Articles
Uncontrollable Stress Potentiates Morphine’s Rewarding Properties

https://doi.org/10.1016/S0091-3057(98)00027-6Get rights and content

Abstract

Strategies used to explore the role of stressors in drug addiction include measuring stressor’s effects on drug’s rewarding properties. The current investigation explored the effect of an acute stressor on morphine conditioned place preference. Twenty-four hours following either inescapable tail shock or home-cage control treatment, all subjects were conditioned with morphine (0, 1, 2, and 3 mg/kg SC) over 2 days, and later tested for conditioned place preference. Inescapably shocked subjects demonstrated a potentiated place preference compared to controls. The inescapable shock-induced potentiated place preference developed even when conditioning was delayed until 6 and 7 days following the stressor, while no longer occurring after a 14- and 15-day interval. The potentiation was not a result of reduced locomotion in the inescapably shocked subjects, as activity in inescapably shocked and home-cage control subjects was the same following “mock” saline conditioning. Furthermore, the anxiogenic methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) (0.3 mg/kg IP), which produces effects similar to those produced by inescapable shock, also potentiated morphine place preference. In addition, the potentiation in inescapably shocked subjects was dependent upon the stressor’s uncontrollability, as identical escapable shock did not potentiate place preference above control subjects. Finally, the inescapable shock-induced potentiated place preference was drug specific, as amphetamine place preference was not affected.

Section snippets

Subjects

Adult male Sprague–Dawley rats (Harlan–Sprague–Dawley, Inc., Indianapolis, IN) weighing 300–400 g, were housed in groups of two in Plexiglas cages in a climate-controlled colony room of 22°C. The subjects were maintained on a 12 L:12 D cycle, and all experiments were conducted during the light phase. They had free access to food and water prior to and throughout the experiment. All subjects were naive and allowed a minimum of 1 week adaptation followed by 2 days of handling before the beginning

Experiment 1: is effects on morphine-conditioned place preference

The purpose of the first experiment was to measure the effects of an acute stressor on morphine’s rewarding properties, using a paradigm in which the stressor precedes the morphine administration by a substantial period of time. Rats were first given a 20-min preexposure to the test apparatus, and time spent in each compartment was measured. Twenty-four hours later they were given either a session of inescapable tailshocks identical to those used in previous experiments 23, 27, 67, or home-cage

Procedure

On day 1, with the partitions removed, the animal was placed in the neutral area and allowed to explore the entire apparatus for 20 min. The session was video recorded, and the amount of time the rat spent in each environment was measured, using the placement of their front paws as the determining factor. This day served to assess the animals initial preferences and any possible box bias. A criteria was set to eliminate any rat that spent less than 4 min (20% of total time) in either side. On

Results

The results are shown in Fig. 1. Morphine resulted in a dose-dependent place preference, and this conditioned preference was potentiated by prior IS. That is, the subjects spent more time in the drug-paired compartment after conditioning than prior to conditioning, and this increase was greater for the IS-treated subjects. A 4 × 2 ANOVA yielded reliable effects of dose, F(3,52) = 14.06, p < 0.001, and IS, F(1,52) = 9.81, p < 0.01, while the interaction between dose and IS was not reliable, F

Experiment 2: time course of is effects on morphine-conditioned place preference

Experiment 1 demonstrated that IS potently increased the rewarding properties of morphine across a range of doses. Experiment 2 investigated the time course of this effect. Morphine conditioning was carried out either 1 and 2, 4 and 5, 6 and 7, or 14 and 15 days postshock. Investigation of the time course of morphine-conditioned place preference potentiation will allow comparison with other IS effects such as potentiation of morphine analgesia. In addition, if the effect is present at any time

Procedure

Day 1 and 2 procedures were identical to the procedures used in Experiment 1. However, the next 2 days of conditioning occurred either 1 and 2, 4 and 5, 6 and 7, or 14 and 15 days postshock, with a 45-min pairing of 3 mg/kg SC morphine in one context, and 4 h later with a 45-min pairing of 1 ml/kg SC saline vehicle in the other context. On the second day, the order of presentation was reversed. Conditioning assignment was counterbalanced randomly. Testing of preference was conducted over a

Results

The results of the time course experiment are shown in Fig. 2. The results show a clear IS-induced potentiation at the 1- and 2-day interval, with the IS-treated subjects reaching control levels 14 and 15 days after IS. A 2 × 2 ANOVA was first conducted comparing conditioned place preferences on days 1 and 2 with days 14 and 15. This was done because both IS and HCC groups were only used at these time points. The effect of time interval, F(1, 27) = 7.0, p < 0.05, IS, F(1, 27) = 12.71, p < 0.01,

Experiment 3: is effects on activity levels during testing period

Exposure to IS is known to reduce subsequent motor activity for some period of time 16, 28. It is possible that this effect would manifest itself in reduced crossings of the preference test apparatus, possibly resulting in only an “apparent” enhancement of morphine place preference. Perhaps the IS subject remains in the morphine-paired environment because it simply has a reduced tendency to move between compartments. The finding that IS potentiates morphine place preference even 7 days after IS

Procedure

Day 1 was identical to the procedure described in Experiment 1; however, the number of neutral area crossings were measured. On day 2, the stressor procedure was conducted in the same manner as in Experiment 1. On days 3 and 4, saline control mock “conditioning” was administered following the same methods as in the original morphine conditioning in Experiment 1, occurring 24 and 48 h after IS or HCC, with a 45-min pairing of 1 ml/kg SC saline in each context, separated by 4 h. Testing of

Results

Activity changes in HCC- and IS-treated subjects are shown in Fig. 3. A significant reduction of crossings between PE and TP trials was observed for both groups, F(1, 14) = 28.76, p < 0.001. However, IS had no significant effect on the magnitude of this reduction, F(1, 14) p > 1.0. Newman–Keuls post hoc analysis further confirmed that no significant activity differences existed as a function of stressor treatment.

