associative tolerance to nicotine analgesia in the rat tail flick and hot plate tests

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Associative tolerance to nicotine analgesia inthe rat: Tail-flick and hot-plate tests

Article in Experimental and Clinical Psychopharmacology · September 1998

Impact Factor: 2.71 · DOI: 10.1037//1064-1297.6.3.248 · Source: PubMed

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Antonio Cepeda-Benito

University of Vermont

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Experimental and Clinical Psvchopliarniat-ology

1998, Vol. 6, No. 3, 248-254

Copyright 1998 by

the

Am

Associative Tolerance to Nicotine Analgesia in the Rat:

Tail-Flick and

Hot-Plate

Tests

Antonio Cepeda-Benito,

Jose Reynoso, and Eric H.

McDaniel

Texas A&M University

Previous

assessments of

associative nicotine

tolerance may have

confounded associative

effects with novelty-induced stress

effects,

instrumental learning

effects,

or both.

That

is,

subjects were

tested in

novel environments, allowed

to

practice

the

test

response, or both

during

the tolerance

development phase.

In the first study, 32 male

Sprague-Dawley rats were

injected

with various doses of

nicotine

and tested for

nociception

in the

tail-flick

and hot-plate

tests to assess nicotine's

analgesic effects.

In the second study, 35 rats

received

nicotine

explicitly paired or unpaired with a distinctive

test

context. A l l animals were equally

preexposed to the test environment, and none had the opportunity to practice the test response.

Paired

rats developed greater nicotine tolerance

than

unpaired rats. This context-dependent

(associative)

tolerance effect was found with both

tail-flick

and hot-plate tests.

Drug tolerance

is a

decrease

in the

effects

of a

drug dose

following

repeated

drug administrations. Drug tolerance

is

central

to the definition of

drug dependence (American

Psychiatric

Association, 1994), and several theorists assign

tolerance, or the mechanisms that produce tolerance, an

important role in the genesis and maintenance of addictive

behaviors (see Ramsay & Woods, 1997;

Trujillo

& Akil.

1995). For example, smokers may smoke more to compen-

sate for the development of tolerance of the reinforcing

effects

of

nicotine. Likewise, tolerance

of the ill

effects

of

nicotine may increase tobacco consumption by allowing

smokers

to smoke more without feeling sick (Alexander &

Hadaway, 1982;

Pomerleau,

1995; Trujillo &

Akil).

Thus,

nicotine tolerance can be a symptom of physical dependence

on nicotine (American Psychiatric Association, 1994) and a

contributor to the severity of the smoker's physical and

psychological

dependence (Pomerleau).

There is considerable evidence that many examples of

drug tolerance represent the operation of classical condition-

ing (Young & Goudie, 1994), and some theorists have

proposed that learning is the primary underlying cause

(Ramsay & Woods, 1997, p. 170) of all drug tolerance

phenomena. Most

of the

support

for the role of classical

conditioning

in the development of

drug tolerance comes

from

investigations of tolerance to the analgesic

effects

of

morphine. In associative tolerance studies, animals

receiv-

ing

morphine explicitly paired with a distinctive test context

Antonio Cepeda-Benito,

Jose

Reynoso, and Eric H. McDaniel,

Department of Psychology, Texas A&M University.

This research was supported by Grant DA10576-01 from the

National

Institute

on

Drug Abuse.

We

thank

Anissa

Norrell,

Thomas Cross,

Andrea

Szabo, Michael Drake,

Eddy

Badrina, Paige

Bonner, Amber

Shipp, Enrique Pizana, Sarah

Manning,

and Jason

Murphy for

help

in

conducting

Ihe experiment.

