β-Endorphin and forgetting

p=Endorphin and forgetting After training, memory is transformed at a loss riom an unstable intoa stable state. The

amnesia for ~anou~ t.l\k\ also naloxonc-rcvcrhrhle’

process is usually called consolidation and its mechmism is unknown. It is modulated.

morphine. hlet-. Lcuenkephalin or other

however. hormonJ

ACTH

by various neurohumoral systems (central dopamine

noradrenaline.

pituitary ACTH

and and

and

adrenaline

release Srndorphin

Thclr clfcct IC

” I” ‘I’. Hoacrer.

and L’c%T>r-Vetdrug\ tmcluding at

high

do\c\)

from rhc ra: drncepha-

and vaso-

Ion. an effect that is not rcverhcd b) nalux-

pressin. peripheral adrenaline) activated by non-associative components of the learning

one’. Therefore. probahlg the dmnctttc influence ot these other \ubrtancc\ I\

experiencea. and drugs or other treatments that alter those systems may either enhance or depress consolidation when applied

mediated at leaht in part h, the /$endorphm that they release. and nalorone amagonize\

short11 after training4 “.“‘.

releasing agents.

An optimum

degree of activity of those systems appears necessary for consolidations.“.‘:‘-‘j. This

article

neurohumoral pendorphin peptides

comments

on

another

system. mediated by and perhaps by other opio.d

as well,

which

appears

designed to induce forgetting. retention.

to ‘X

rather than

Brain /kndarphin releaseduring training lmmediatriy

after a 29-min

shuttle avoidance

!+cs$lon of

using paired

ing using random tones and iocltshockc. of tones alone (habituation). or imshdik

lent to 2&-W

post-training i.p. injec-

training

tones and footshocks. of pseudocondition-

alone. there endorphialike

Post-trainingadministrationof pendorphin cansesforgetting ‘The immediate

the effect of the latter rather than that of the

is a decrease immunoreactivity

of fiequtvs

ng of /3-endorphin in the rat

brain (excluding

hypothalamus.

olfaLttb,r?

’ ia.

tion of subanalgesic doses of /.3-endorphin

bulbs.

causes retrograde amnesia for shuttle and

Since tones alone have the Name effect ah the other forms of training. rhe decrease can

inhibitory avoidance and for habituation learning in ra~b”.“‘~‘4~‘5~‘H.In the shuttle avoidance task the amnesric EDSO is 0.8-l

.O pg kg -‘ (Refs 9 and 14). Inhibit-

ory avoidance is sensitive to as little as 0. I pg kg makes

(2.8 * IO ” mol kg ‘)la. which /3-endorphin the most poacrful

’

cerebellum

and

midbrain)‘;,

not be attributed to stress or pain”. OnI> after footshock stimulation is there a depletion

of

pituitary

munoreactivity the plasma’>. The

effect

/.3-rndorphm-like

im

and a aimultaneou> rise in of

trainrng

on

+endorphin-like

effect

best be explained by release and \uhsequent degradation of the subhtancr. S>ntheG% inhibition may be ruled our for two reabonh:

is

independent

of

the

response

requirements of the tasks and of the presence of pain during training. Amnesia is alsoobtained using ore-training sdministrs tions of the drug”“.

Naloxone

(0.2

GYP

immunoreactiv+

brain

amnestic drug known so far. Note that the

can

first. the synthesis of&cndorphin m~mun+ reactive ma,zrial i3 ver\ slnu and. rbcn if it

kg ‘) given i.p. immediately after training. reverses the amnestic effect of &endorphin*~“~‘5. The antagonism appears

were completely arrested during 3 min one would nor rxpect an) major change m

to be competitive (Fig. I)“.“.

strictly dependent on !,cneral protein b!nthesis. alid the tramin procrdurc~ men-

The amnestic effect of &cndorphia

~5

brsin levels oi kuch m;ttt:nal; second. it i\

centrally mediated: it can be obtained \\ ;th

tioned above actualI> increa.x.

as little as 5 or 25 ng per rat given i.c.v.“. Even if the entire i.c.v. dose leaked to the

depress. brain protein synthesis”. ‘j.

periphery,

alone) training have no effect on Metenkephalin immunoreactivit? measured in the amygdala, hypothalamus or rest ot the

which is very unlikelyJ. plasma

levels would be much smaller than those expected after effective i.p. injection+“. Subanalgesic Met-. Leuenkephalin’“‘”

doses of morphineh.“‘.“‘, or also

even

dee’fyr-Met-

cause

retrograde

rather thar

Shuttle avoidance or habituution (rones

brdin of rats: footshltrk stimulation. instead. causes a small decrease in the former two structures”. Therefore.

brain

456 when theformer is given systemicaity”, is no8known.