Experiment 4: dmcm + restraint effects on morphine-conditioned place preference

It is possible that IS does not increase the rewarding properties of morphine per se, but rather produces difficult to detect physical injury and persistent pain. IS does stimulate intense motor activity while the subject is confined to the restraint chamber, and injury or inflammation is certainly a potential outcome. Morphine might then produce increased place preference conditioning in IS subjects because it reduces this persistent pain while the subject is in the morphine-paired

Procedure

Day 1 was identical to the procedure described in Experiment 1. On day 2, the inverse benzodiazepine receptor agonist DMCM (0.3 mg/kg IP) or vehicle was administered to separate groups immediately prior to placing subjects in restrainer tubes for a period equal to the shock session. Restraint was used following the administration of DMCM and vehicle to mimic the IS environment as closely as possible, as well as to control for the restraint environment by itself. Conditioning occurred 24 and 48

Results

Place preferences for DMCM and vehicle-treated subjects are shown in Fig. 4. The subjects treated with the inverse benzodiazepine agonist DMCM + restraint showed a significant potentiation of conditioned place preference relative to the subjects who received vehicle + restraint, F(1, 13) = 5.51, p < 0.05.

Experiment 5: stressor controllability effects on morphine-conditioned place preference

Many of the sequelae of IS depend on the uncontrollability of the stressor and do not occur if the tail shock is escapable or controllable 17, 38, 63. This is true of the potentiation of morphine analgesia produced by IS (67). However, the potentiation of morphine-conditioned place preference follows a time course that is different from the effects of IS that have been shown to depend on stressor controllability (Experiment 2). Experiment 5, therefore, explored whether stressor controllability

Apparatus

Escapable and yoked inescapable shocks were administered in small Plexiglas wheel-turn boxes. The entire box was made of clear Plexiglas. A small wheel extended 1.7 cm into the front of the chamber through a hole 8.0 cm from the floor of the box. The wheel required a force of about 0.50 N to turn. The tail of the rat was extended through a slot in the rear wall of the chamber and was taped to a Plexiglas rod parallel to the floor of the chamber. Shock was applied through electrodes attached to

Results

The effects of stressor controllability on morphine-conditioned place preference are depicted in Fig. 5. Yoked IS potentiated morphine conditioned place preference relative to restraint, while ES did not. ANOVA indicated a reliable effect of type of stressor, F(2,24) = 8.19, p < 0.01. Further Newman–Keuls post hoc comparisons also indicated that morphine place preference was greater in the IS than in the ES or restraint group, which did not differ among themselves. Furthermore, the magnitude of

Experiment 6: is effects on amphetamine conditioned place preference

The experiments described above indicate that IS potentiates morphine conditioned place preference conditioning. Whether IS would also augment conditioned place preferences produced by other rewarding drugs is unknown. Dopamine (DA) agonists such as amphetamine also produce conditioned place preference, but interestingly, IS might be expected to have a different effect on amphetamine-conditioned place preference. DA release in the nucleus accumbens has often been implicated as a mediator of the

Procedure

Day 1 was identical to the procedure described in Experiment 1. On day 2, rats were given the same stressor treatment as in Experiment 1 or remained in their home cages. The first of four conditioning sessions began 5 h following the end of the stressor session. The subsequent conditioning sessions were held at the same time of the day separated by approximately 24 h, instead of 4 h as in prior experiments, due to amphetamine having a longer half-life than morphine. Assignment was

Results

Figure 6 shows amphetamine place preference for the various groups. Amphetamine-conditioned place preference showed an orderly increase with amphetamine dose in HCC subjects. This did not occur in IS subjects, and there was no clear amphetamine-conditioned place preference in these subjects at any of the doses. IS did not potentiate amphetamine-conditioned place preference and may have even interfered with amphetamine-conditioned place preference at the 3 mg/kg dose. A 4 × 2 ANOVA yielded no

General Discussion

The results presented here clearly indicate that IS potentiates morphine’s rewarding properties, as measured by conditioned place preference. A significant potentiation of conditioned place preference in the IS-treated animals relative to control levels was observed at two of the three doses tested, while showing a tendency in this direction at the third and lowest dose. The IS-potentiated place preference developed even when conditioning was delayed until 6 and 7 days following the stressor.

Acknowledgements

This research was supported by NIMH Grant MH50479 to Steven Maier. We gratefully acknowledge the assistance of Jason Poole and Colin Zappone.

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