Correspondence concerning this article

should

be addressed to

Antonio

Cepeda-Benito,

Department of Psychology, Texas A&M

University, College Station, Texas 77843-4235. Electronic mail

may

be sent to [email protected].

are more tolerant to morphine's analgesic effects than

animals receiving

the

same drug exposure regimen

in an

environment other than the distinctive context (e.g., Cepeda-

Benito &

Tiffany,

1996a). The conditioning explanation for

these findings

is

that

the

distinctive context

has

become

a

conditioned stimulus (CS)

that

elicits associative tolerance

effects (Baker &

Tiffany,

1985; Poulos & Cappell,

1991;

Siegel, 1975). Some authors have also proposed that the

interoceptive effects of drugs may also function as CSs

capable

of

producing associative tolerance effects (e.g.,

Cepeda-Benito & Short, 1997; Grisel, Wiertelak, Watkins, &

Maier, 1994).

Despite

the prominence of learning accounts of drug

tolerance, we know of only five studies that

investigated

the

impact of cue

associations

on the

development

of

nicotine

tolerance (Caggiula

et

al, 1991, 1993; Caggiula, Epstein,

Stiller, 1989; Epstein, Caggiula, Perkins, McKenzie, &

Smith, 1991; Epstein, Caggiula, & Stiller, 1989). These

studies investigated tolerance to nicotine's (a) anorectic

effects

(Caggiula et al., 1989, 1991), (b) corticosterone-

elevating effects (Caggiula

et

al., 1991),

(c) tachycardiac

effects (Epstein

et

al., 1991),

and (d)

analgesic effects

(Caggiula et

al.,

1993; Epstein et

al.,

1989). These research-

ers found evidence of nicotine tolerance in subjects tested in

the same context in which they had received repeated

administrations

of

nicotine. However, these subjects failed

to

display tolerance effects when they were tested

in the

presence

of a

novel

set of

contextual stimuli (challenge test).

Thus, the

researchers

concluded that these subjects had

developed a context-dependent, or associative, form of

nicotine tolerance.

