Hypothalamic self-stimulation: Its suppression by blockade of norepinephrine biosynthesis and reinstatement by methamphetamine

Hypothalamic self-stimulation: Its suppression by blockade of norepinephrine biosynthesis and reinstatement by methamphetamine

Life Sciences Yol . 5, pp . 11-16, 1966 . Printed in Great Britain. HYPOTHALAMIC SELF-STIMULATION : Pergamon Press Ltd . ITS SUPPRESSION BY BLOCKAD...

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Life Sciences Yol . 5, pp . 11-16, 1966 . Printed in Great Britain.

HYPOTHALAMIC SELF-STIMULATION :

Pergamon Press Ltd .

ITS SUPPRESSION BY BLOCKADE OF NOREPINEPHRINE

BIOSYNTHESIS P.ND REINSTATEMENT BY METHAMPHETAMINC B . P . H . Poschel and F . W. Ninteman Parke,

Davis b Company

Research Division, Ann Arbor,

Michigan

(Received 3 September 1965 ; in final form 5 Iiovember 1965) PREVIOUS experiments in

this

available a sustained high sites .

series

(1,2,3) employed various drugs to make

level of free norepinephrine at central reactive

The resulting effects on self-stimulation behavior supported the

tentative conclusion that norepinephrine serves as an excitatory neurohormone for reward neurons of the lateral posterior hypothalamus .

It was

suggested that norepinephrine may act as a transmitter at the synapses concerned . or perhaps as a modulator of the actual

transmitter .

Another approach to testing the above notion drug DL-al ha-methyl-tyrosine sine hydroxylase (4), dopa,

(:~-MT) .

the enzyme

the rate-limiting step

is now made possible by the

This drug is a potent

involved

in

inhibitor of tyro-

the hydroxylation of tyrosine to

in the biosynthesis of catecholamines

(5,6) .

Thus . appropriate doses of .~-MT block the biosynthesis of cate:cholamines and consequently greatly lower the brain concentrations of norepinephrine and dopamine

in guinea pigs

affected .

Therefor :,

(6) and rats

(7) . while leaving serotonin levels un-

if norepinephrine

is

involved

in the functioning of the

reward system of the posterior lateral hypothalam~~s, appropriate doses of ~7-MT should suppretis the powerful region .

reward effect normally obtained from this brain

Furthermore . after this suppression has developed,

reinstate the reward effect at central

if

~eactive site, ($) .

it serves

amphetamine should

to mimic the action of norepinephrine

In the present paper we report experiments

which confirmed both of these expectations . 1?

12~

HYPO ~sT~~~TC SELF-STIMULATION

Yol . 5, No . 1

Method Five male albino rats of the Holtzman strain, weighing about 285 9m, were

implanted with permanent electrodes aimed at the medial

of the posterior lateral hypothalamus . fled histologically .)

electrode placements were veri

The electrodes were monopolar, were made of 30-gauge

platinum wire, and were completely the tip .

(AJ1

forebrain bundle

insulated except for a 0 .5 mm segment at

Approximately four weeks after surgery,

the subjects were trained to

press a lever to stimulate their brains electrically .

The lever was housed

in

a box with an open top and with wire-mesh flooring . The box provided an experimental space 8 in . wide, 11

in . long, and 18

in . tall .

Each depression of

lever delivered 60-cycle sine wave sti.mulatlon, 0 .4 sec . s.timulus .was generated by an high

resistance .

jects,

The

isolation transformer in series with a relatively

The intensity of stimulation was set at 50 NA for four sub-

and at 40 NA for the other animal .

employed

i n duration .

the

These high stimulus

in order to elicit a near-maximal

In the critical

levels were

reward effect from the hypothalamus .

tests which followed, seven days

control test and a drug test on each subject .

intervened between a

The control test was run prior

to the drug test in three subjects ; for the other subjects this order was reversed .

Each test ran at least S hrs .

