a-procedure-to-study-effect-prolonged-food-restriction-on-heroin

A Procedure to Study the Effect of Prolonged Food Restriction on Heroin Seeking in Abstinent Rats

In human drug addicts, exposure to drug-associated cues or environments that were previously associated with drug taking can trigger relapse during ...

Concordia University

Neuropeptide Y (NPY), an orexigenic peptide that is released during periods of food restriction, has been shown to have a significant modulatory impact on drug-related behaviors. We have previously reported that both acute food deprivation (FD) and NPY injections can reinstate extinguished drug-seeking behavior, a proposed animal model of relapse to drug abuse. However, it is not clear whether the FD effect on drug seeking is dependent on NPY transmission. Here, we used the reinstatement model to assess the role of NPY Y1 and Y5-receptor-mediated transmission in FD-induced reinstatement of heroin seeking.

A role for neuropeptide Y Y5 but not the Y1-receptor subtype in food deprivation-induced reinstatement of heroin seeking in the rat.

Food deprivation (FD) or restriction augments the locomotor activating and reinforcing effects of drugs of abuse. It has been proposed that these effects might be mediated by FD-induced increase in plasma levels of ghrelin, a 28-amino acid orexigenic peptide demonstrated to functionally interact with the mesolimbic dopaminergic system. However, a role for ghrelin has been demonstrated only with psychostimulant drugs and alcohol associated behaviors. We therefore examined the role of ghrelin in ongoing heroin self-administration and FD-induced reinstatement of extinguished heroin seeking. As expected, infusions of ghrelin [0.0, 1.5 and 3.0 µg/rat, intracerebroventricular (i.c.v.)] produced increases in breakpoints on a progressive ratio schedule of heroin reinforcement. In contrast, central administration of a ghrelin receptor antagonist, [D-Lys-3]-GHRP-6 (0.0, or 20.0 µg/rat, i.c.v.) had no effect on ongoing heroin self-administration under a fixed-ratio 1 schedule, or on FD-induced reinstatement of heroin seeking. These results suggest that signals mediated through ghrelin receptors play a limited role in FD-induced augmentation of heroin reinforcement and reinstatement of extinguished heroin seeking.

A limited role for ghrelin in heroin self-administration and food deprivation-induced reinstatement of heroin seeking in rats.

Previous research with an animal model of relapse has shown that acute food deprivation will reinstate extinguished drug seeking. Recent evidence with humans, however, suggests that chronic food restriction rather than acute food deprivation is related to increases in drug taking and relapse, emphasizing a need for an animal model to elucidate the neural mechanisms mediating the effects of chronic food restriction on drug seeking. Here we studied the effects of chronic food restriction during a period of abstinence on heroin seeking in rats.

The effects of chronic food restriction on cue-induced heroin seeking in abstinent male rats.

The neurotransmitter dopamine (DA) plays a critical role in both priming-and cue-induced reinstatement of extinguished drug-seeking behavior, but its role in stress-induced reinstatement is less clear. Our laboratory has recently demonstrated that systemic administration of the DA D1-like receptor antagonist, SCH 23390, attenuates acute food deprivation (FD) stress-induced reinstatement. The current study was designed to elucidate the brain regions critical to the effect of SCH 23390 on FD stress-induced reinstatement. Rats were trained to press a lever to self-administer heroin (0.1 mg/kg/inf) over a period of 10 days. Following training, heroin was removed leading to an extinction of lever pressing. Next, rats were tested for reinstatement twice, under extinction conditions: once following 21-48 h FD; and once under sated conditions. Prior to testing, SCH 23390 was administered into the nucleus accumbens (NAc) shell (0.0, 0.3, 0.6 μg/side), NAc core (0.0, 0.3, 0.6 μg/side), dorsomedial prefrontal cortex (dmPFC; 0.0, 0.2, 2.0 μg/side), ventromedial prefrontal cortex (vmPFC; 0.0, 2.0 μg/side) or basolateral amygdala (BLA; 0.0, 1.0, 2.0 μg/side). An attenuation of FD-induced reinstatement of heroin seeking was seen in rats injected with SCH 23390 into the NAc shell, dmPFC or BLA, but not into the NAc core or the vmPFC. These findings support the hypothesis that DA transmission through the DA D1-like receptors plays a critical role in stress-induced reinstatement of heroin seeking.

Antagonism of the dopamine D1-like receptor in mesocorticolimbic nuclei attenuates acute food deprivation-induced reinstatement of heroin seeking in rats.

Drug addiction is a chronic disease characterized by recurring episodes of abstinence and relapse. The precise mechanisms underlying this pattern are yet to be elucidated, but stress is thought to be a major factor in relapse. Recently, we reported that rats under withdrawal and exposed to a mild chronic stressor, prolonged food restriction, show increased heroin seeking compared to sated controls. Previous studies demonstrated a critical role for corticotropin-releasing factor (CRF) and corticosterone, hormones involved in the stress response, in acute food deprivation-induced reinstatement of extinguished drug seeking. However, the role of CRF and corticosterone in chronic food restriction-induced augmentation of drug seeking remains unknown. Here, male Long-Evans rats were trained to self-administer heroin for 10 days in operant conditioning chambers. Rats were then removed from the training chambers, and subjected to 14 days of unrestricted (sated rats) or a mildly restricted (FDR rats) access to food, which maintained their body weight (BW) at 90% of their baseline weight. On day 14, different groups of rats were administered a selective CRF1 receptor antagonist (R121919; 0.0, 20.0 mg/kg; s.c.), a non-selective CRF receptor antagonist (α-helical CRF; 0.0, 10.0, 25.0 μg/rat; i.c.v.) or a glucocorticoid receptor antagonist (RU486; 0.0, 30.0 mg/kg; i.p.), and underwent a 1 h drug seeking test under extinction conditions. An additional group of rats was tested following adrenalectomy. All FDR rats showed a statistically significant increase in heroin seeking compared to the sated rats. No statistically significant effects for treatment with α-helical CRF, R121919, RU486 or adrenalectomy were observed. These findings suggest that stress may not be a critical factor in the augmentation of heroin seeking in food-restricted rats.

Firas Sedki

Department of Psychology,
Center for Studies in Behavioural Neurobiology/Groupe de Recherche en Neurobiologie Comportementale,
Department of Psychology, Center for Studies in Behavioural Neurobiology/Groupe de Recherche en Neurobiologie Comportementale

Concordia University

A Procedure to Study the Effect of Prolonged Food Restriction on Heroin Seeking in Abstinent Rats