Alternatively, when animals

are

tested

in a

novel environ-

ment, an apparent loss of tolerance also may be accounted

for by the presence of novelty-induced stress in the test

situation. That is, environmental stress may interact with a

drug dose to augment the drug effects being measured. For

example, exposure to a novel environment can elevate

corticosterone levels (e.g., Caggiula et al., 1993) or induce

analgesia (e.g., Netto,

Siegfried,

&

Izquierdo, 1987; Sher-

248

https://www.researchgate.net/publication/15328222_Acute_stress_or_corticosterone_administration_reduces_responsiveness_to_nicotine_Implications_for_a_mechanism_of_conditioned_tolerance?el=1_x_8&enrichId=rgreq-99eb7359-a013-480a-9527-99d4119e2b4e&enrichSource=Y292ZXJQYWdlOzEzNTYwNzUxO0FTOjEwMjU4NzMwMjk0MDY4MUAxNDAxNDcwMTI3NTk3https://www.researchgate.net/publication/15328222_Acute_stress_or_corticosterone_administration_reduces_responsiveness_to_nicotine_Implications_for_a_mechanism_of_conditioned_tolerance?el=1_x_8&enrichId=rgreq-99eb7359-a013-480a-9527-99d4119e2b4e&enrichSource=Y292ZXJQYWdlOzEzNTYwNzUxO0FTOjEwMjU4NzMwMjk0MDY4MUAxNDAxNDcwMTI3NTk3https://www.researchgate.net/publication/15328222_Acute_stress_or_corticosterone_administration_reduces_responsiveness_to_nicotine_Implications_for_a_mechanism_of_conditioned_tolerance?el=1_x_8&enrichId=rgreq-99eb7359-a013-480a-9527-99d4119e2b4e&enrichSource=Y292ZXJQYWdlOzEzNTYwNzUxO0FTOjEwMjU4NzMwMjk0MDY4MUAxNDAxNDcwMTI3NTk3https://www.researchgate.net/publication/15328222_Acute_stress_or_corticosterone_administration_reduces_responsiveness_to_nicotine_Implications_for_a_mechanism_of_conditioned_tolerance?el=1_x_8&enrichId=rgreq-99eb7359-a013-480a-9527-99d4119e2b4e&enrichSource=Y292ZXJQYWdlOzEzNTYwNzUxO0FTOjEwMjU4NzMwMjk0MDY4MUAxNDAxNDcwMTI3NTk3https://www.researchgate.net/publication/15328222_Acute_stress_or_corticosterone_administration_reduces_responsiveness_to_nicotine_Implications_for_a_mechanism_of_conditioned_tolerance?el=1_x_8&enrichId=rgreq-99eb7359-a013-480a-9527-99d4119e2b4e&enrichSource=Y292ZXJQYWdlOzEzNTYwNzUxO0FTOjEwMjU4NzMwMjk0MDY4MUAxNDAxNDcwMTI3NTk3https://www.researchgate.net/publication/15328222_Acute_stress_or_corticosterone_administration_reduces_responsiveness_to_nicotine_Implications_for_a_mechanism_of_conditioned_tolerance?el=1_x_8&enrichId=rgreq-99eb7359-a013-480a-9527-99d4119e2b4e&enrichSource=Y292ZXJQYWdlOzEzNTYwNzUxO0FTOjEwMjU4NzMwMjk0MDY4MUAxNDAxNDcwMTI3NTk3https://www.researchgate.net/publication/15328222_Acute_stress_or_corticosterone_administration_reduces_responsiveness_to_nicotine_Implications_for_a_mechanism_of_conditioned_tolerance?el=1_x_8&enrichId=rgreq-99eb7359-a013-480a-9527-99d4119e2b4e&enrichSource=Y292ZXJQYWdlOzEzNTYwNzUxO0FTOjEwMjU4NzMwMjk0MDY4MUAxNDAxNDcwMTI3NTk3https://www.researchgate.net/publication/15328222_Acute_stress_or_corticosterone_administration_reduces_responsiveness_to_nicotine_Implications_for_a_mechanism_of_conditioned_tolerance?el=1_x_8&enrichId=rgreq-99eb7359-a013-480a-9527-99d4119e2b4e&enrichSource=Y292ZXJQYWdlOzEzNTYwNzUxO0FTOjEwMjU4NzMwMjk0MDY4MUAxNDAxNDcwMTI3NTk3https://www.researchgate.net/publication/15328222_Acute_stress_or_corticosterone_administration_reduces_responsiveness_to_nicotine_Implications_for_a_mechanism_of_conditioned_tolerance?el=1_x_8&enrichId=rgreq-99eb7359-a013-480a-9527-99d4119e2b4e&enrichSource=Y292ZXJQYWdlOzEzNTYwNzUxO0FTOjEwMjU4NzMwMjk0MDY4MUAxNDAxNDcwMTI3NTk3https://www.researchgate.net/publication/15328222_Acute_stress_or_corticosterone_administration_reduces_responsiveness_to_nicotine_Implications_for_a_mechanism_of_conditioned_tolerance?el=1_x_8&enrichId=rgreq-99eb7359-a013-480a-9527-99d4119e2b4e&enrichSource=Y292ZXJQYWdlOzEzNTYwNzUxO0FTOjEwMjU4NzMwMjk0MDY4MUAxNDAxNDcwMTI3NTk3https://www.researchgate.net/publication/15328222_Acute_stress_or_corticosterone_administration_reduces_responsiveness_to_nicotine_Implications_for_a_mechanism_of_conditioned_tolerance?el=1_x_8&enrichId=rgreq-99eb7359-a013-480a-9527-99d4119e2b4e&enrichSource=Y292ZXJQYWdlOzEzNTYwNzUxO0FTOjEwMjU4NzMwMjk0MDY4MUAxNDAxNDcwMTI3NTk3https://www.researchgate.net/publication/15328222_Acute_stress_or_corticosterone_administration_reduces_responsiveness_to_nicotine_Implications_for_a_mechanism_of_conditioned_tolerance?el=1_x_8&enrichId=rgreq-99eb7359-a013-480a-9527-99d4119e2b4e&enrichSource=Y292ZXJQYWdlOzEzNTYwNzUxO0FTOjEwMjU4NzMwMjk0MDY4MUAxNDAxNDcwMTI3NTk3https://www.researchgate.net/publication/15328222_Acute_stress_or_corticosterone_administration_reduces_responsiveness_to_nicotine_Implications_for_a_mechanism_of_conditioned_tolerance?el=1_x_8&enrichId=rgreq-99eb7359-a013-480a-9527-99d4119e2b4e&enrichSource=Y292ZXJQYWdlOzEzNTYwNzUxO0FTOjEwMjU4NzMwMjk0MDY4MUAxNDAxNDcwMTI3NTk3https://www.researchgate.net/publication/15328222_Acute_stress_or_corticosterone_administration_reduces_responsiveness_to_nicotine_Implications_for_a_mechanism_of_conditioned_tolerance?el=1_x_8&enrichId=rgreq-99eb7359-a013-480a-9527-99d4119e2b4e&enrichSource=Y292ZXJQYWdlOzEzNTYwNzUxO0FTOjEwMjU4NzMwMjk0MDY4MUAxNDAxNDcwMTI3NTk3https://www.researchgate.net/publication/15328222_Acute_stress_or_corticosterone_administration_reduces_responsiveness_to_nicotine_Implications_for_a_mechanism_of_conditioned_tolerance?el=1_x_8&enrichId=rgreq-99eb7359-a013-480a-9527-99d4119e2b4e&enrichSource=Y292ZXJQYWdlOzEzNTYwNzUxO0FTOjEwMjU4NzMwMjk0MDY4MUAxNDAxNDcwMTI3NTk3https://www.researchgate.net/publication/15328222_Acute_stress_or_corticosterone_administration_reduces_responsiveness_to_nicotine_Implications_for_a_mechanism_of_conditioned_tolerance?el=1_x_8&enrichId=rgreq-99eb7359-a013-480a-9527-99d4119e2b4e&enrichSource=Y292ZXJQYWdlOzEzNTYwNzUxO0FTOjEwMjU4NzMwMjk0MDY4MUAxNDAxNDcwMTI3NTk3https://www.researchgate.net/publication/20657075_Environment-specific_tolerance_to_nicotine?el=1_x_8&enrichId=rgreq-99eb7359-a013-480a-9527-99d4119e2b4e&enrichSource=Y292ZXJQYWdlOzEzNTYwNzUxO0FTOjEwMjU4NzMwMjk0MDY4MUAxNDAxNDcwMTI3NTk3


