Elsevier

Physiology & Behavior

Volume 76, Issue 3, July 2002, Pages 353-364
Physiology & Behavior

Augmentation of drug reward by chronic food restriction: Behavioral evidence and underlying mechanisms

https://doi.org/10.1016/S0031-9384(02)00759-XGet rights and content

Abstract

Chronic food restriction and maintenance of low body weight have long been known to increase the self-administration and motor-activating effects of abused drugs. Using a lateral hypothalamic self-stimulation (LHSS) rate-frequency method, it is shown that chronic food restriction augments the rewarding (i.e., threshold lowering) effect of diverse drugs of abuse. Further, the effect is attributed to increased sensitivity of a neural substrate, rather than a change in drug bioavailability or pharmacokinetics, because it is preserved when drugs are injected directly into the lateral cerebral ventricle (intracerebroventricularly). The food restriction regimen that augments drug reward also increases the induction of c-fos, by intracerebroventricular amphetamine, in limbic forebrain dopamine (DA) terminal areas. The possibility of increased DA receptor function is suggested by findings that rewarding and motor-activating effects of direct DA receptor agonists are augmented by food restriction, and the augmented behavioral effects of amphetamine are reversed by an otherwise subthreshold dose of D-1 antagonist. Initial studies of DA receptor-mediated signal transduction, that are focused on the D-2 receptor, suggest increased functional coupling between receptor and G-protein (i.e., quinpirole-stimulated [35S]GTPγS binding) in dorsal striatum. Unlike behavioral sensitization induced by intermittent stress or psychostimulant treatment, which persist indefinitely following induction, the augmenting effect of food restriction abates within 1 week of restored ad libitum feeding and weight gain. The possible involvement of endocrine hormones and/or ‘feeding-related’ neuropeptides, whose levels change dynamically with depletion and repletion of adipose stores, is therefore under investigation. Initial tests have been limited to acute treatments aimed at attenuating the effects of hypoinsulinemia, hypoleptinemia and elevated corticosterone levels in food-restricted rats. None of these treatments has attenuated the behavioral effect of food restriction. While a melanocortin receptor agonist has been found to enhance drug reward, melanocortin receptors do not seem to mediate the augmenting effect of food restriction. Continuing investigations of endocrine adiposity signals, ‘feeding-related’ neuropeptides and dopaminergic signal transduction may further elucidate the way in which drugs of abuse exploit mechanisms that mediate survival-related behavior, and help explain the high comorbidity of drug abuse and eating disorders.

Introduction

One of the goals of preclinical research in drug abuse is the identification of organismic and environmental variables that may increase vulnerability to the reinforcing and addictive properties of drugs. Two of the most intensively researched variables are chronic stress and intermittent drug exposure, both of which sensitize animals to drug challenge [1], [2], [3]. In the majority of instances, sensitization has been demonstrated behaviorally using locomotion or other motor activity measures. While the neuroadaptations underlying behavioral sensitization have yet to be fully characterized, sensitization by prior psychostimulant exposure is accompanied by numerous functional and molecular changes in the mesocorticolimbic dopamine (DA) pathway [2], [3], [4], [5]. Cross-sensitization occurs between stress and psychostimulants, with chronic stress augmenting the nucleus accumbens (NAC) DA release and locomotion induced by psychostimulant challenge [1]. However, the mechanisms underlying the induction of stress and psychostimulant sensitization may differ insofar as adrenalectomy (ADX) selectively prevents stress- [6], [7], [8] and NMDA antagonists selectively prevent psychostimulant-induced sensitization [3], [9] (although the basis of this latter observation is currently under debate [10]).

In addition to stress and drug history, chronic food restriction and maintenance of low body weight have been identified as variables that enhance drug-induced locomotion and self-administration [11], [12], [13]. In fact, this may be just one expression of a close behavioral and neurobiological relationship between ingestive behavior and drug-seeking. For example, the propensity of animals to ingest sweet solution predicts the magnitude of their locomotor and NAC DA response to passively administered psychostimulants [14], [15] and, in some cases, their speed to acquire active self-administration ([16], [17]; however, see [18], [19]). Furthermore, when palatable solutions and drugs are concurrently available, one can modify the reinforcing efficacy of the other; access to sucrose diminishes cocaine self-administration [20] and use of saccharin solution as a conditioned stimulus for drug availability suppresses the ingestion of saccharin [21].

