Enhanced cocaine-induced locomotor sensitization and intrinsic excitability of NAc medium spiny neurons in adult but not in adolescent rats susceptible to diet-induced obesity

Abstract

Rationale: Basal and diet-induced differences in mesolimbic function, particularly within the nucleus accumbens (NAc), may contribute to human obesity; these differences may be more pronounced in susceptible populations.

Objectives: We examined differences in cocaine-induced behavioral plasticity in rats that are susceptible vs. resistant to diet-induced obesity and basal differences in striatal neuron function in adult and in adolescent obesity-prone and obesity-resistant rats.

Methods: Susceptible and resistant outbred rats were identified based on "junk-food" diet-induced obesity. Then, the induction and expression of cocaine-induced locomotor sensitization, which is mediated by enhanced striatal function and is associated with increased motivation for rewards and reward-paired cues, were evaluated. Basal differences in mesolimbic function were examined in selectively bred obesity-prone and obesity-resistant rats (P70-80 and P30-40) using both cocaine-induced locomotion and whole-cell patch clamping approaches in NAc core medium spiny neurons (MSNs).

Results: In rats that became obese after eating junk-food, the expression of locomotor sensitization was enhanced compared to non-obese rats, with similarly strong responses to 7.5 and 15 mg/kg cocaine. Without diet manipulation, obesity-prone rats were hyper-responsive to the acute locomotor-activating effects of cocaine, and the intrinsic excitability of NAc core MSNs was enhanced by ∼60 % at positive and negative potentials. These differences were present in adult, but not adolescent rats. Post-synaptic glutamatergic transmission was similar between groups.

Conclusions: Mesolimbic systems, particularly NAc MSNs, are hyper-responsive in obesity-prone individuals, and interactions between predisposition and experience influence neurobehavioral plasticity in ways that may promote weight gain and hamper weight loss in susceptible rats.

Keywords: Cocaine; Excitability; Nucleus accumbens; Obesity; Sensitization; Striatum.

Fig. 1

Food intake and weight gain in outbred rats. a Average weekly food intake (±SEM) in Junk-Food Gainers (JF-G) vs. Junk-Food Non-Gainers (JF-N). b Average (±SEM) weekly weight gain in Junk-Food Gainers vs. Junk-Food Non-Gainers. c Weight gain of individual rats (±SEM) after 9 weeks of junk-food. When given access to junk-food, some outbred rats (JF-G, n=7) eat significantly more food (a) and gain more weight (b) than others given the same free access to junk-food (JF-N, n=8). * = p < 0.05

Fig. 2

The induction of locomotor sensitization was similar, but the expression of sensitization after cocaine deprivation was enhanced in Junk-Food Gainers. a Average locomotor response (±SEM) per 5 min after each cocaine injection. b Total locomotion (±SEM) during 40 min after the first and last cocaine injection. c Average locomotor response (±SEM) per 5 min to 7.5 mg/kg cocaine after 14 days of cocaine deprivation (i.e., cocaine “challenge”). d Total locomotion (±SEM) during 40 min after cocaine challenge (7.5 mg/kg) and in response to the first cocaine injection (15 mg/kg). While still on the junk-food diet, Junk-Food Gainers (JF-G, n=7) and Junk-Food Non-Gainers (JF-N, n=7; one Non-Gainer was removed from the study because it developed a urinary tract infection and the treatment required could compromise cocaine metabolism) the induction of locomotor sensitization was similar between groups (a, b). However, Junk-Food Gainers show more robust sensitization than Junk-Food Non-Gainers after 14 days of cocaine deprivation and cocaine challenge (c). In addition, the locomotor response to 7.5 mg/kg cocaine during the challenge was as large as the response to the first injection of 15 mg/kg cocaine in Junk-Food Gainers only. Together, these data show that repeated cocaine exposure produces more robust locomotor sensitization in rats that are susceptible to diet-induced obesity compared to those that are obesity resistant. * = p < 0.05

Fig. 3

Adult obesity-prone rats were more sensitive to the locomotor-activating effects of cocaine than obesity-resistant rats. a Average locomotor response (±SEM) to increasing concentrations of cocaine in adult obesity-prone (OP) and obesity-resistant rats (OR; n=8/group). b Total locomotion (±SEM) during 40 min after each dose of cocaine in adult rats (P70-P80). c Total locomotion (±SEM) during 40 min after each dose of cocaine in adolescent rats (P30-P40; n=10/group). Adult obesity-prone rats showed a stronger locomotor response to cocaine than obesity-resistant rats (i.e., OPs are sensitized compared to ORs) (a,b), consistent with enhance responsivity of mesolimbic circuits. In contrast, cocaine-induced locomotion was similar between groups tested during adolescence. * = p < 0.05

Fig. 4

Intrinsic excitability of MSNs in the NAc core is enhanced in obesity-prone vs. obesity resistant adult, but not adolescent, rats. All data shown are average ±SEM. a Example traces from current-clamp recordings of MSNs from obesity-prone (OP; n=11 cells from 7 rats) and obesity-resistant rats (OR; n=11cells from 8 rats). b The change in membrane potential at each current injection in MSNs from adult rats (−200 pA to 100 pA). Rectification is reduced in MSNs from adult obesity-prone rats, consistent with increased excitability. c The change in membrane potential at each current injection in MSNs from adolescent rats (−200 pA to 100 pA). Rectification was similar in MSNs from adolescent obesity-prone and obesity-resistant rats, suggesting that differences in adulthood emerged after initial development. d The number of action potentials elicited by each current injection (0 to 175 pA). The same current injection elicited more action potentials in MSNs from obesity-prone vs. obesity-resistant rats, consistent with enhanced excitability. e The input resistant was determined by the change in voltage from −50 to +50 pA. Input resistance is greater in MSNs from obesity-prone vs. obesity-resistant rats. f The minimum amount of current injection needed to elicit an action potential (rheobase). The rheobase was lower in MSNs from obesity-prone rats. g Table of basic membrane properties from adult MSNs. Measurements were taken from the first action potential elicited by the minimum current injection. Action potential threshold was determined by the maximum second derivative method. Action potential amplitude is the difference between the action potential threshold and peak. The 1st interspike interval (ISI) is the difference in time between the first two action potentials. The amplitude of the AHP is the difference between the firing threshold and the lowest point of the hyperpolarizing potential of the AHP; * = p < 0.05, ** = p < 0.01.