3/8

TOLERANCE

TO NICOTINE

ANALGESIA

IN THE RAT

249

man,

1979). Various investigations have demonstrated that

some examples

of

context-specific drug tolerance

may

reflect the presence of stress

effects

rather than the presence

of absence of associative tolerance

effects

(e.g., Bardo &

Hughes, 1979; Sherman, 1979; Sherman, Proctor, & Strub,

1982).

In the two studies that investigated the development of

tolerance to the analgesic effects of nicotine (Caggiula et

al.,

1993; Epstein et

al.,

1989), the subjects were allowed to

practice

the

test response during

the

tolerance development

phase. This method could be problematic because

animals

permitted to practice a task while drugged can develop more

tolerance to the disruptive

effects

of the drug on perfor-

mance than animals given as much drug but without the

opportunity

for

drugged practice (sec reviews

by

Goudie

&

Demellweek, 1986;

Wolgin,

1989;

Young

& Goudie, 1994).

Some investigators have argued that this intoxicated-

practice

effect

represents

the

operation

of

instrumental

conditioning resulting in the learning of specific compensa-

tions for drug-induced disruptions in performance, that is,

behavioral contingent tolerance (e.g., LeBlanc,

Gibbins,

&

Kalant, 1973).

In all fairness,

some theorists

do not

concep-

tually differentiate between instrumental and associative

forms

of

drug tolerance (see Poulos

&

Cappell, 1991).

