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Brain Research 1049

Short communication

Brief access to sweets protect against relapse to cocaine-seeking

Chuang Liu*, Patricia Sue Grigson

Department of Neural and Behavioral Sciences, Pennsylvania State University College of Medicine, H181, 500 University Drive, Hershey, PA 17033, USA

Accepted 9 May 2005

Available online 2 June 2005

Abstract

The availability of alternative rewards can reduce acquisition and maintenance of cocaine self-administration in rats and humans. Once

acquired, however, addiction is an intractable disease where relapse is elicited by exposure to drug-associated cues, the drug itself, or stress.

The present study shows that both cocaine-seeking and drug-induced relapse are significantly reduced when drug-experienced, but abstinent,

rats are given just 5 min daily prior access to a palatable glucose + saccharin mixture. The results suggest that presentation of an alternative

reward may be useful as a therapeutic intervention for cocaine seeking and relapse.

D 2005 Elsevier B.V. All rights reserved.

Theme: Neural basis of behavior

Topic: Drugs of abuse: cocaine

Keywords: Cocaine; Self-administration; Reinstatement; Relapse; Natural reward; Glucose; Saccharin; Rat

Natural rewards and drugs of abuse are readily compared ature-, humidity-, and ventilation-controlled environment

and this reward comparison process affects behavior in rats,

monkeys, and humans. Specifically, drugs of abuse can

devalue natural rewards, leading to a decrease in intake of

sweets, food, or running in a running wheel [6,8,13,15].

Alternatively, the availability of natural rewards such as

food, a palatable solution, or money can attenuate cocaine

self-administration in animals [4,12] and humans [7,9].

While it is important to identify treatment strategies of this

nature to reduce drug intake during maintenance, it is even

more critical to identify treatment strategies that will reduce

drug seeking during relapse. Relapse after withdrawal is a

key impediment to recovery from addiction [14]. Therefore,

a rat model [8,16] was used to test whether brief access to a

palatable glucose + saccharin mixture would reduce both

cocaine-seeking and drug-induced relapse following a 3-

month period of withdrawal.

Twenty-seven male Sprague–Dawley rats (Charles River

Laboratories, Wilmington, MA) weighing 500–630 g at the

start of the experiment were housed individually in

suspended stainless steel cages and maintained in a temper-

0006-8993/$ - see front matter D 2005 Elsevier B.V. All rights reserved.

doi:10.1016/j.brainres.2005.05.013

* Corresponding author. Fax: +1 717 531 6916.

E-mail address: chliu@psu.edu (C. Liu).

under a 12:12-h light/dark cycle (lights on at 7 A.M.). Food

and water were available ad libitum, except where noted

otherwise. The rats were anesthetized with the intramuscular

administration of ketamine hydrochloride (70 mg/kg) and

xylazine hydrochloride (16 mg/kg) and surgically implanted

with a catheter into the right jugular vein using a method

similar to that described previously [8]. The catheter was

then routed subcutaneously to the back and attached to a

coupling assembly. The syringe pump was connected to a

swivel system in the test chambers which enabled the

computer controlled intravenous infusion of cocaine. The

catheters were flushed daily with 0.2 ml sterile heparinized

saline to maintain catheter patency. When indicated,

Propofol (0.1 ml) was administered intravenously to test

for patency. Data were discarded from all rats that failed to

demonstrate rapid anesthesia. Each chamber was equipped

with two retractable sipper tubes. A stimulus light was

located 6 cm above each tube. A lickometer circuit was used

to monitor licking. One week after surgery, rats were placed

on a water-deprivation regimen in which they received

access to distilled water (dH2O) for 5 min each morning and

for 1 h each afternoon in the home cages. Food was available

ad libitum.

(2005) 128 – 131

C. Liu, P.S. Grigson / Brain Research 1049 (2005) 128–131 129

1. Training

The rats were given 5-min access to dH2O in the home

cage and then were placed in the test chambers (MED

Associates, St. Albans, VT). Two empty spouts advanced

for a 1-h self-administration session [8]. The stimulus light

was illuminated above the right spout (active spout) and the

house light was off. The rats were placed on a fixed ratio

(FR) 10 schedule of reinforcement where completion of 10

licks on the active spout led to an intravenous infusion of

0.2 ml of cocaine (0.33 mg/infusion) delivered over a 6-s

period. Drug delivery was signaled by offset of the stimulus

light, retraction of the spout, and onset of the tone and house

light, which remained on for a total of 20 s. Further

responding during this time was not reinforced. Responses

on the left spout (inactive spout) were recorded but had no

programmed consequence. Afternoon water was provided

daily for 1 h, no sooner than 45 min after the rats were

returned to the home cages.

