DEVELOPMENT

OF

OF

AMPHETAMINE,

MORPHINE,

REINFORCEMENT

TOLERANCE

SYSTEM

Yu. V. B u r o v

TO
AND

THE

ACTIVATING

ALCOHOL

ON

ACTION
THE

POSITIVE

IN R A T S

a n d S. A. B o r i s e n k o

U D C 615.212.7+615.31:547.262].015.5

KEY WORDS: morphine; amphetamine; alcohol.

C a s e s of polynarcomania - the taking of a combination of drugs causing euphoria, and, if need be, the
r e p l a c e m e n t of one such drug by another [8], known in clinical p r a c t i c e suggest that the effects of these drugs
a r e r e a l i z e d by common, including neurochemical, b r a i n m e c h a n i s m s . This is confirmed, in p a r t i c u l a r , by
data in the l i t e r a t u r e [1, 5, 9, 12] showing that changes in the n e u r o m e d i a t o r systems of the brain arising under
the influence of the different drugs causing n a r c o m a n i a a r e qualitatively s i m i l a r in direction. Besides euphoria, an indispensable element in the chain of f o r m a t i o n of n a r c o m a n i c dependence is the development in
the c o u r s e of this effect of t o l e r a n c e to the narcotic used. The w r i t e r s showed previously [2-4] that substances
giving r i s e to toxicomania lead to activation of the positive r e i n f o r c e m e n t s y s t e m in r a t s , w h e r e a s substances
unable to induce toxicomania a r e without this effect.
The object of the p r e s e n t investigation was to study the development of t o l e r a n c e , and also of c r o s s e d
t o l e r a n c e to the activating effect of morphine, amphetamine, and alcohol on the positive r e i n f o r c e m e n t s y s t e m
in rats.

EXPERIMENTAL

METHODS

E x p e r i m e n t s w e r e c a r r i e d out on 11 m a l e r a t s weighing 250-350 g, into which e l e c t r o d e s w e r e implanted

in accordance with coordinates from De Groot's b r a i n atlas [10], into the medial f o r e b r a i n bundle at the level
of the l a t e r a l hypothalamus: A =4.4 ram, L =1.5 nun, H = 8.5 ram. The operation was p e r f o r m e d under pentobarbital anesthesia (40-50 m g / k g , intraperitoneally). Seven days a f t e r the operation the r a t s w e r e t r a i n e d in
s e l f - s t i m u l a t i o n until the threshold of the r e s p o n s e and n u m b e r of s e l f - s t i m u l a t i o n s in a period of 10 rain,
using c u r r e n t s of different strengths, were stable. The brain was stimulated by sinusoidal pulses with a d u r a tion of 0.02 sec and a frequency of 50 Hz. A f t e r training of the animals to a stable level of self-stimulation
skill, the initial degree of activation o 9 t h e r e s p o n s e was d e t e r m i n e d by m e a s u r i n g the lowering of the t h r e s h o l d
and the i n c r e a s e in the number of self-stimulations under the influence of equivalent doses of amphetamine
(0,5 m g / k g ) , morphine (3 m g / k g ) , and ethanol (0.5 g / k g of the 15% solution), which w e r e injected i n t r a p e r i toneally, 30 rain before the e x p e r i m e n t began. Animals in which a facilitatory effect on self-stimulation was
o b s e r v e d as e a r l y as a f t e r the f i r s t injections of the drugs were used in the e x p e r i m e n t s . The above-mentioned
doses of the drugs, as was shown previously [2, 4], a r e the minimal equivalent doses in which these drugs
exhibit a distinct, quantitatively practically equal, activating effect on self-stimulation in the same animal.
Immediately a f t e r subsequent single testing injections of each drug, one of them was injected once daily in the
same dose until the development o f t o l e r a n c e to it, i.e., until it c e a s e d to have any facilitating effect on selfstimulation. Against the background of t o l e r a n c e to the main drug, subsequent testing was c a r r i e d out with
two o t h e r drugs in the initial doses, and also with the main drug in twice the initial dose. F i s h e r ' s method
[7] was used for the statistical analysis of the r e s u l t s .
E X P E RINIE N T A L R E S U L T S