Our main objective was to obtain contextual nicotine

tolerance

effects by

using procedures

that

minimize

the

influence

of novelty and

instrumental

confounding factors

during testing. Given that nicotine has analgesic properties

(e.g., Rogers & Iwamoto, 1993), we modeled our procedures

after those of studies that have produced robust associative

tolerance to morphine's analgesic

effects

(e.g., Carter

Tiffany,

1996; Cepeda-Benito &

Tiffany,

1992, 1996a,

1996b).

In

these associative tolerance studies,

the influence

of

novelty-induced stress

was

controlled

or minimijed by

extensively prchabituating the animals to the experimental

and tolerance assessment procedures (sec also Ramsay &

Woods, 1997). These associative tolerance investigations

also showed that intoxicated practice is not

necessary

for the

production of robust associative tolerance (e.g., Cepeda-

Benito

& Tiffany,

1992).

Study 1

We

designed

Study

1 to verify

that

we

could assess

nicotine's

antinociceptive effects in a

dose-dependent man-

ner

with tail-flick

and

hot-plate devices. Although

it is

generally accepted that nicotine reliably produces analgesic

effects in

rats,

in

some cases

the

antinociceptive

effects of

nicotine in the tail-flick test have not been observed (e.g.,

Yang,

Wu, & Zbuzek, 1992). Unlike previous dose-related

analyses (Caggiula, Epstein, Perkins, & Saylor, 1995; Rog-

ers & Iwamoto, 1993), our analyses attempted to minimize

stress

factors during

the

test session

by

extensively prehabitu-

ating

the

rats

to the

experimental procedures

and the

test

environment.

Epstein et al.

(1989) demonstrated

the

presence

of

toler-

ance

of nicotine's

analgesic

effects by

snowing that

with

repealed administrations, nicotine lost its

ability

to increase

tail-withdrawal

latencies.

In order to

establish

the

specificity

or generality of this reported nicotine tolerance effect in

tail-flick reflexes, we measured responses mediated both

spinally (tail flick) and supraspinally (hot plate).

Method

Subjects. The

subjects,

32

experimentally naive, male Sprague-

Dawley rats, weighed between 300 and 350 g at the beginning of

the experiment. They were

housed

individually

in plastic

cages

with a bed of wood shavings.

The

colony was constantly illumi-

nated, and the rats had continuous access to food and water in their

home cages.

Drugs. Nicotine bitartrate was dissolved in physiological sa-

line

to

produce

the

following nicotine concentrations: 0.125, 0.25,

0.375, 0.50, 0.60,

and

0.75,

mg/ml. All

solutions were

subcutane-

ously injected in the scruff of the neck (1 ml/kg of body weight).

Tail-jllck analgesia

assessment.

The

tail-nick

test

measures

the

latency for the rat to move its tail away

from

a hot beam of light

(e.g.,

Cepeda-Benito &

Tiffany, 1996a).

A rat was

restrained

in an

opaque cylinder (6.8

x 22 cm)

that

had a

Plexiglas base (5.5

X 22

cm). Ventilation

holes

were made on top of and in front of the tube.

The rat's tail

protruded

from the back of the tube and was placed in

a

grooved plate such that

the

tail

was

directly under

the

light source

(HTC tail

flick,

model

33B).

When

the rat

moved

its

tail away from

the

light beam,

a

photosensitive cell tripped

a

timer

and the

tail-flick latency was automatically

recorded.

To avoid interactions

between tail area stimulated and degree of analgesia (Yoburn,

Morales, Kelly, & Inturrisi,

1984),

each

assessment

was the mean

of three consecutive trials with the location of the beam

being

varied

among the proximal, middle, and distal thirds of the rat's

tail.

The

beam intensity

was

adjusted such that undrugged animals

nicked their tails

at

about

4 s. A 15-s limit was

used

to

prevent

damage to the tail. The tester was blind to the rat's group condition.

