesthetic (15 mg/kg, i.p., t.i.d, for 6 days) doses of ketamine [a noncompetitive N-methyl-D: -aspartate (NMDA) receptor antagonist] on amphetamine (presynaptic dopamine releasing agent; 10 mg/kg, i.p.) and apomorphine (a D(2) receptor agonist; 1 mg/kg, i.p.)-induced stereotyped behaviors. The effect of acute and chronic ketamine on haloperidol (a D(2) receptor antagonist; 1.6 mg/kg, i.p.)-induced catalepsy was also examined. Acute ketamine and chronic ketamine pretreatment increased amphetamine-induced stereotyped sniffing and locomotion compared with control groups. Acute ketamine significantly increased apomorphine-induced stereotyped sniffing. However, chronic ketamine had no significant effect on apomorphine-induced stereotyped sniffing. Acute, but not chronic ketamine treatment abolished haloperidol-induced catalepsy. The increase in amphetamine-induced stereotyped behaviors and the reversal of haloperidol-induced catalepsy by acute ketamine suggest that blockade of NMDA receptors by ketamine facilitates dopaminergic transmission. The absence of significant effect of chronic ketamine on apomorphine-induced stereotyped sniffing and haloperidol-induced catalepsy suggests that chronic ketamine does not modulate postsynaptic dopaminergic D(2) receptors. It is suggested that chronic ketamine increased amphetamine-induced behaviors by causing hypersensitivity of presynaptic dopamine releasing mechanisms on dopaminergic terminals.