Elsevier

Physiology & Behavior

Volume 91, Issue 5, 15 August 2007, Pages 459-472
Physiology & Behavior

Review
Chronic food restriction: Enhancing effects on drug reward and striatal cell signaling

https://doi.org/10.1016/j.physbeh.2006.09.021Get rights and content

Abstract

Chronic food restriction (FR) increases behavioral sensitivity to drugs of abuse in animal models and is associated with binge eating, which shares comorbidity with drug abuse, in clinical populations. Behavioral, biochemical and molecular studies conducted in this laboratory to elucidate the functional and mechanistic bases of these phenomena are briefly reviewed. Results obtained to date indicate that FR increases the reward magnitude and locomotor-activating effects of abused drugs, and direct dopamine (DA) receptor agonists, as a result of neuroadaptations rather than changes in drug disposition. Changes in striatal DA dynamics, and postsynaptic cell signaling and gene expression in response to D-1 DA receptor stimulation have been observed. Of particular interest is an upregulation of NMDA receptor-dependent MAP kinase and CaM Kinase II signaling, CREB phosphorylation, and immediate-early and neuropeptide gene expression in nucleus accumbens (NAc) which may facilitate reward-related learning, but also play a role in the genesis of maladaptive goal-directed behaviors. Covariation of altered drug reward sensitivity with body weight loss and recovery suggests a triggering role for one of the endocrine adiposity hormones. However, neither acute nor chronic central infusions of leptin or the melanocortin 3/4 receptor agonist, MTII, have attenuated d-amphetamine reward or locomotor activation in FR rats. Interestingly, chronic intracerebroventricular leptin infusion in ad libitum fed (AL) rats produced a sustained decrease in food intake and body weight that was accompanied by a reversible potentiation of rewarding and locomotor-activating effects of d-amphetamine. This raises the interesting possibility that rapid progressive weight loss is sufficient to increase behavioral sensitivity to drugs of abuse. Whether weight loss produced by leptin infusion produces the same neuroadaptations as experimenter-imposed FR, and whether any of the observed neuroadaptations are necessary for expression of increased behavioral responsiveness to acute drug challenge remain to be investigated.

Section snippets

Effects of chronic FR on measures of drug reward and reward seeking

Early results of this laboratory indicated that chronic FR lowers the electrical brain stimulation reward threshold, in perifornical hypothalamic sites, in a manner that covaries with body weight, suggesting that negative energy balance, and perhaps adipose depletion in particular, triggers neuroadaptations in brain reward circuitry [35]. Subsequent studies implicated endogenous opioid mechanisms [36] and the endocrine adiposity hormones, leptin [37] and insulin [38] in this effect. To

D-1 DA receptor binding, signal transduction, and neuropeptide gene expression

In agreement with the results of a previous autoradiographic study [56], radiologand binding assays, using the D-1 DA receptor antagonist [3H]SCH-23390, indicated no difference between FR and AL subjects with regard to the density or ligand affinity of binding sites in CPu or NAc [65]. Further, unlike behavioral sensitization induced by chronic psychostimulant treatment and stress [e.g., [66], [67], stimulation of adenylyl cyclase activity by SKF-82958 in CPu and NAc was not increased by FR [64]

NMDA receptor involvement in signaling responses to D-1 DA receptor stimulation and relation to mechanisms involved in synaptic plasticity

In striatal medium spiny neurons, the D-1 DA and NMDA glutamate receptors are coexpressed [74], [75] and are functionally associated in controlling excitatory synaptic currents [76], [77], signal transduction [78], gene expression [79], and instrumental [80] and Pavlovian [81] learning. Most importantly, NMDA receptor stimulation activates the ERK cascade [for review, see Ref. [82]], and stimulation of the D-1 DA receptor leads to phosphorylation of the NMDA receptor NR1 subunit [83], thereby

Possible changes in DA synthesis and utilization

There is reason to consider whether the upregulated striatal cell signaling in response to D-1 DA receptor stimulation in FR rats represents a compensatory response to decreased physiological DA release. The decreased basal levels of preprodynorphin and preprotachykinin mRNA observed in NAc of FR relative to AL rats, could be reflective of a persistently lower level of D-1 DA receptor stimulation in these subjects (Fig. 9) [73]. Further, there is the microdialysis result indicating that under

Potential endocrine contributions

A consistently observed characteristic of the enhancing effect of FR on drug reward sensitivity is that it reverses over a period of days/weeks in parallel with body weight recovery when ad libitum access to food is reinstated (e.g., Fig. 2) [42], [47]. This raises the possibility of a role for one of the endocrine adiposity hormones – leptin or insulin – which circulate in plasma and cerebrospinal fluid (CSF) in proportion to body adipose mass [114], [115], penetrate the blood–brain-barrier

Summary and conclusions

In summary, chronic FR increases central sensitivity to drugs of abuse, as evidenced in various assays of drug reward magnitude, locomotor activation, and immediate-early and neuropeptide gene expression in subcortical DA terminal fields. Upregulation of striatal cell signaling upon D-1 DA receptor stimulation represents one set of neuroadaptations associated with FR that may play a role in these effects. The NMDA receptor-dependent activation of CaMK II, ERK 1/2, and CREB have been implicated

Acknowledgements

The author would like to thank Drs. Soledad Cabeza de Vaca, Sandra Haberny, and Yemiliya Berman for the major contributions to the research of the laboratory summarized in this review. Essential support was provided by NIDA/NIH (DA03956 and K02 DA00292).

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