(racemate) was administered the session . omitted,

However,

In the drug tests, 50 mg/kg of a-MT

immediately after the lst,

3rd,

and 5th hrs . of

for two of the subjects the third dose of the drug was

since self-stimulation had already been attenuated markedly by the

first two doses . suspended in 2 .5

All

injections were administered

cc of methocel

solution .

above procedure with pure methocel

I .P .,

50 mg of drug being

The control tests duplicated

the

solution serving as the placebo .

The action of methamphetamine against the effect induced by a-MT was tested

in two of the above subjects .

(At the time we decided to run this

test, most of the subjects had already been in Fig .

l .

subjects .)

run in the experiment surtmarized

Exhaustion of our supply of a-MT prevented testing additional The animals received methamphetamine hydrochloride (0 .5 mg/kg,

Yol .

5,

No .

1

IiYPCTHAI~ALQC SELF-STIIIIILA,TICN

I .P .) immediately after the 8th hr . of the a-MT session . receiving methamphetamine,

the animals were

13

Directly after

returned tq the test chamber and

were run overnight . The tests were programmed autanatically by relay circuitry, and leverpresses were recorded continuously by a cumulative recorder . Results To assess the effect produced by ~-MT, the number of self-stimulations made by the animals during each hour of the test was tabulated . the mean scores

from this tabulation of the data

A graph of

is presented in Fig .

1 .

The control scores show good consistency, although a gradual slight decrease in response rate occurred over the 8 hr . test, probably reflecting an accumu-

FIG .

I

Mean number of self-stimulations made each hr . during the tests . Alpha -MT (54 mg/kg) or placebo was administered (I .P .) immediately after the lst, 3rd, and 5th hrs . However, the final (5th hr .) infection was omitted for two of the five subjects . Of primary significance, Fig . 1 shows that under the influence of AMT the rate of self-stimulation gradually declined and then virtually stopped . Analysis of variance indicated that the two curves different from parallel

( .001

in Fig . 1 are significantly

level of confidence) .

The effect methamphetamine had against the suppression induced by ~-MT is shown in Fig . 2 .

Reproduced are segments of the self-stimulation records

14

HYPOT$ALAMIC SELF-STIMULATION

YT 11.

ILl11 - Ii fFFEIf II111N11f1

IIIH 11 IUJI -/f

'

I

Yol .

5,

No .

 ~ill/Ilfil111f

//f,

rJ'

'

r F-HI

I~~ Î ~~~1~~~

_-

1 i I __ i ;~ ;rr

'r

1r~

1

-_

._

FIG . 2 Cunulatlve records of self-stimulation from two subJects . Records read from left to right . Each reset of recorder pen equals 55o self-stimulations . First record shown for both subJects is 1 hr . long ; second record, 3 hrs . long . The arrow Indicates the point where methamphetamine (0 .5 mg/kg) was given I .P . In the case of rat E-133, the methamphetamine was given 3 hr . after the final dose of a-MT . This interval was 5 hrs . for rat E-149, since this~sub)ect received only the first two doses of cx-MT . of the two animals employed in this phase of the study .

In these records,

each reset of the recorder pen represents 550 self-stimulations . segment of behavior shown for each animal

The first

is 1 hr . long ; it shows the rate

of self-stimulation rtlalntained during the lst hr . of the test, prior to any drug .

The second segment is 3 hrs . long .

It first shows the final

(8th)

hour of self-stimulation under cx-MT, when the behavior had virtually stopped . Then, at the point indicated by the arrow, 0 .5 mg/kg of methamphetamine hydrochloride was administered . ~ansued in the next 2 hrs .

The remainder of the record shows the effect that It is apparent that the drug, even at the small

dose employed, counteracted the suppressive affect of ~-MT . Discussion For the following reasons, a-MT appears to suppress self-stimulation because it lowers the level of brain cetecholamines .

First, other experiments

show that the dosing regimen used in the present study should reduce brain catecholamlnes substantially, but not affect serotonin levels at all

(6,7) .

Second, the rate at which the behavioral effect developed in the present study (Fig . 1) is consistent with the rate at which brain catecholamines fell

Yol . 5, No . 1

HYPOTHALAIQC SELF-~TIYULATION

in the other experiments (6,7) . that catecholamines play an self-stimulation .

