1955_woolley_4109_1.pdf

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*VI LSD No. 221 (§102a)

Gy (§75d)

serotonin (§90a)

carbamylcholine (§55d)

physostigmine (§52a)

M 500 effect on mice

L 256 antiserotonin

action

WOOLLEY, D.W. (Rockefeller Inst.for Med.Res., New York)

oduction of abnormal (psychotic?) behavior in mice with ly-

rgic acid diethylamide, and its partial prevention with cho-

nergic drugs and serotonin.

Proc.Nat.Acad.Sc.

L1, 338 (1955).

PROBLEM : see title.

RESULTS: LSD given i.p. causes mice to behave in a way si-

milar to that of untreated mice faced with the prospect of sli-

ding down an inclined plane. Approximately 3 minutes after LSD

i_p., mice look rapidly and apprehensively from side to side,

the toes are spread wide and the animals begin to push back-

ward, then start to walk backward. The pushing and walking back-

ward continues, sometimes intermittently,

for 10-30 minutes.

With sufficient LSD the walking backward is always seen. With

smaller doses the pushing backward occurs, but not the actual

walking. The agitation of the mouse increases and marked tre-

mors ensue, usually about 7-10 minutes after injection. Very

soon after the injection the ears become markedly red, and,

as this sign subsides, the hair stands on end. These last 3

Signs are not seen in normal mice placed on an inclined plane.

The dosage of ISD required is shown in the following table:

Dosage of LSD required to cause mice to walk backward

LSD i.p.

No. of animals

No. walking back-

ward

per

mouse)

3OO

150

I00

1.00% of the animals are affected by doses subsequently used

in the study (lO0/_g = 4 mg per kg). If the dose is too large,

the walking backward is not always seen. It seems the mice are

not sufficiently coordinated to be able to walk.

C_msreVentionof walking backward with serotonin + cholinergic

: Intracerebral injection of serotonin (20/_g) + ca_amyl-

ne (Oo2,_g) or serotonin + physostigmine prevents the

walking and pushing backward of LSD-treated mice in about 1/4

of the cases° Acetylcholine + serotonin has no protective ef-

fect_ The carbamylcholine can be replaced by physostigmine. In-

tracerebral serotonin alone (30/_g) gives no protection. Car-

bsmylcholine alone or physostigmine alone offers no protection

in the amounts used together with serotonin. However, larger

amounts, e.g_ 0.6_g carbamylcholine or 3/_g physostigmine of-

fer some protection. The minimal amounts required for protec-

tion are 20_

of serotonin and Ool_g carbamylcholine, or 0.3

_g physostigmine ÷ the serotonin.

"Failure by drugs given i op. to protect against LSD: Attempts to

prevent the LSD effect by i.p. injection of serotonin (up to

lO0_g)

+ carbamylcholine or physostigmine fail uniformly. There

is also no evidence of protection when the cholinergic

drugs are given intracerebrally and serotonin given i.p ....

Effects on other signs due to LSD: Although the walking and

pushing backward caused by LSD are prevented in some cases by

intracerebral serotonin + cholinergic drugs, the animals do not

behave normally. The reddening of the ears is diminished but

not abolished. Agitation is largely controlled, but the tre-

mors are not completely abolished. The most difficult sign to

overcome is the marked raising of the hair. Furthermore, the

mice protected from walking and pushing backward are less ac-

tive than normal mice.

Ineffective protection by nembutal: As mice given serotonin +

carbamylcholine

or physostigmine intracerebrally

are more

lethargic than those given only saline, the possibility of par-

tial anaesthesia was examined. Mice given nembutal prior to LSD

become, without exception, more active than previously and walk

backward in characteristic fashion.

Serotonin versus ISD on artery rings: Experiments utilizing the

method of WOOLLEY & SHAW (J.biol.Chem. 203, 69,1953) show that

LSD was much more active as an antiserotonin than Gy or

....

ergotoxin.

Serotonin versus LSD in the contraction of carotid artery

rings

serotonin

LSD

Decreasein diameter

(_0cc)

ofring 0 (%)

0,03

0oi

0o3

Io0

-3

COMMENT 0 LSD a_so causes Siamese fighting fish to move back®

ward (ABRAMSON & EVANS_ LSD No_66) o w8 (E 10'284)_gNKT/ev1256

(_0cc)

0.2

0o2

0°2

0o2

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