~curs

SC-s,

SD

An endogermus smnestic mechsnism mediated by /Sendorphin The evidence summarized above points unequivocally ta the existence of an endogenousamnestic mechanism mediated by been, which prevents memory from being as gocui as it could be. &Endorphin is (apparently) released in the bram during many forms of Iraining; the anwunt released is compatible with doses of the substancetbt, when injected. cause partial amnesia; the amnestic effect d ~~e~o~hin is reversed by naloxone: in normal animals, t,aloxone causes memory facili4on” ts.t*. When th mechanism operates‘in excess’ , as, for example, when animals are submitted lo elcctroconvulsive s’wck or to other amnestic treatments (see above), /Lendorphin is releaxd also in excess and total amnesia may ensue. This toial amnesia is naloxone reversible. Are other @oi&

5

I

0

involved in th?

operation of the mnnestk mecbsnism? At least in the case of Met-, Leu- and desTyr-Met-enkephalin there is indirect evidence that they are not involved in the eaters amnestic ~~n~sm. In order tobe acandidate for sucharole. a substance mtit ncttinterfm with acquisitiaa at doses thawcauseamnesia; if it did, it would make learning impossible. &Endorphin does not affect acquisidon of shuttle ava&_+ance @r babimaaion at doses that produce full antere or retrograde amnesia tup to 5.0 i’g kg ‘)7e*. Mel-. Leu- and desTyrMet-enkep;halin,on the other hand, disrupt acquisition over a wide dose ranges.“, including doses lower than those that may prod= amnesiay.Obviously, if they were released dllring uaining they would make iearning ineffectual. And, in fact, as mentioned above, Met-e~e~~in (and the= fore prcsumabiy also its metabolite, de+ T.+r-Met-enkephalin) are not releasedin the brain by all typesof uaining. as O;CCurs with /3-endotphin~~‘3. The pretraining administration of 1.0 ct~ kg ’ of y-endorphin. i.p., appears to f&&ate relizntionof an ~~~i~ avoidancc task’*; however, a much l.arger dose ~aboutSU-60 pg kg ‘) given s.c immedii ately after training causes amnesia for the s*rne task”. Experiments with a-edorphin have yielded conflicting and confusing results. Using the same task (inhibitory avr~) and the same stock of rats, one gioup reported memory faci!&ation with approximately 10.0 pg kg-’ of a-endorphin given s.c.‘~, and another group repoti no effect over a very wide C&X range”. More will be known about the

eventual involvement of theseother endorphins in behaviour when the effect of training on their brain levels is determined. and their metabolic relation to @.endorphimis belter understood”. Dynorphin appearsnot to have been investigatedin this respect. Inverted u dose+espo=

cllrve5: a

digression into the diierences between phy~, toxicoiqy zutdscience fktkm Most drugs that affecctretention present inverted U dose-response curves. In the case of stimulant drugs, the right arm of the inverted U may be explained by the fact that they may be adding to endogenous arousal-related substancesbeing released and so they may ‘push’ arousallevels too far and away from the optimum required for consolidaGon4.L5. The opioid peptides and morphine cause amnesi? at moderate doses. have no effect at high dosesl”~‘S~sy, and may have an opposite effect at huge doses’,‘““. What is a moderate, a high and a huge dose? in the case of endogenous compounds with tea tral actions, a moderate dose may be defmed as one which. when given by bolus injection, does not surpassthe total brain content of the coin~u~. Rat brains contain 100-200 ng of ~e~hin or Metenkephaiin2*Z’J. The i.c.v. injection of, say, 100 ng or less. or the i.p. injection of 2.5 pg kg-’ [of which 20?4 reaches the brain within 2 h I[Ref. 5)j or less, of those compounds may he consideredas a m&r-