The original values for the t h r e s h o l d of the self-stimulation r e s p o n s e in different animals v a r i e d f r o m

20 to 140 #A. The intensity of self-stimulation was i n v e r s e l y proportional to the original values of the r e sponse t h r e s h o l d and amounted to 220-560 p r e s s e s on the pedal in 10 rain. Amphetamine in a dose o f 0.5
Institute of P h a r m a c o l o g y , Academy of Medical Sciences of the USSR, Moscow. ( P r e s e n t e d by A c a d e m i c ian of the Academy of Medical Sciences of the USSR V. V. Zakusov.) T r a n s l a t e d f r o m Byulleten' E k s p e r i m e n tal~aoi Biologii i Meditsiny, Vol. 89, No. 6, pp. 698-700, June, 1980. Original a r t i c l e submitted October 10, 1979.

786

0007-4888/80/8906-0786507.50 9 1980 Plenum Publishing Corporation

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Fig. 1 . D e v e l o p m e n t of t o l e r a n c e to the a c tivating action of a m p h e t a m i n e (I), alcohol

(II), and m o r p h i n e (I]/) on the s t r u c t u r e of
p o s i t i v e r e i n f o r c e m e n t . A b s c i s s a , day of
injection of p r i n c i p a l (a) o r testing (b)
drugs; ordinate, n u m b e r of s e l f - s t i m u l a t i o n s
in 10 rain. Am) Amphetamine; A) alcohol;
M) m o r p h i n e . A v e r a g e d values given f o r
n u m b e r of s e l f - s t i m u l a t i o n s obtained a g a i n s t
the background of each drug in all a n i m a l s
u s e d in the e x p e r i m e n t s .
m g / k g , m o r p h i n e in a dose of 3 m g / k g , and ethanol in a dose of 0.5 g / k g l o w e r e d the t h r e s h o l d of self-stixnulation by 5-40 #A (P < 0.05) and i n c r e a s e d the n u m b e r of s e l f - s t i m u l a t i o n s in r e s p o n s e to a c u r r e n t of t h r e s h o l d
s t r e n g t h by 120-310 (P < 0.05) c o m p a r e d with the initial values. Under t h e s e c i r c u m s t a n c e s , a m o r e m a r k e d
lowering of the r e s p o n s e t h r e s h o l d , d e t e r m i n e d f r o m absolute values of intensity of the s~Xmulating c u r r e n t ,
was o b s e r v e d in a n i m a l s with c o m p a r a t i v e l y h i g h e r initial values of the s e l f - s t i m u l a t i o n t h r e s h o l d . The d u r a tion of the p e r i o d of d e v e l o p m e n t was individual in c h a r a c t e r in different a n i m a l s , and amounted on a v e r a g e
to 3 d a y s f o r a m p h e t a m i n e , 3.2 days f o r ethanol, and 7.3 days f o r m o r p h i n e (Fig. 1). A d m i n i s t r a t i o n of the
o t h e r two s u b s t a n c e s in the initial doses, when t o l e r a n c e had developed to the p r i m a r y drug, did not l e a d to
activation of s e l f - s t i m u l a t i o n , but in m o s t c a s e s the tendency t o w a r d weakening of s e l f - s t i m u l a t i o n which was
o b s e r v e d p e r s i s t e d a f t e r injection of the t e s t s u b s t a n c e s . If the dose of the principal drug was doubled, as
a r u l e , f a c i l i t a t i o n of s e l f - s t i m u l a t i o n was o b s e r v e d , once only in the c a s e of a m p h e t a m i n e (1 m g / k g ) and
ethanol (1 g / k g ) , o r for l o n g e r (2-4 days in different a n i m a l s a f t e r injection of morphine in a dose of 6 m g / k g ) ,
and this was followed by weakening of s e l f - s "timulation to the level which e x i s t e d against the background of
t o l e r a n c e . The duration of facilitation of s e l f - s t i m u l a t i o n a f t e r a d m i n i s t r a t i o n of twice the dose of the drug
c o r r e l a t e d directly with the duration of the p e r i o d of development of t o l e r a n c e to it. In one c a s e , a f t e r adm i n i s t r a t i o n of a m p h e t a m i n e , and in two c a s e s a f t e r a d m i n i s t r a t i o n of ethanol, doubling the dose led to a m o r e
f o r c e d weakening of s e l f - s t i m u l a t i o n .
It can be concluded f r o m t h e s e r e s u l t s that r e p e a t e d a d m i n i s t r a t i o n of a m p h e t a m i n e , ethanol, and m o r phine in m i n i m a l d o s e s effective f o r the facilitation of s e l f - s t i m u l a t i o n l e a d s to initial activation of the positive
r e i n f o r c e m e n t s y s t e m , followed by weakening of the r e a c t i v i t y of this s y s t e m to a d m i n i s t r a t i o n of the drugs, and