Hot-plate analgesia

assessment. The hot-plate test measures a

rat's latency to lick a paw or

jump

(e.g., Caggiula el al., 1995;

Cepeda-Benito

&

Tiffany, 1996b;

Krank,

1987).

A rat was

confined

to the hot-plate's surface in a chamber (30 X 30 X30 cm) with a

clear Plexiglass lid. The hot plate consisted of a metal surface

thermostatically

controlled to a

constant temperature

of 50° C

(IITT hot

plate, model 35D).

Two independent observers,

blind

to

the

rat's

group condition,

timed

to the nearest

hundredth

of a

second

each rat's

latency

to

either

lick a paw or

jump, whichever

came

first

(e.g., Krank).

The response

latency

was the

mean

of the

two observations. The median difference between observers was 1.47 s.

Rats were removed

from

the hot plate as soon as they either licked a paw

or jumped. Animals that neither licked a paw nor jumped after 60 s were

removed

from the

apparatus

to

prevent tissue

damage.

Tail-flick prehahituation and

testing phase.

After

1

week

of

accommodation to their new home environment, the rats

were

weighed once daily for 3 days and weighed twice daily for an

additional

3

days. Rats were then habituated

to

injection

and

mock-testing procedures. Rats

received

five saline injections paired

with

a

distinctive context

and five

saline injections paired with

their

home cage environment.

The

interval between distinctive context

injections

was 48

hr. Each home

cage

injection

was

given

24 hr

after

each

distinctive

context

exposure. For distinctive context

exposures, each rat was weighed, individually carried in a small

plastic container to the distinctive context room, injected with

saline, placed inside

a

tube,

placed in a

dark cabinet,

and

mock

tested in the tail-flick device 4, 8, and

13

min after the injection. In

the distinctive

context room,

the

room's light

was

dimmed,

apple-cinnamon air

fresheners scented

the

holding cabinet,

and

white noise was continuously played. Rats were not removed from

their holding tubes. Each

mock

tail-flick test consisted of placing

https://www.researchgate.net/publication/20657075_Environment-specific_tolerance_to_nicotine?el=1_x_8&enrichId=rgreq-99eb7359-a013-480a-9527-99d4119e2b4e&enrichSource=Y292ZXJQYWdlOzEzNTYwNzUxO0FTOjEwMjU4NzMwMjk0MDY4MUAxNDAxNDcwMTI3NTk3https://www.researchgate.net/publication/20657075_Environment-specific_tolerance_to_nicotine?el=1_x_8&enrichId=rgreq-99eb7359-a013-480a-9527-99d4119e2b4e&enrichSource=Y292ZXJQYWdlOzEzNTYwNzUxO0FTOjEwMjU4NzMwMjk0MDY4MUAxNDAxNDcwMTI3NTk3https://www.researchgate.net/publication/20657075_Environment-specific_tolerance_to_nicotine?el=1_x_8&enrichId=rgreq-99eb7359-a013-480a-9527-99d4119e2b4e&enrichSource=Y292ZXJQYWdlOzEzNTYwNzUxO0FTOjEwMjU4NzMwMjk0MDY4MUAxNDAxNDcwMTI3NTk3


4/8

250

CEPEDA

BENITO,

REYNOSO, AND

McDANIEL

the rat in the

tail -f l ick

apparatus an d going through th e motions of

conducting three

tail - f l ick tests

i.e., without aiming

the l ighl

beam

at the

tail).

Af te r

each mock test,

the rats

were returned

to the

scented cabinets. Rats were returned

to

their home cage environ-

ments 3 3 minafter

th e

last mock lesl. For home cage

injections ,

th e

rats were individually weighed

and

placed back

in their

home

cages. Each

rat was

then removed from

its

home cage, injected with

saline, and

returned

to its

cage.

Rats

were

tested

in the

distinctive context

48 hr

after

the

fifth

distinctive context exposure session

(or 24 hr

after

the

last home

cage injection). Rats were randomly divided into five groups, with

on e group receiving saline an d each

r e m a i n i n g

group receiving a

different test dose

of

nicotine (0.25, 0.5, 0.6,

and

0.75 mg/kg). Rats

were tested in actual

tail-flick

trials 4, 8, and 13 m in after being

injected with nicotine.