Fig. 1. Brief access to a glucose + saccharin solution from the start of

extinction significantly attenuates cocaine-seeking in cocaine-experienced

rats following 3 months of withdrawal. Shown are mean (TSEM) number of

responses/1 h daily session. (A) Last 3 sessions of mean number of

response/1 h (FR20) on the active spout for cocaine during maintenance

(left panel), during extinction when no drug was delivered (middle panel),

and during reinstatement when non-reinforced responding was elicited by

2. Maintenance

After 10 days of training, in order to better delineate

active from inactive responding, the FR10 was increased to

an FR20 for 4 final sessions. At this point, it was clear that

16 rats acquired very stable cocaine self-administration (i.e.,

inactive spout responding was less than 25% of active spout

responding). This group of rats made significantly more

responses on the active than the inactive spout during

maintenance, F(1,28) = 43.48, P < 0.0001 (see Figs. 1A and

B, left panel). Seven other rats also responded more on the

active than the inactive lever but failed to meet this strict

requirement. Thus, these rats, along with 4 rats that lost

catheter patency, were excluded from the remainder of the

experiment.

an injection of a 5-mg/kg dose of cocaine (right panel). Rats were given 5

min access to either dH2O (>) or G + S (.) immediately prior being placed

in the test chamber. Significant differences are indicated by an asterisk. (B)

Number of responses/1 h session made on the inactive spout across the

same conditions.

3. Withdrawal

The 16 rats were returned to their home cages for a 3-

month period of withdrawal. They were handled at least

three times per week. The rats had free access to food and

water for 80 days, after which the water deprivation

schedule was reinstituted for the last 10 days of the 90-

day withdrawal phase.

4. Extinction

The rats weighed 700.5 T 23.34 g (mean T SEM) at the

start of extinction. They were matched into two groups on

the basis of responding during the maintenance phase.

Eight rats were given 5 min access to dH2O (dH2O group)

and 8 rats were given 5 min access to a palatable [18] 3%

glucose + 0.125% saccharin (G + S group) solution instead

of 5 min morning water in the home cages. Immediately

thereafter, the rats were placed in the test chambers for a 1-

h extinction session. This procedure was repeated for 10

days in succession. Conditions were identical to those

found in the Maintenance section, except that responses on

the active spout did not lead to cocaine infusions. The

results of post hoc Newman–Keuls tests of a significant 2

(G + S, dH2O) � 10 (sessions) mixed factorial analysis of

variance, F(1,14) = 8.20, P < 0.05, revealed that just 5

min access to G + S significantly reduced cocaine seeking

during extinction compared to the water controls across

trials 1–4 (P < 0.05), see Fig. 1A, middle panel. There

was no significant difference in inactive responses between

groups, F < 1, see Fig. 1B, middle panel.

Fig. 2. (A) Mean (TSEM) intake (ml/5 min) of dH2O (dH2O group) or

glucose + saccharin solution (G + S group) in the home cages before placed

in the test chambers across extinction and reinstatement. (B) Mean (TSEM)

intake of total fluid every day in the home cages across extinction and

reinstatement.

C. Liu, P.S. Grigson / Brain Research 1049 (2005) 128–131130

5. Drug-induced reinstatement

In an effort to habituate the rats to the IP injection

procedure, all rats were injected with saline (1 ml/kg) just

prior to being placed in the test chamber on extinction

sessions 8–10. To test for drug-induced reinstatement, this

procedure was repeated on session 11. Twenty-four hours

later, the procedure was repeated for all rats immediately

following an ip injection of cocaine (5 mg/kg). Post hoc

Newman–Keuls test of a 2 (G + S, dH2O) � 2 (cocaine,

saline) � 2 (active, inactive) interaction, F(1,28) = 4.42, P <

0.05, revealed that while drug-induced reinstatement was

robust in the dH2O group, it was fully prevented by prior

access to the palatable G + S solution (P < 0.05), see Fig.

