Elsevier

Behavioural Brain Research

Volume 326, 30 May 2017, Pages 265-271
Behavioural Brain Research

Compulsive methamphetamine taking under punishment is associated with greater cue-induced drug seeking in rats

https://doi.org/10.1016/j.bbr.2017.03.009Get rights and content

Highlights

  • A rat model that mimics negative events associated with METH addiction is presented.

  • It used contingent punishments with mild footshocks during self-administration.

  • This model distinguishes two addiction-like phenotypes: high and low METH takers.

  • We identified potential differences in relapse-like behaviors in the two phenotypes.

  • Compulsive drug-taking is positively correlated with greater incubation of METH craving.

Abstract

Methamphetamine (METH) addicts lose control over drug consumption despite suffering multiple adverse medicolegal consequences. To mimic the negative events associated with drug addiction in humans, we recently introduced a rat model of self-administration (SA) with response-contingent punishment on METH intake. These procedures allowed us to distinguish between two addiction-like phenotypes in rats, those that sustained METH taking despite negative consequences (shock-resistant, SR) and rats that significantly reduced their METH intake (shock-sensitive, SS). Here, we further developed our adverse consequence model and examined incubation of METH craving by measuring cue-induced drug seeking in SR and SS rats. Male Sprague–Dawley rats were trained to self-administer METH (0.1 mg/kg/injection) or saline intravenously (i.v.) during twenty-two 9-h sessions that consisted of 3 separate 3-h sessions separated by 30 min. Subsequently, rats were subjected to incremental footshocks during thirteen additional 9-h METH SA sessions performed in a fashion identical to the training phase. Cue-induced drug craving was then assessed at 2 and 21 days after the footshock phase. All rats escalated their intake of METH, with both phenotypes showing similar drug taking patterns during SA training. In addition, rats that continued their METH intake despite negative consequences showed even greater cue-induced drug craving following withdrawal than the rats that reduced METH intake following negative consequences. Taken together, our adverse consequence-based model highlights the possibility of identifying rats by addiction-like phenotypes and subsequent vulnerability to relapse-like behaviors. The use of similar SA models should help in the development of better therapeutic approaches to treat different stages of METH addiction.

Introduction

Methamphetamine (METH) addiction is a serious neuropsychiatric disorder characterized by deficits in executive function, impairments in motor control, and in memory formation [1], [2]. Additionally, clinical research has shown that METH addicts can relapse to drug taking despite long periods of abstinence [3], [4]. These clinical observations have led to sustained research activities aimed at developing therapeutic approaches to reduce relapse rates [5], [6] that are related to both individual and environmental factors [7], [8]. Using self-administration (SA) procedures, several groups of investigators have measured cue-induced drug-seeking behaviors termed ‘incubation of drug craving’ [9], [10] as a rodent model to represent the propensity of human drug seeking after periods of sustained abstinence. In this model, animals show increases in the number of presses on drug-associated levers after various time intervals of withdrawal from drug SA [10], [11], [12]. Rats that undergo METH SA also show incubation of craving when presented with drug-associated cues and contexts [11], [12], [13], [14]. Nevertheless, experimental approaches used to study cue-induced drug craving have not, for the most part, included contingent negative consequences known to be associated with drug addiction [10], [15]. These negative outcomes are among factors that can lead to abstinence in some patients [16]. Moreover, continuation of compulsive drug use despite adverse consequences is an important criterion often used to reach a diagnosis of drug addiction in humans [17], [18], [19].

To mimic the negative consequences associated with addiction in humans, we recently used contingent punishments with mild footshocks during METH SA. These procedures allowed us to distinguish between two distinct phenotypes in rats, namely animals that continue to take METH despite negative outcomes (shock-resistant, SR) and rats that significantly reduce their METH intake (shock-sensitive, SS) [20], [21]. In the present study, we used the same model in order to identify potential differences in relapse-like behaviors in the two phenotypes. We thought it likely that SR rats which show compulsive METH taking behaviors in the presence of mild footshocks might also show higher cue-induced drug seeking than SS rats which developed abstinence. To test this possibility, we measured cue-induced drug-seeking behavior at two different intervals of withdrawal from METH SA. Herein, we report that compulsive drug-taking is positively correlated with greater incubation of METH craving. In agreement with our previous work, these results further implicate the notion of developing more clinically relevant models to study the human condition of drug addiction.

Section snippets

Animals and intravenous surgery

Male Sprague-Dawley rats (Charles River, Raleigh, NC), weighing 350–400 g, were used in these experiments. Rats were group-housed (two per cage) for 1 week before surgery and maintained in the animal facility under a reversed 12:12 h light/dark cycle with freely available (home-cage) food and water. Before surgery, rats were anesthetized with a ketamine/xylazine mixture (50 and 5 mg/kg, i.p., respectively) and were inserted with catheters into the jugular vein, as described previously [20].

METH SA caused rapid escalation and maintenance of METH intake

Fig. 1A illustrates the timeline of our study. Fig. 1B, shows the number of METH infusions taken during the training period of 22 days. The statistical analysis for infusions included the between-subject factor of group (SR, SS, and controls) and the within-subject factor of SA session (days 1–22). All rats significantly escalated their METH intake during the first 9 days of METH SA training [F (16,144) = 5.85, p < 0.01] (Fig. 1B). Newman-Keuls post-hoc tests revealed significant increases in active

Discussion

The major findings of this study include: [i] demonstration that adverse consequences can help to segregate rats into distinct phenotypes of METH intake based on their resistance or sensitivity to contingent footshock punishments during SA sessions; and [ii] cue-induced drug seeking behavior after suppression of METH SA by contingent mild punishment was more prominent in a subpopulation of animals that had continued to lever press for METH despite incremental footshock punishments.

The major

Conclusions

In conclusion, we demonstrate that mild footshocks can cause the segregation of rats with distinct addiction-like phenotypes, with some rats becoming compulsive METH takers and other rats developing significant reduction of their METH intake in the presence of adverse consequences. We found, in addition, that cue-induced drug craving is more prominent in rats with the compulsive drug taking phenotype. In contrast, rats with reduced intake showed decreased incubation of METH craving. Taken

Authors contributions

JLC and OVT conceived and designed the experiments. OVT wrote the NIDA/IRP-ACUC protocol. BL, MM, INK and OVT performed the rodent METH SA training. JLC, OVT and SJ prepared the manuscript.

Disclosure/conflict of interest

All the authors declare no competing financial interests or conflicts of interest.

Acknowledgment

This research was supported by funds of the Intramural Research Program of the DHHS/NIH/NIDA.

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    These authors contributed equally to this work.

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