Hot-plale prehabituation and testing phase. Rats began

five

additional d is t inc t ive

context

exposure

sessions 48 hr after

they

were tested with the tail-flick device. Except for mock tests, these

exposure sessions were identical to the

tail -f l ick

exposure sessions.

For

each mock

test,

the rat was removed

from

it s tube a nd placed on

a nonfunctional ho t plate for 60 s. The rat was then placed back

inside its tube and returned to the scented cabinet. Rats received

saline injections

in

their home cage environment

24 hr

after each

distinctive

context exposure.

Rats were tested

in the

distinctive context

48 hr

after

th e

last

distinctive context exposure session

(or 24 hr

after

the

last home

cage injection). Rats were randomly divided

into five

groups,

with

one

group

r ece iv ing

saline an d each remaining group receiving a

different

dose

of

nicotine

(0.125,

0.25,

0.375, and

0.50

mg/kg) .

Rats were tested

in actual hot-plate trials 4, 8, and 13 min

after

being injected with nicotine.

Results

Animals responded to

nicotine

in a

dose-related

manner.

Thai is, tail-flick and

hot-plate

latencies increased as nico-

tine doses were raised. Figure 1A

tail-flick

test)

and

Figure

2A

hot

plate test) depict the

mean

response

latencies

for

each nicotine

dose

at each testing point. Figures

1B

and 2B

depict mean dose-response curves across the three testing

points.

Within

each

testing

method, mean

latencies

across

the assessments conducted

4, 8, and 13 min

after

the nicotine

injections were

subjected to simple

regression

analysis

(Cohen

& Cohen, 1975). Latencies were

regressed

on log

dose level of nicotine. These analyses showed statistically

significant effects with both

the

tail-flick

test, tf

2

=

.23,

F(\, 24) = 1.12,p


5/8

TOLERANCE

TO

NICOTINE ANALGESIA

IN THE RAT

251

A

Hot-Plate Test

60

50

oj

« 40

30

20

10

.25

nic

.125

nic

saline

B

Testing Time min)

Dose-Response

Curve

13

60

„

50

o

40

30

D

ra 20

10

0.125 0.25 0.375 0.5

Logarithmic Scale of Nicotine Dose mg/kg)

Figure

2. Hot-plate latencies. Each point represents the

mean

hot-plate latency obtained for each nicotine (nic) dose at each

testing time

after

nicotine administration

A) and

across testing

times (B). The

horizontal

bar represents the mean latency for

animals injected with saline.

Brror

bars depict

SE

above and below

the

mean.

The

interval between context exposures

was 72

hr. During

the 2

days that followed each

context

exposure session,

rats

received

a

daily injection

in

their home cage environment.

DC

rats received

nicotine

in the

distinctive context

an d

saline

in the

home cage

environment. HC rats received saline in the distinctive context and

nicotine and saline for the first and second home cage injections,

respectively.

SC rats received saline in both

environments.

Tolerance development in the hot-plate phase. Following the

tail-flick

test sessions, animals received two daily saline injections

in

their home cages for 2 days. Then,

each

rat was given 5

injections

paired with the distinctive context and 20 injections in its

home

cage environment. That is, the ratio of saline to nicotine

injections

was greater in the hot-plate phase

than

in the

tail-flick

phase. Previous research has shown

that

these cues can support

associative tolerance

effects in HC

animals (e.g.,

Cepeda-Benito &

Tiffany, 1995). After observing

high

levels

of

tolerance

in HC

rats

in

the

tail-flick

assay,

we

were concerned that

H C

rats were

using

injection

cues to support associative tolerance

effects.

Therefore.

we reduced the likelihood of rats receiving nicotine in the presence

of

injection cues.

