Compulsive methamphetamine taking under punishment is associated with greater cue-induced drug seeking in rats
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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Modeling methamphetamine use disorder and relapse in animals: Short- and long-term epigenetic, transcriptional., and biochemical consequences in the rat brain
2023, Neuroscience and Biobehavioral ReviewsSex- and Brain Region-specific Changes in Gene Expression in Male and Female Rats as Consequences of Methamphetamine Self-administration and Abstinence
2021, NeuroscienceCitation Excerpt :In the present study, we focused on identifying potential sex differences in the expression of several PFC and HIP neuropeptides that have been implicated in psychostimulant addiction (Cadet et al., 2019). We performed SA training procedures (METH SA and withdrawal day) and used METH dose according to our previous publications (Cadet et al., 2016; Torres et al., 2017; Daiwile et al., Hu et al., 2019; Job et al., 2020). Briefly, twenty-four female and male Long Evans rats weighing 350–500 g and 450–600 g, respectively, were used in these experiments.
Compulsive methamphetamine taking and abstinence in the presence of adverse consequences: Epigenetic and transcriptional consequences in the rat brain
2019, Pharmacology Biochemistry and BehaviorCitation Excerpt :We therefore reasoned that these experiments would provide us with a window into ways that these factors might influence drug taking behaviors in the two shock-induced phenotypes described above. We found that these two groups of rats did indeed show differences in gene expression in their DS after a month of withdrawal from METH SA and contingent footshocks (Torres et al., 2017). Specifically, Bdnf, Ngf, Vgf, Trkb, and Ntf3 mRNA levels were increased in the DS of sensitive rats compared to resistant rats at that time.
Behavioral and neural mechanisms underlying habitual and compulsive drug seeking
2018, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :Punishment resistance has also been observed in animals with an extended history of exposure to other types of drugs. Animals with a history of methamphetamine self-administration or alcohol dependence showed increased resistance to footshock punishment (Radke et al., 2017; Seif et al., 2013; Torres et al., 2017). Additionally, using a different type of punishment, several studies found that animals with a long history of oral exposure to alcohol, opiates, or amphetamine became insensitive to the addition of aversive quinine to the solution they self-administered (Heyne, 1996; Heyne and Wolffgramm, 1998; Hopf et al., 2010; Lesscher et al., 2010; Seif et al., 2013; Vendruscolo et al., 2012; Wolffgramm and Heyne, 1991).
Punishment of alcohol-reinforced responding in alcohol preferring P rats reveals a bimodal population: Implications for models of compulsive drug seeking
2018, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :Therefore, it is likely that there are important differences in the factors that lead to punishment-resistant alcohol versus cocaine seeking. However, studies examining the effect of punishment of methamphetamine self-administration have consistently shown no difference in drug intake between groups that are punishment-sensitive or punishment-resistant (Cadet et al., 2016a,b; Torres et al., 2017). In addition, the conflict model has shown that increasing the shock intensity can fully suppress cocaine seeking (Cooper et al., 2007).
Interoceptive Stimulus Effects of Drugs of Abuse
2018, Neural Mechanisms of Addiction
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These authors contributed equally to this work.