15

Third, previous studies (1,2,3) have indicated

important role in lateral posterior hypothalamic

Therefore,

cessation of self-stimulation after a-MT seems

to be associated with a deficit of brain catecholamines, under which even intense stimulation of the lateral posterior hypothalamus seems unable to yield a satisfactory amount of . reward . This effect

is not equivalent to general sedation, because the animals

in the present study did not appear particularly sedeted even when selfstimulation had virtually stopped .

Weissman and Kce (7) also failed

observe sedation of gross behavior

in rats after a-MT .

to

In fact, they employed

higher doses of a-MT than used here, and their drug was in the levo form--the active

isomer with respect to enzyme

We expected

inhibition .

that methamphetamine would reinstate self-stimulation after

its suppression by a-MT, because the amphetamines seem to mimic the effect of norepinephrine at central reactive sites (8) .

Our positSve finding,

conflicts with the report of Weissman and Kce (7) .

however,

Using doses of d-amphet-

amine up to 10 times greater than the dose of methamphetamine employed here, these investigators reported that amphetamine stimulation is blocked by ~-MT . The exact reason for the discrepancy is not clear . will

Probably an explanation

be found in the very different aspects of behavior tested . Alpha-MT affects norepinephrine and dopamine equally (6,7), so it

clear which amine is critical

for hypothalamic self-stimulation .

grounds,

however, a good case can be made for norepinephrine .

nephrine

is highly concentrated

the reward system

On other

Thus, norepi

the hypothalamus and other structures of

(9), while most of the brain's dopamine

the corpus striatum (10) . stimulation of

in

is not

Moreover,

is concentrated in

recent work has indicated that electrical

the lateral hypothalamus

(or the amygdala) which elicits excited

emotional behavior, also causes a depletion of brain norepinephrine while leaving dopamine levels unaffected

(11) .

Yhus, of the two amines, norepineph-

rine appears more closely associated with neural

systems which subserve

16

üYPOTHALAHIC SELF-STIlIiTLATION

motivational and emotional processes .

If this

is

Vol . 5, No . 1 true, norepinephrine should

also be more closely associated with reward phenomena . Summary Rats were trained to press a lever for highly rewarding electrical lation of the lateral posterior hypothalamus . with alpha -methyl-tyrosine, a potent

stimu-

The animals were then treated

inhibitor of tyrosine hydroxylase .

drug gradually suppressed self-stimulation behavior almost completely .

The This

affect appeared to be associated with a decrease in brain norepinephrine levels resulting fran the blockade of catecholamine biosynthesis .

The suppres-

sion of self-stimulation was antagonized by a small dose of methamphetamine . This may mean that methamphetamine can mimic, at

least in part, the central

action of catecholamines . Acknowledgment We wish to thank Merck b Co .,

Inc . for their generosity

in supplying

DL-al ha-methyl-tyrosine . References 1 . B . P . H . Posche l and F. W . Ninteman, Life Sciences 2,

782 (1963) .

2 . B . P . H . Posche l and F. W . Ninteman, Life Sciences

903 (1964) .

3 . B . P . H . Poschel, (1965) "

3,

F. W . Ninteman and S . C . Stanat, Life Sciences 4, 53

4 . T. Nagatsu, M . Levitt and S . Udenfriend, J . Blol . Chem . 239,

2910

(1964) .

5 . M . Lovitt, S . Spector, A . Sjoerdsma and 5 . Udenfriend, _J . Pharmacol . Exptl . Thera . 148, I (1965) . Exptl 6. S . Spector, A . Sjoerdsma and S . Udenfriend, _J . Pharmacol . . The rap . 147, 86 (1965) . 7. A . Weissman and B . K . Koe,

life Sciences 4,

1037

(1965) "

8 ~B . B . Brodie and P. A. Shore, Ann . N. Y . Acad . Sçi . 66, 631 9 . M . Vogt, J . Physlol . ~,

451

10 . A. Bertler and E . Rosengren, 11 . D . J . Rois and L .-M. Gunne,

(1954) . Experientia ~,

10 (1959) "

Science 14~, 450 ( .1965) .

(1957) "