The interval between context exposures continued to be 72 hr,

bu t

home cage injections were administered twice daily

after

each

distinctive

context exposure. The first of the home cage injections

consisted

of

nicotine

for the HC

animals.

All

other home cage

injections consisted

of saline for these

animals.

The

interinjection

interval for

each

daily

pair

of

home cage injections

was 4 hr. DC

animals continued

to

receive nicotine

in the

distinctive context

and

saline for their home cage injections. SC animals received saline in

both environments. All other experimental procedures were the

same as those used in the hot-plate prehabituation phase of Study

1.

Tail-flick an d hot-plate analgesia assessments.

Analgesia

as -

sessments were identical to those conducted in Study 1. Each rat

received a

1 - m g / k g

dose

of nicotine

and was

tested

4,

8,

and

13

m in

after

the injection. Tail-flick and hot-plate test sessions were

conducted 72 hr after the eighth and last

nicotine

context pairings,

respectively.

Data analysis. Within each testing method, the data were

studied

with

a one-between,

one-within

repeated measures analy-

ses of variance. Mean response latency was the dependent variable,

group

Condition

was the

betweenfactor,

an d

testing

time was the

within

factor. To

control

fo r

heterogeneity

of covariance

across

repeated measures, we used the Greenhouse-Geisser (1959) tech-

nique

to adjust the degrees of freedom for the error terms.

Following a

priori

directional hypothesis , we

compared mean

response latencies between SC and HC rats and between HC and

DC

rats.

Results

Tail

flick.

Figure

3

depicts

mean tail-flick

latencies

for

each

group of rats at each of the three testing

times.

The

tail-flick

latencies

differed between groups and

declined

with the passage of time, and this decline was

not uniform

across groups. This description

of the

results

was

corrobo-

rated by a significant condition effect, F(2, 32) — 16.00, p <

.001,

a significant

time effect, F(2,

64) = 49.99

;

p


6/8

252 CEPEDA-BENITO, REYNOSO, AND

McDANIEL

0.95. p > .05. However, tail-flick latency decrements were

significantly

higher for HC

rats

than for SC rats

(M ~

3.25,

SD

= 3.47), f(21) =

2.88, p


7/8

TOLERANCE

TO

NICOTINE ANALGESIA

IN THE RAT

253

design. First, testing

of the

same rats

first in the

tail-flick test

and then in the hot-plate test did not allow us to compare

tolerance effect sizes across both testing methods. That is,

the tail-flick

test

was given after 8 conditioning sessions,

whereas the hot-plate test was given after 14 nicotine

context

pairings. Therefore, any

effect

size differences

between the two methods could not be interpreted. More-

over,

we did not control for the possibility that testing of the

rats

in the tail-flick

test

first

could have

influenced the

hot-plate

test

results.

These

problems could have been

avoided by counterbalancing the order of testing across

measurements

or by

testing independent groups

of

rats

in

each testing device. Nevertheless, we believe that it is safe to

affirm that the order of testing docs not compromise our

interpretation of the results. That is, compared to DC rats,

HC

rats

had a lower probability of receiving nicotine inside

the distinctive context and a higher probability of receiving

nicotine outside the distinctive context in both test sessions.

Both sets

of

probabilities

are

congruent with

the

prediction

that DC

animals would develop

a

stronger context-drug

association than

HC

animals (see Rescorla

&

Wagner,

1972).

The experimental design also could have been improved

by including

a

placebo test control group

for

each

of the

three conditions, SC, HC, and DC. Given that we repeatedly

paired

the

testing environment with nicotine

for DC but not

SC and HC rats, undrugged control latencies could have

helped

to

clarify

whether the context

effects

were attribut-

able to differential changes in distinctive context baseline

latencies across groups.

For

example,

the

development

of

contextual tolerance could have been mediated

by a

condi-

tioned hyperalgesic response (e.g., Siegel, 1975).

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Received November

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Accepted March 25, 1998

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associative tolerance to nicotine analgesia in the rat tail flick and hot plate tests

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