Limbic activation to novel versus familiar food cues predicts food preference and alcohol intake

Abstract

Expectation of salient rewards and novelty seeking are processes implicated in substance use disorders but the neurobiological substrates underlying these associations are not well understood. To better understand the regional circuitry of novelty and reward preference, rats were conditioned to pair unique cues with bacon, an initially novel food, or chow, a familiar food. In the same animals, after training, cue-induced brain activity was measured, and the relationships between activity and preference for three rewards, the conditioned foods and ethanol (EtOH), were separately determined. Activity in response to the food paired cues was measured using brain glucose metabolism (BGluM). Rats favoring bacon-paired (BAP) cues had increased BGluM in mesocorticolimbic brain regions after exposure to these cues, while rats favoring chow-paired (CHP) cues showed relative deactivation in these regions. Rats exhibiting BAP cue-induced activation in prefrontal cortex (PFC) also consumed more EtOH while rats with cortical activation in response to CHP cues showed lower EtOH consumption. Additionally, long-term stable expression levels of PFC Grin2a, a subunit of the NMDA receptor, correlated with individual differences in EtOH preference insomuch that rats with high EtOH preference had enduringly low PFC Grin2a mRNA expression. No other glutamatergic, dopaminergic or endocannabinoid genes studied showed this relationship. Overall, these results suggest that natural variation in mesocorticolimbic sensitivity to reward-paired cues underlies behavioral preferences for and vulnerability to alcohol abuse, and support the notion of common neuronal circuits involved in food- and drug-seeking behavior. The findings also provide evidence that PFC NMDA-mediated glutamate signaling may modulate these associations.

Figure 1

Animals were conditioned to chambers paired with bacon or chow, and then scanned using FDG when exposed to each chamber without the paired food-cue. (A) Animals were conditioned to distinct cues using CPP, assessed for sustained cue-preference (Test 1 and 2) and scanned using FDG-μPET (μPET 1 and 2). To reduce neophobia, animals were initially exposed to bacon, along with chow, twice prior to conditioning (Habituation period, Days 3 through 1). (B) On scan days, animals were injected with FDG, and during the uptake phase (~30 minutes), animals were conscious and placed in either the BAP or CHP chamber. Each animal’s BAP and CHP scans occurred on separate days, and the order was random and counter-balanced.

Figure 2

Consumption of appetitive rewards and cue-preference for these rewards. (A) Whereas chow intake was variable, bacon consumption rapidly escalated, then stabilized, and was significantly greater than chow consumption on conditioning Days 1 and 3 (*p < 0.05 compared to chow). (B) After 8-days of conditioning, there was no change in the amount of time spent in the bacon-paired (BAP) chamber. Individual points indicate each animal. The dotted line indicates the mean preference on Pretest. Preferences above baseline indicate bacon cue-preference (dark gray), below indicate chow cue-preference (light gray), and a single animal (black) did not show clear preference.

Figure 3

Brain glucose metabolism (BGluM) during bacon expectation was significantly correlated with bacon chamber preference after conditioning but not before conditioning. (A) Orbital Cortex, (B) Nucleus Accumbens, (C) Ventral Pallidum, (D) Caudate/Putamen, (E) Hypothalamus, (F) Thalamus, (G) Ventral Midbrain and (H) Ventral Pons. (Open circles = Pretest; closed circles = Test Day 1, color-coded to indicate preference-strength; dotted line = fit corresponding to pretest; solid line = fit corresponding to Test Day 1.)

Figure 4

Cortical cue-induced metabolism predicts future preference for an entirely different, yet unfamiliar reward. (A) Regional brain glucose metabolism (BGluM) in response to bacon-paired cues in prefrontal cortex was significantly correlated with 8% ethanol (EtOH) preference. (B) Relative expression of Grin2A mRNA in the prefrontal cortex was negatively correlated with EtOH preference. (In both, dark gray indicates bacon cue-preference while light gray indicates chow cue-proference, see Figure 2B for details.)