Incubation of Methamphetamine and Palatable Food Craving after Punishment-Induced Abstinence

Abstract

In a rat model of drug craving and relapse, cue-induced drug seeking progressively increases after withdrawal from methamphetamine and other drugs, a phenomenon termed 'incubation of drug craving'. However, current experimental procedures used to study incubation of drug craving do not incorporate negative consequences of drug use, which is a common factor promoting abstinence in humans. Here, we studied whether incubation of methamphetamine craving is observed after suppression of drug seeking by adverse consequences (punishment). We trained rats to self-administer methamphetamine or palatable food for 9 h per day for 14 days; reward delivery was paired with a tone-light cue. Subsequently, for one group within each reward type, 50% of the lever-presses were punished by mild footshock for 9-10 days, whereas for the other group lever-presses were not punished. Shock intensity was gradually increased over time. Next, we assessed cue-induced reward seeking in 1-h extinction sessions on withdrawal days 2 and 21. Response-contingent punishment suppressed extended-access methamphetamine or food self-administration; surprisingly, food-trained rats showed greater resistance to punishment than methamphetamine-trained rats. During the relapse tests, both punished and unpunished methamphetamine-and food-trained rats showed significantly higher cue-induced reward seeking on withdrawal day 21 than on day 2. These results demonstrate that incubation of both methamphetamine and food craving occur after punishment-induced suppression of methamphetamine or palatable food self-administration. Our procedure can be used to investigate mechanisms of relapse to drug and palatable food seeking under conditions that more closely approximate the human condition.

Genome-wide DNA hydroxymethylation identifies potassium channels in the nucleus accumbens as discriminators of methamphetamine addiction and abstinence

“…26,31 Rats were anesthetized with ketamine (50 mg kg , intraperitoneal) and inserted with silastic catheters into the jugular vein. The catheters were attached to a modified 22-gauge cannula that was mounted to the rats' skulls with dental cement.…”

“…26 On the first day of training, the rats were brought to the SA room where they were chronically housed in SA chambers. Rats were randomly assigned to either METH SA or control groups.…”

“…32 METH was dissolved in sterile saline and the rats self-administered the drug at a dose of 0.1 mg kg − 1 per infusion over 3.5 s (0.1 ml per infusion). 26 Control rats (n = 10) self-administered saline (0.1 ml per infusion). The number of infusions per 3 h session was limited to 35 in order to control for potential overdosing.…”

“…In addition, 50% of the reinforced active lever presses resulted in the concurrent delivery of a 0.5-s footshock through the grid floor. 26 The initial footshock was set at 0.18 mA and was increased by 0.06 mA daily up to 0.30 mA. Thereafter, the rats received footshocks of 0.30 mA for 4 days followed by 0.36 mA for another 4 days.…”

“…[20][21][22][23] In addition to changes in the expression of immediate early genes, 4,22 METH can also alter the expression of several neuropeptides including prodynorphin in the METH SA model. 23 Nevertheless, experimental approaches that use all rats that self-administer a drug to measure biochemical or physiological consequences of drugs do not strictly model human conditions [24][25][26] because not all humans who use rewarding drugs become addicted to them. Importantly, criteria for the addiction diagnosis include the persistence of drug taking in the presence of adverse consequences (American Psychiatric Association (APA) and Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM V)) by definition.…”