706 
PHARMACOLOGY 
jump from a circular platform — a high labora- 
tory stool. The number of animals jumping is 
used as a quantal measure of the degree of de- 
pendence. No analogous test has as yet been de- 
vised for man. 
Shemano and WendeF^ have proposed that 
the Straub reaction be used as a rapid screening 
test for the potential addiction liability of new 
analgesics. They have proposed a use of the 
ratio of the CD50 to the Straub ED50, the 
"Straub-index", as a predictor of human addic- 
tion liability ; it seems to work quite well. 
The rat has been used for many years as one 
of the preferred species in which to study both 
the development of tolerance and physical de- 
pendence and the abstinence syndrome has 
been described in almost as much detail as 
in the monkey. A simple discriminatory train- 
ing test has been used to show both toler- 
ance and abstinence in the rat,^^ ^nd the shak- 
ing behavior seen in abstinence, called "wet 
dog" shakes, has been proposed as a quantita- 
tive measure of abstinence severity.^^ Although 
morphine-like drugs induce a somewhat differ- 
ent profile of effects in the rat than in man, the 
rat is nevertheless an eminently satisfactory 
test animal for the assessment of dependence 
liability. It is much easier to use than the mon- 
key, more feasible for early screening, and the 
parallelism between rat and man is not much 
less than between monkey and man. 
The cat presents some difficulties, since it, as 
well as the tiger and the lion, reacts to mor- 
phine with a profile of stimulatory behavior. 
The pattern is consistent, however, and is re- 
versed by the antagonists. It has not been 
widely used — the mere sight of a cat after a 
morphine injection is enough to make most in- 
vestigators turn to other species for their stud- 
ies. 
A large number of investigations of tolerance 
and physical dependence have been carried out 
with dogs, and methods for the estimation of 
dependence in both the intact and spinal dog 
have been developed at the NIMH Addiction 
Research Center.^^-^^ These techniques in- 
volve infusions of morphine for 8 hours and 
precipitation of abstinence by an antagonist. 
They may have some usefulness as preliminary 
screening techniques. Chronic spinal dogs also 
exhibit a stereotyped withdrawal and have been 
used to screen new analgesics over long periods 
of time. There are obvious difficulties in prepar- 
ing and maintaining spinal preparations and 
this has discouraged widespread use. 
EVALUATION OF 
PSYCHOLOGICAL DEPENDENCE 
Although it had long been thought that the 
measurement of subjective drives in animals 
was not an attainable goal in the forseeable fu- 
ture, recent developments have not only made it 
possible but practical. The development of oper- 
ant-conditioning techniques and the adaptations 
of these techniques to the problems of self ad- 
ministration of drugs by animals have enabled 
investigators to address themselves to the study 
of the phenomenon of psychological dependence 
— drug-seeking behavior. 
One of the simplest animal models for drug- 
seeking behavior was one proposed years ago by 
Spragg,^*' a psychologist working at the Yerkes 
Primate Center. In the course of a study of add- 
tion in chimpanzees, he noticed that his sub- 
jects showed purposive drug-seeking behavior 
after a long period of morphine administration. 
They would clamor to be taken from the cages 
to the injection room and clearly preferred the 
syringe to food when they were both abstinent 
and hungry, whereas shortly after an injection 
they chose food. While this study showed that 
the relief of abstinence is a sufficient reinforce- 
ment -for the drug drive in the primate, the 
question of euphoria as a reinforcement in ani- 
mals remains unanswered. However, the find- 
ings of Tatum and Seevers^^ that dogs develop 
cocaine-seeking behavior is evidence that the 
drug itself serves as a reinforcement since no 
physical dependence develops with cocaine. A 
number of investigators have looked at the elec- 
tive drinking of water or drug solutions by 
chronically morphinized rats as a simple model 
of drug-seeking behavior, but the aversive taste 
of narcotic solutions has confounded the results 
in most cases. 
In 1962 Weeks^*'^^ developed a most ingen- 
ious and practical technique for self administra- 
tion of drugs that has stimulated a large 
number of studies in the rat and the monkey. 
