5-HT & Cognitive Impairment

From: Ian Goddard (igoddard@erols.com)
Date: Sun Jul 16 2000 - 11:14:20 MDT

At 11:24 AM 07/16/2000 -0400, Eliezer S. Yudkowsky wrote:

>Prozac is a selective serotonin reuptake inhibitor, meaning that
>serotonin released by serotonergic axons hangs around the synapses
>longer. This may produce a stronger on/off qualitative signal, but it
>seems likely to me to blur the transmissions of any information-carrying

   IAN: Research tends to support
   that hypothesis. For example, several
   studies show that raising 5HT routinely
   impairs memory, such that the higher the
   level of synaptic 5HT, the lower memory.
   One study composed of multiple substudies
   concluded that "excessive release, but not
   depletion, of serotonin produces profound
   retention performance impairment." These
   studies used PCA, which causes a sudden
   release of 5HT, followed by depletion,
   and cognitive impairment seems to be
   linked to the increased release. Now,
   that's not the same mechanism SSRIs
   exert to increase synaptic 5HT levels,
   but it's probably reasonable to extrapolate
   those finding to increased synaptic 5HT per se.


Eur J Pharmacol 1996 Jan 4;295(1):7-17

Excessive serotonin release, not depletion, leads to memory
impairments in rats.

Santucci AC, Knott PJ, Haroutunian V

Psychiatry Service, Bronx VA Medical Center, NY 10468, USA.

Eight experiments compared and contrasted the effects
of serotonin release and depletion on performance by
rats in two tests of memory. Most experiments
(Experiments 1-5) examined the effects of the serotonergic
releasing/depleting agent p-chloroamphetamine on passive
avoidance performance. Additional experiments explored
p-chloroamphetamine's effects on retention performance
by animals trained in an 8-arm radial maze (Experiment 6),
and the effects of dorsal raphe nucleus lesions on passive
avoidance in animals treated with (Experiment 8) or not
treated with (Experiment 7) p-chloroamphetamine. In general,
acute increases in serotonin release produced consistent
and extensive retention performance deficits in both
passive avoidance and radial arm maze. Results from an
ancillary control experiment indicated that the
p-chloroamphetamine-induced passive avoidance impairment
was not related to drug-induced alterations in pain
sensitivity. Other experiments ruled out the possibility
that p-chloroamphetamine was disrupting passive avoidance
retention performance by affecting post-trial consolidation
processes, producing state-dependent retention, having
direct effects at postsynaptic receptors, or indirectly
by affecting non-serotonergic neurotransmitter systems.
Depletion of serotonin resulting from either the
long-term residual effects of p-chloroamphetamine or
lesions of the dorsal raphe nucleus failed to alter
passive avoidance retention scores although it produced
extensive depletion (45-85%) of serotonin and
5-hydroxyindoleacetic acid in the cortex and hippocampus.
These data contribute to the growing body of literature
indicating an important role of serotonin in cognitive
processes by demonstrating that excessive release, but
not depletion, of serotonin produces profound retention
performance impairment.


Brain Res Bull 1986 May;16(5):645-60

Analysis of the avoidance learning deficit induced by
the serotonin releasing compound p-chloroamphetamine.

Ogren SO

The effects of the serotonin-releasing compound
p-chloroamphetamine (PCA, 2.5 mg/kg) on avoidance
acquisition, retention and memory retrieval were examined
in male Sprague-Dawley rats using a one-way active avoidance
and a one-trial passive avoidance task. The drug was injected
IP prior to training, following acquisition and prior to the
retention test 24 hr after training using a state-dependent
design. In the normal context situation pretraining
administration of PCA markedly impaired active avoidance
acquisition, but PCA-treated rats did not differ from
controls in their retention performance when tested 24 hr
after training. In the dark/light box test pretraining
administration of PCA caused a dose-dependent impairment of
both active and passive avoidance retention which could not
be explained in terms of changes in locomotor activity or
behavioural disinhibition at the time of testing or state-
dependent retention. Post-training administration of PCA
failed to affect avoidance retention in both tasks. The
drug was found to impair memory retrieval in a dose- and
time-dependent fashion in the one-way active but not in
the passive avoidance test. Pretraining administration of
PCA produced a progressive loss of passive and active
avoidance performance at increasingly longer retention
intervals. The present results suggest that serotonin has
dual effects on processes underlying learning and memory
involving effects on both associative and non-associative
learning processes in the rat. The time-dependent loss of
memory retention following 5-HT release indicates that
serotonin has a role in the way information is processed
in the brain.


Acta Physiol Scand 1986 Mar;126(3):449-62

Serotonin receptor involvement in the avoidance learning
deficit caused by p-chloroamphetamine-induced serotonin

Ogren SO

The receptor involvement in the p-chloramphetamine (PCA,
2.5 mg kg-1) induced impairment of active avoidance
acquisition was examined in the male rat. The avoidance
deficit was blocked at low doses by serotonergic
(5-HT)-receptor blocking agents but not by alpha-adrenergic-,
beta-adrenergic-, opiate-, muscarinic- or dopamine D2-receptor
antagonists. The potency of the 5-HT antagonists to block
the PCA-induced deficit correlated with their affinity in
displacing [3H]ketanserin but not [3H]5-HT binding in the
frontal cortex. The potencies of the 5-HT antagonists to
block the action of PCA could not be related to their
action on muscarinic-, histaminergic H1- or dopaminergic
D2-receptor binding in vitro. It is concluded that the
avoidance learning deficit caused by PCA-induced 5-HT
release is related to activation of 5-HT receptors in
the frontal cortex having the characteristics of a 5-HT2


Med Biol 1975 Jun;53(3):165-8

5-Hydroxytryptamine and learning: long-term effects of
P-chloroamphetamine on acquisition.

Ogren S, Ross SB, Baumann L

The effect of p-chloroamphetamine (PCA) on the acquisition
of a conditioned avoidance response in the rat was examined.
Eleven rats were injected with saline or 2 X 10 mg/kg of PCA
i.p. on two consecutive days and the learning procedure was
started eight days later and lasted for six days. The
acquisition of the conditioned avoidance response was strongly
impaired by PCA compared with the control group. It is
suggested that the impaired learning is due to a long-term
effect of PCA on a 5-hydroxytryptamine system directly or
indirectly linked to learning.

GODDARD'S JOURNAL: http://www.erols.com/igoddard/journal.htm
Asking the "wrong questions," challenging the Official Story

To subscribe send email with "subscribe" to Ian@Goddard.net


This archive was generated by hypermail 2b29 : Mon Oct 02 2000 - 17:34:40 MDT