1A, right panel. No differences occurred in inactive

responding between the groups or treatments, P > 0.05,

see Fig. 1B, right panel.

The effect of the palatable G + S solution on the

reduction in cocaine-induced reinstatement cannot be

attributed to differences in fluid balance, as neither 5 min

fluid intake, F(1,14) = 4.02, P > 0.05, nor total fluid intake/

day, F(1,14) = 0.73, P > 0.05, differed between the G + S

group and the dH2O group, see Figs. 2A and B. The

protective effects of the G + S solution also cannot be

attributed to differences in body weight as body weight did

not differ between the two groups by more than 11 g

throughout testing. The rats in the present study were not

food deprived. However, water deprivation usually is

accompanied by a decrease in food intake and food-

deprivation can increase drug self-administration, extinction

responding, and reinstatement [3,17]. It also is unlikely,

however, that a decrease in food deprivation at the time of

testing accounts for the protective effects of the sweet.

Specifically, in a separate experiment (Twining, R.C,

Grigson, P.S. Program No. 237.10. Neuroscience 2004

Abstract, San Diego), a history of brief daily access to 1.0 M

sucrose served to protect against acquisition of cocaine self-

administration regardless of the concentration (low or high)

that was presented on the day of testing. Thus, a Flocal_attenuation of food deprivation at the time of testing cannot

account for the protective effects of the sweet.

The inactive spout responses in the first extinction session

were significantly more than those made during the final

maintenance session in both the G + S group (t(14) = 2.54,

P < 0.05) and the dH2O group (t(14) = 2.87, P < 0.05), see

Fig. 1B. This finding suggests that the rats were activated, in

general, when they were returned to the test chamber for the

first time following 3 months drug-free in the home cage.

Likewise, active spout responses also increased during the

first extinction session relative to responding during the final

maintenance session, but only for the dH2O group (t(14) =

2.38, P < 0.05), not for the rats in the G + S condition (t(14) =

�1.52, P > 0.05), see Fig. 1A. This observation further

demonstrates the effectiveness of the G + S treatment.

Rats drink 3 times more of a 3% glucose + 0.125%

saccharin mixture than they will of each of the components

when presented alone [18]. As such, G + S is recognized as

a highly palatable solution for rats and it has been shown to

reduce cocaine self-administration during acquisition and

maintenance [5]. Our results extend these finding by

showing that even brief access to this alternative reward is

sufficient to greatly reduce cocaine seeking and drug-

induced relapse to cocaine seeking following an extended

period of withdrawal. This finding suggests that even the

brief availability of an alternative reward may be useful not

only in reducing drug self-administration during acquisition

and maintenance [7,9], but also in reducing drug seeking

(i.e., relapse) after extended periods of abstinence in

humans. The discovery of the underlying neural mecha-

nisms by which brief access to an alternative reward comes

to confer such robust protective effects is critical and the

present model will be useful in this pursuit. Whether drugs

and natural rewards activate the same [11] or separate [1,2]

circuits in the brain, the intersection clearly is sufficient for

C. Liu, P.S. Grigson / Brain Research 1049 (2005) 128–131 131

the availability of one reward type to affect responding for

the other. The present paradigm serves as a window on that

intersection. Indeed, in a separate report, we have found that

5 min access to a sweet fully blunts the dopamine peak that

typically follows the first administration of a drug of abuse

(Grigson, P.S., Acharya, N.K. and Hajnal, A. Program No.

119.17. Neuroscience 2004 Abstract, San Diego). Further

study is required to determine additional mechanisms that

may contribute to the protective effects of an alternative

reward during acquisition, maintenance, and importantly

during relapse of drug-seeking behavior. Given that differ-

ent mechanisms have been found to mediate drug-, cue-, and

stress-induced relapse [10,16], future studies also will assess

the protective effects of sweets on cue- and stress-induced

reinstatement of cocaine-seeking behavior.

Acknowledgments

The authors thank Anne E. Baldwin for editing a draft of

the manuscript. This work was supported by PHS grants DA

09815 and DA 12473 from the National Institute on Drug

Abuse (NIDA). We thank NIDA for generously providing

the cocaine hydrochloride.

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