Haloperidol prevents ketamine- and phencyclidine-induced HSP70 protein expression but not microglial activation.
Riitta Näkki, J Nickolenko, J Chang, S M Sagar, FR Sharp
Experimental Neurology February 1, 1996 DOI: 10.1006/exnr.1996.0022 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental animal study Peer reviewed |
|---|---|
| Population | Rats (Sprague-Dawley), including adult and 10- to 90-day-old animals |
| Interventions | Ketamine Phencyclidine (PCP) Haloperidol |
| Dose | Ketamine 40, 80, 80-140 mg/kg (ip); PCP 10 and 50 mg/kg (ip); haloperidol 1.0, 5, 10 mg/kg (ip or im) |
| Measures | HSP70 immunohistochemistry, microglial activation (histological assessment) |
| Topics | Ketamine Esketamine |
| Keywords | Microglia Animals Rats, sprague-dawley Haloperidol Phencyclidine Immunohistochemistry Gene expression Female Hsp70 heat-shock proteins |
| Key findings | Ketamine and PCP produced signs of neuronal injury in the posterior cingulate and retrosplenial cortex of adult rats, including HSP70 induction and microglial activation. Haloperidol blocked ketamine-induced HSP70 expression but did not prevent microglial activation by ketamine or PCP, suggesting single haloperidol doses do not completely protect neurons from NMDA antagonist toxicity. |
Abstract
Noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists, inclu ding ketamine and phencyclidine (PCP), produce abnormal intracellular vacuoles in posterior cingulate and retrosplenial cortical neurons in the rat. Ketamine also induces 70-kDa heat shock protein (HSP70) expression in pyramidal neurons in the posterior cingulate and retrosplenial cortex and, as shown by this study, activates microglia in the retrosplenial cortex of the rat. Whereas HSP70 protein expression was induced with ketamine doses of 40 mg/kg (ip) and higher, doses of 80 mg/kg and higher were required to activate microglia. HSP70-positive neurons were observed in 30- to 90-day-old rats but not in younger, 10- to 20- day old animals following ketamine (80 mg/kg, ip). Pretreatment with the antipsychotic drug haloperidol at doses of 1.0 mg/kg and above abolished all HSP70 immunostaining produced by ketamine (80 mg/kg). However, a single dose of haloperidol (5 mg/kg, im) did not decrease the number of microglia activated in retrosplenial cortex by ketamine (80-140 mg/kg). Similarly, PCP (10 and 50 mg/kg, ip)-induced microglial activation in the posterior cingulate and retrosplenial cortex of adult rats was not blocked by haloperidol (10 mg/kg, im, 1 h prior to PCP). These results suggest that ketamine and PCP injure neurons in the posterior cingulate and retrosplenial cortex of adults rats. Though haloperidol may afford some protection against this injury since it inhibits induction of HSP70 expression, the failure to prevent microglial activation suggests that single doses of haloperidol do not completely protect neurons from NMDA antagonist toxicity.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cited by 2
- The immune regulatory mechanism of ketamine-induced psychiatric disorders: A new perspective on drug-induced psychiatric symptoms. Progress in Neuro-Psychopharmacology and Biological Psychiatry January 10, 2025
- Expression of heat shock protein HSP-70 in the retrosplenial cortex of rat brain after administration of (R,S)-ketamine and (S)-ketamine, but not (R)-ketamine. Pharmacology, Biochemistry, and Behavior September 2018