Cocaine conditioned place preference (CPP) is more persistent in food-restricted than ad libitum fed rats. This study assessed whether food restriction acts during conditioning and/or expression to increase persistence. In Experiment 1, rats were food-restricted during conditioning with a 7.0 mg/kg (i.p.) dose of cocaine. After the first CPP test, half of the rats were switched to ad libitum feeding for three weeks, half remained on food restriction, and this was followed by CPP testing. Rats tested under the ad libitum feeding condition displayed extinction by the fifth test. Their CPP did not reinstate in response to overnight food deprivation or a cocaine prime. Rats maintained on food restriction displayed a persistent CPP. In Experiment 2, rats were ad libitum fed during conditioning with the 7.0 mg/kg dose. In the first test only a trend toward CPP was displayed. Rats maintained under the ad libitum feeding condition did not display a CPP during subsequent testing and did not respond to a cocaine prime. Rats tested under food-restriction also did not display a CPP, but expressed a CPP following a cocaine prime. In Experiment 3, rats were ad libitum fed during conditioning with a 12.0 mg/kg dose. After the first test, half of the rats were switched to food restriction for three weeks. Rats that were maintained under the ad libitum condition displayed extinction by the fourth test. Their CPP was not reinstated by a cocaine prime. Rats tested under food-restriction displayed a persistent CPP. These results indicate that food restriction lowers the threshold dose for cocaine CPP and interacts with a previously acquired CPP to increase its persistence. In so far as CPP models Pavlovian conditioning that contributes to addiction, these results suggest the importance of diet and the physiology of energy balance as modulatory factors.

Rationale Chronic food restriction (FR) increases rewarding effects of abused drugs and persistence of a cocaine-conditioned place preference (CPP). When there is a single daily meal, circadian rhythms are correspondingly entrained, and pre- and postprandial periods are accompanied by different circulating levels of metabolic hormones that modulate brain dopamine function. Objectives The present study assessed whether rewarding effects of d-amphetamine, cocaine, and persistence of cocaine CPP differ between FR subjects tested in the pre- and postprandial period. Materials and methods Rats were stereotaxically implanted with intracerebral microinjection cannulae and an electrode in lateral hypothalamus. Rewarding effects of d-amphetamine and cocaine were assessed using electrical self-stimulation in rats tested 1-4 or 18-21 hrs after the daily meal. Non-implanted subjects acquired a cocaine CPP while ad libitum fed, then were switched to FR and tested for CPP at these same times. Results Rewarding effects of intra-nucleus accumbens (NAc) d-amphetamine, intraventricular cocaine, and persistence of cocaine CPP did not differ between rats tested 18-21 hrs food deprived, when ghrelin and insulin levels were at peak and nadir, respectively, and those tested 1-4 hrs after feeding. Rats that expressed a persistent CPP had elevated levels of p-ERK1, GluA1, and p-Ser845-GluA1 in NAc core, and the latter correlated with CPP expression. Conclusions Psychostimulant reward and persistence of CPP in FR rats are unaffected by time of testing relative to the daily meal. Further, NAc biochemical responses previously associated with enhanced drug responsiveness in FR rats are associated with persistent CPP expression.

Previously, a learning-free measure was used to demonstrate that chronic food restriction (FR) increases the reward magnitude of a wide range of abused drugs. Moreover, a variety of striatal neuroadaptations were detected in FR subjects, some of which are known to be involved in synaptic plasticity but have been ruled out as modulators of acute drug reward magnitude. Little is known about effects of FR on drug-conditioned place preference (CPP) and brain regional mechanisms that may enhance CPP in FR subjects. The purpose of the present study was to compare the expression and persistence of a conditioned place preference (CPP) induced by a relatively low dose of cocaine (7.0 mg/kg, i.p.) in ad libitum fed (AL) and FR rats and take several brain regional biochemical measures following the first CPP conditioning session to probe candidate mechanisms that may underlie the more robust CPP observed in FR subjects. Behaviorally, AL subjects displayed a CPP upon initial testing which extinguished rapidly over the course of subsequent test sessions while CPP in FR subjects persisted. Despite previous reports of elevated BDNF protein in forebrain regions of FR rats, the FR protocol used in the present study did not alter BDNF levels in dorsal hippocampus, nucleus accumbens or medial prefrontal cortex. On the other hand, FR rats, whether injected with cocaine or vehicle, displayed elevated p-ERK1/2 and p-Ser845-GluA1 in dorsal hippocampus. FR rats also displayed elevated p-ERK1/2 in medial prefrontal cortex and elevated p-ERK1 in nucleus accumbens, with further increases produced by cocaine. The one effect observed exclusively in cocaine-treated FR rats was increased p-Ser845-GluA1 in nucleus accumbens. These findings suggest a number of avenues for continuing investigation with potential translational significance.