787

ultimately to the development of tolerance to thmn. The fact that against the background of tolerance developtug to the principal drug, testing drugs in equivalent doses have no activating effect on the positive reinforcement system, i.e., that crossed tolerance is found, may be accepted as evidence that the effect of these drugs
a r e realized through common neurophysiological and neurochernical mechanisms.
The role of activating component in the positive reinforcement systems of the hypothalamus is known to
be played mainly by adrenergic structures [6, 14]. It has been shown that alcohol, amphetamine, and morphine
act in a similar direction on adrenergic structures, increasing the release of adrenergic mediators, causing
changes in reassimilation processes, and leading to a reduction and exhaustion of their reserves [1, 11-13].
Hence, it canbe concluded that the effects of these drugs on the positive reinforcement system are realized
at the hypothalamic level with the aid of adrenergic mechanisms. This fact, in our view, also explains the
development of crossed tolerance to alcohol, amphetamine, and morphine which was obtained in the present
experiments. The unequal periods of development of tolerance to these drugs may be explained by their action
on different stages of adrenergic mediation processes,
LITERATURE

1.
2.
3.
4.
5.

CITED

I . P . Anokhina, in: Abstracts of Proceedings of the 2nd All-Union Conference on the Clinical Picture,
Prevention, and Treatment of Alcoholism and Drug Additions [in Russian], Moscow (1978), pp. 69-72.
Yu. V. Burov and S. A. Borisenko, Byull. ]~ksp. Biol. Med., No. 1, 43 (1976).
S.A. Borisenko, Byull. Eksp. Biol. Med., No. 4, 429 (1977).
Yu. V. Burov and S. A. Borisenko, Farmakol. Toksikol., No. 3, 291 (1979).
E. Gellhorn and G. N. Loofbourrow, Emotions and Emotional Disorders [Russian translation], Moscow

(1966).
6.
7.
8.
9.
10.
11.
12.
13.
14.

788

N.A. Patkina, in: Proceedings of an All-Union Conference on Problems in Higher Nervous Activity [in
Russian], Moscow (1974), pp. 89-90.
N . A . Plokhinskii, Biometrics [in Russian], Moscow (1970).
I . N . Pyatnitskaya, Clinical Aspects of the Study of Narcotics [in Russian], Leningrad (1975).
F. Svec, Pharmacodynamics of Drugs [in Russian], Bratislava (1963).
J. De Groot, The Rat Forebrain in Stereotaxic Coordinates, Amsterdam (1959).
B . E . Leonard, Biochem. Pharmacol., 21, 1289 (1972).
E. Maynert and G. Klingman, J. Pharmacol. Exp. Ther., i_~35, 285 (1962).
L. McGunne, Acta Physiol. Scand., 58, Suppl. 204, 1 (1963).
L. Stein, in: Psychopharmacology. A Review of Progress, Washington (1968), pp. 105-123.