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