Development in rats In the late 1980s,
John Olney, a researcher specializing in
excitotoxicity, the phenomenon where persistently high
neurotransmitter concentrations damage
nerve cells, began to investigate the
pharmacology of
NMDA receptor antagonists. Other workers had recently begun proposing to use NMDA antagonists
PCP,
MK-801 (dizocilpine) and
ketamine in
clinical trials for various
psychological effects; but the
drugs' current illegality meant that scientists had no record of pharmacological response to guide safe use. Olney and his coworkers discovered that, when they injected rats with PCP, dizocilpine, ketamine, or the addition NMDA antagonist
tiletamine, the rat brains rapidly developed cell-level
vacuolation, a sign of biochemical stress. Within two hours,
mitochondria had begun to
lyse, and other cytotoxic changes were apparent, peaking at 12 hours following administration. If cells were to recover, they did so within 24 hours, but unrecovered cells went on to neuronal
cell death in dissected animals. The regions of the brain that show neuronal death are remarkably restricted, and consist chiefly of the cingulate and retrosplenial cortex. Varying the dosing regimes revealed that the drugs' lesiary potency correlated with their NMDA antagonism (MK-801 > PCP > tiletamine > ketamine). Repeated administration had the same effect as single administration, leading to the conclusion that either the drugs were not
cumulatively neurotoxic or that neurotoxicity had already proceeded irreversibly after a single administration. Researcher
Roland N. Auer conducted similar studies to look at the
correlation between age and sex and the development of NMDA receptor antagonist neurotoxicity in test rats. Older rats experienced a much higher
mortality rate after the development of NAT, and female rats were found, at all ages, to have a higher incidence of
necrotic (dead)
neurons as a result of NAT.
Dextromethorphan, a common
antitussive often found in
cough medicines, has been shown to cause vacuolization in rats' brains when administered at doses of 75 mg/(kg ip). However, oral administration of dextromethorphan hydrobromide (DXM HBr) to female rats in single doses as high as 120 mg/kg did not result in detectable neurotoxic changes at 4–6 hours or 24–26 hours post-dose (female rats are more sensitive to NMDA antagonist neurotoxicity). The same researchers also found no evidence of neurotoxic changes in retrosplenial or cingulate cortices of male rats orally administered up to 400 mg/(kg day) DXM HBr or female rats orally administered 120 mg/(kg day) DXM HBr, both for 30 days. Carliss et al. (2007) also found that rats administered 9 mg/(kg day sc) (+)-MK-801 hydrogen maleate for 30 days did produce detectable vacuolation as expected. When 30 mg/(kg ip)
dextrorphan was administered to male rats, neurotoxic changes were observed only 30 minutes post-dose.
Nitrous oxide, a common
anesthetic for humans (especially in
dentistry), has also been shown to cause
vacuolization in rats' brains, but caused no irreversible lesions.
Controversy regarding human analogues In 1999, an autopsy study by
Johannes Kornhuber of 8 patients who had received
amantadine therapy looked at the selectively vulnerable brain regions where Olney's lesions occur, the cingulate and retrosplenial cortex, and found no evidence of Olney's lesions. In
Ketamine: Dreams and Realities, Karl Jansen writes: In 2013 a study using magnetic resonance imaging showed brain lesions in ketamine addicts (using from 0.2g twice a week up to 1g daily for 0.5 up to 12 years) with severity depending on the duration of addiction and daily intake of ketamine. Cortical atrophy and holes in superficial white matter are seen early on. After 4 years of addiction lesions spread throughout the brain and damage is evident in the pons and other deeper brain structures. ==See also==