ate or physiol~ica~ dose. Two or three times that amount may be considered as a high dose. Memory facilitation may be obtained with 20 times that amount of fi-endorphin given s.c.” or with IV times the total content of brain Met-enkephalin given i.c.v.‘. Those may bc consideredas huge doses. When a pha~~ologist wishes to study the possibie physiological role of an endogenous compound he must rcsirict himself to the use of moderate doses. He might need to resort lo high doses if he wishesto studydose-responsecurvesor the effect of an antagonist. If he chooses to employ huge doses, he must be aware that he is pr~tising toxicology and abstain&om giving physiological interpt-etations to whatever findings he might obtain. len he be accused of practising science fictimon. The fattening and ultimately lethal effen of a bolus injection of 10 or 100 kgof glucose to a man, aside from its technical d~~~i~uli:y. does not reflect the physiological role of glucose. There are various possible explanaltions for the strangeeffects of opiatesand opioids on memory at huge doses’,“. One cd:the fust that must be considered is an aversive effect due to toxicity. Indeed, memory f~ilitation with huge doses of these substances has so far only been reoorted in aversely motivated tasks*~YJ~l’. O&iously, an extra punishment given shortly after an aversive training session will add to the motivational component of the task.

Why would an animal need an mnnestic meclmnism? One possiblereason is LXonomical. Mosl ot’ the informalion we acquire is clthcr completely useless or becomes. obsolete very soon, like most of the telephone num bet3 we learned last year. It save:,energy to simply discard that information. Another possible use of an amncsuc mechanism is to make animals quickly forget the incidental learning that occurs during the acquisition of any given task. Such learning is normally weaker than. but may seriously interfere with, the main task for which the animals are being trained. For example. a rat that is learning IO run in responseto a tone in order to avoid a footshock must quickly forget any incidental classically conditioned freezing reaction to the tone that may simultaneously develop. It is possible that the opioid-mediated amneslic mechanism acts rather indis criminately during a training session. but that’the main task is better retained than the incidental learning becauseit is stronger (it is specifically reinforced. etc.). Some recent experiments support this view, suggestingthat the ,&endorphin that is released during training actually helps acquisition. The i.p. administration of 0.8-1.6 mg kg-’ of naloxone prior to shuttle avoidance or habituation training hinders acquisition of both tasks’.*. (Note, again, that the effect is independentof pain and of response requirements.) The administration of Bendorphin (2.0 pg kg-‘. i.p.) prior to a test sessionof any of these two behaviours facilitates performance during that session.&Endorphin is normaliy not released during test ses sion+“. so it acts as if it were necessary and had been missing. As would be predicted from the hypothesis that Pendorphin is necessary for learning (or for relearning, as in test sessions) because of its proactive amnesticeffect, a huge dose of the peptide (20.0 ug kg ‘) disrupts acquisiilon not only of the incidental leamit-g but also of the main task, an effect which is also naloxonc reversible”. It is possible that Bendorphin has an effect on retrieval independentfrom the one on consolidation’:‘~‘7.It is also possible that both effects are faces of the same coin. Ihe drug facilitates performance in test sessions due to a sum of two factors: a rentwed proactive ‘trimming’ of the main task srconddry to an amnestic intluence on a&en-

titious bchavicurs. and the p,\inve bia\ on test sessionperformance caused b) mem or); of the previous training resslon Thehe possibilitiesdeserve further UUJ A find comment The effects of &endorphin on memory arc obtained at doses compatible uith the amounts endngcnously released durmg training. and much lower than hu: needed to cause analgesia. The 3ame ir true 03 behavioural effects of other opic,ld> u: general”‘-‘7I’. Thu\. many author\ habc suggested.starting with Ka\tin in 11176(~2 Ref. I3 9. that the primary role nt tbex sub stances may be IO modulate hehr\inLi rather than to mimic the suphonc or analgesiceffect of opidte\. ‘And yet and yet .’ pam I\ proh ably the only sensation thal can nrvcr h. recalled in all ia quality and inre!~suy. People who have been tortured. or atrmrn who have borne children may remember very vividly all the circumstancessurrounding. or pertaining to. their painful rxperb ence. hut can never acmally revive the parn itself. One wonders whether there might not be a relation. after all, betweenopiate or opioid analgesia and quick forgetting at the pain. sometimes nearly as qtucklq as It i\ produced; sometimes. unfortunatet.. noL qmckly enough. Acknowledgement Work supported h> Financiador;n de Estudose Projetos
3 Gdlagkr. 23.

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