Among the most robust findings indicative of a relationship between ingestive behavior and drug abuse are that chronic food restriction enhances the rewarding [12], [22], [23], [24] locomotor- [13], [23] and cellular-activating effects [25], [26] of abused drugs. The potency of food restriction as a modulator of drug reward is emphasized by the recent finding that DBA/2JIco mice, which are phenotypically less sensitive to amphetamine-induced locomotion and place preference than the C57/BL6J strain, become more sensitive than the C57/BL6J strain following a regimen of food restriction that lowers body weight by 20% [27].

Section snippets

Studies of drug reward in food-restricted rats

Studies conducted in this laboratory have utilized a lateral hypothalamic self-stimulation (LHSS) paradigm to assay drug reward. LHSS is associated with ingestive behavior [28], and the reinforcing efficacy of stimulation can be modulated by food restriction [29], concurrent sweet taste [30] and forced feeding to supersatiety [31]. Drugs of abuse reliably lower the threshold for LHSS (for reviews, see [32], [33]), and this phenomenon is one among many that suggest an association between food

Possible involvement of endocrine and/or neuropeptidergic responses to food restriction

Both insulin and leptin represent adiposity signals that are involved in the CNS response to changes in body weight and energy balance [37]. Food restriction produces marked reductions in circulating insulin and leptin, and either could plausibly be involved in the modulation of drug reward circuitry. The highest densities of leptin and insulin receptors in brain are within the hypothalamic arcuate nucleus (ARC) where leptin is transported from blood via the median eminence [38] and insulin

Food restriction as a stressor

In light of the phenomenon of stress-induced sensitization (see above), it is important to consider whether food restriction exerts its effect on drug reward in its capacity as a stressor. Food-restricted rats have elevated plasma levels of corticosterone [29], and corticosterone levels correlate with propensity to self-administer amphetamine and cocaine [7], [57]. Moreover, ADX blocks the enhanced locomotor response of food-restricted rats to psychostimulant challenge [13], and ketoconazole, a

Involvement of endogenous opioid peptides

The brain opioid system is believed to play an important role in regulating the incentive effects of food [62], [63], [64], and displays a variety of adaptive changes in response to food restriction [65], [66], [67], [68], [69]. In addition, evidence has been obtained to suggest that endogenous opioids are involved in the enhanced perifornical self-stimulation [70] and low dose cocaine self-administration of food-restricted rats [71]. Despite these observations, naltrexone, at a dose that

Studies of brain regional c-fos expression in food-restricted rats

Expression of the immediate early gene c-fos is increased during functional activation of neurons that utilize a variety of intracellular signal transduction pathways [72] and has been used to map the neuroanatomical patterns of cellular activation induced by amphetamine and other drugs [73], [74], [75]. Amphetamine induces the expression of c-fos throughout the terminal fields of the nigrostriatal and mesocorticolimbic DA pathways [74], [76], and the response is dependent upon stimulation of

Possible dopaminergic neuroadaptations

Because all drugs whose rewarding effects had been augmented by food restriction in the experiments cited above increase extracellular concentrations of DA, the augmenting effect on drug reward and c-fos expression could be due to enhanced DA releasability or diminished reuptake. If so, direct DA receptor agonists that bypass the presynaptic DA neurons might be expected to ‘escape’ the augmenting effect of food restriction. However, it was demonstrated that the rewarding effects of the D-1

Summary and conclusions

The findings outlined above suggest that negative energy balance is accompanied by increased sensitivity of a neural substrate for drug reward, and that this increase is maintained until energy balance is restored. It is presumed that the neural substrate is one that normally mediates incentive effects of food, and that the increased sensitivity adaptively serves to lower the stimulus requirements for behavioral approach and reinforcement. The neurobiological mechanisms underlying the

Acknowledgements

Research, by the author, reviewed in this paper was supported by KO2-DA00292 and RO1-DA03956 from NIDA/NIH.

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