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Chloral Hydrate

Wise Young wisey at nyc.pipeline.com
Mon Jul 3 10:59:32 EST 1995

In article <C.Hinrichsen-0307951048520001 at mg1_122.plant.utas.edu.au>, Colin
Hinrichsen writes: 
>I have an experiment going involving testing the response to hypoxia in 
>rats and requiring recovery of the animals for a week or so.  I would be 
>grateful for some information on the CNS effects of chloral hydrate (or 
>whether there is some better anaesthetic agent that I can use).  I cannot 
>use pentobarbital because of its depression nor urethane because the 
>animals do not recover nor ketamine because of its glutamate antagonism.  
>Gaseous anaesthetics are out because of the need to administer hypoxic gas

>Many thanks 
At the NYU Neurosurgery Laboratories, we use pentobarbital because it is
better understood than most anesthetic agents.  There are relatively few
papers that address the question of chloral hydrate anesthesia mechanisms
in animals.  One paper may be of interest; Korneyev, et al. found that
chloral hydrate produce sharp and sustained increases in rat brain
pregnenolone levels... something that Guth, et al. has reported to be
neuroprotective.   Chloral hydrate has long been used to prevent seizures
in alcoholic humans undergoing delerium tremens.  Pregnenolone has been
reported to be a potent inhibitor of neuronal GABA channels, similar in
potency to picrotoxin.  No matter what you choose, anesthesia has
undesirable side-effects.  Sometimes it may be better to stick with a devil
that you know rather than a devil that you don't know. 
1. Korneyev, A. Y., Costa, E. and Guidotti, A. (1993). During
anesthetic-induced activation of hypothalamic pituitary adrenal axis,
blood-borne steroids fail to contribute to the anesthetic effect.
Neuroendocrinology 57, 559-65. 
Abstract:  Anesthetic doses of ethanol (100 mmol/kg p.o.), chloral hydrate
(2 mmol/kg i.p.), and urethane (9 mmol/kg i.p.) induce sharp and sustained
(6- to 10-fold) dose-dependent increase in rat brain pregnenolone and
progesterone content. In contrast, other general anesthetics such as
ketamine (0.7 mmol/kg i.p.) and pentobarbital (0.2 mmol/kg i.p.), and the
sedative/hypnotic clonazepam (17 mumol/kg i.p.) decrease brain pregnenolone
and progesterone content. The increase in brain pregnenolone and
progesterone content fails to occur if ethanol, chloral hydrate, and
urethane are administered to hypophysectomized-adrenalectomized rats
suggesting that the increase of brain steroids requires the hypophysis and
probably originates in peripheral tissues and not in brain. The
administration to hypophysectomized rats of 5 IU/kg of ACTH produces a
brain pregnenolone and progesterone accumulation by an extent comparable to
that elicited by anesthetic doses of ethanol, chloral hydrate, or urethane
in intact animals. However, the increase in brain pregnenolone and
progesterone content induced by ACTH is devoid of anesthetic or sedative
effects and does not appear to change central GABAergic tone. In fact,
ACTH, unlike allopregnanolone and allodeoxicorticosterone, failed to delay
the onset of isoniazid-induced seizures, to reduce the fear of novelty in
the elevated plus maze test as inferred by the increase in the number of
entries or the time spent in the open arm. Thus, the data suggest that
blood-borne steroids cannot function as precursors of brain neurosteroid
modulators acting on GABAA receptor. 
2.  Guth, L., Zhang, Z. and Roberts, E. (1994). Key role for pregnenolone
in combination therapy that promotes recovery after spinal cord injury.
Proceedings of the National Academy of Sciences of the United States of
America 91, 12308-12. 

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