Rationale When ad libitum fed (AL) rats undergo cocaine place preference conditioning (CPP) but are switched to food-restriction (FR) for testing, CPP is enhanced and preference scores correlate with phosphorylation of AMPA receptor GluA1 at Ser845 in nucleus accumbens (NAc) core. Objectives The present study tested whether a similar association exists in AL rats, and whether an inhibitor of Ca2+-permeable AMPARs blocks CPP expression in either diet group. Materials and methods In Experiments 1-3, AL rats were conditioned with cocaine (12.0 mg/kg, i.p.). Three weeks later, CPP was tested daily and brains were harvested after the 5th test. Western analyses were used to probe for levels of AMPA receptors in NAc. In Experiment 4, AL rats were conditioned, half were switched to FR for testing, and half in each diet group received NAc core microinjection of NASPM (25.0 μg) prior to each test. Results In Experiment 1, CPP expression in AL rats was associated with elevated pSer845-GluA1, GluA1 and GluA2 in NAc. In Experiment 2, the correlation between pSer845-GluA1 and CPP was localized to NAc core. In Experiment 3, pSer845-GluA1 following a CPP test was higher in NAc synaptic membranes of FR relative to AL rats. In Experiment 4, NASPM blocked CPP expression in both diet groups. Conclusions Results support a scheme in which pSer845-GluA1 in NAc core underlies expression of cocaine CPP, and does so by stabilizing or trafficking Ca2+-permeable AMPARs to the synaptic membrane. The more robust CPP of FR rats may result from upregulation of stimulus-induced pSer845-GluA1.

Rationale When ad libitum fed rats undergo cocaine place preference conditioning (CPP) but are switched to food restriction for testing, CPP becomes resistant to extinction and correlates with phosphorylation of AMPA receptor GluA1 at Ser845 in nucleus accumbens (NAc) core. Objectives This study tested whether food restriction increases persistence of morphine CPP and conditioned place aversions (CPA) induced by LiCl and naloxone-precipitated morphine withdrawal. Materials and methods Ad libitum fed rats were conditioned with morphine (6.0 mg/kg, i.p.), LiCl (50.0/75.0 mg/kg, i.p.), or naloxone (1.0 mg/kg, s.c.) 22 hours post-morphine (20.0 mg/kg, s.c.). Half the subjects were then switched to food restriction. Daily testing resumed three weeks later and brains were harvested when one diet group met extinction criterion. Western analyses probed for pSer845-GluA1, pERK1 and pERK2 in NAc. Results Food restriction increased persistence of morphine CPP and preference scores correlated with pSer845-GluA1 in NAc core and shell. LiCl CPA was curtailed by food restriction, yet pSer845-GluA1 and pERK2 were elevated in NAc core of food restricted rats. Food restriction increased persistence of naloxone CPA, elevated pSer845-GluA1 in NAc core and shell, and aversion scores were negatively correlated with pERK1 and pERK2 in NAc core. Conclusions These results suggest that food restriction prolongs responsiveness to environmental contexts paired with subjective effects of both morphine and morphine withdrawal. A mechanistic scheme, attributing these effects to upregulation of pSer845-GluA1, but subject to override by CPA-specific, pERK2-mediated extinction learning, is explored to accommodate opposite effects of food restriction on LiCl and naloxone CPA.