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Effects of nucleus accumbens insulin inactivation on microstructure of licking for glucose and saccharin in male and female rats

Carr, Kenneth D; Weiner, Sydney P
Insulin of pancreatic origin enters the brain where several regions express a high density of insulin receptors. Functional studies of brain insulin signaling have focused predominantly on hypothalamic regulation of appetite and hippocampal regulation of learning. Recent studies point to involvement of nucleus accumbens (NAc) insulin signaling in a diet-sensitive response to glucose intake and reinforcement of flavor-nutrient learning. The present study used NAc shell microinjection of an insulin inactivating antibody (InsAb) to evaluate effects on the microstructure of licking for flavored 6.1% glucose. In both male and female rats, InsAb had no effect on the number of lick bursts emitted (a measure of motivation and/or satiety), but decreased the size of lick bursts (a measure of reward magnitude) in a series of five 30 min test sessions. This effect persisted beyond microinjection test sessions and was shown to depend on previous flavored glucose consumption under InsAb treatment rather than InsAb treatment alone. This suggests learning of diminished reward value and aligns with the previous finding that InsAb blocks flavor-nutrient learning. Specificity of the InsAb effect for nutrient reward was indicated by failure to affect any parameter of licking for flavored 0.25% saccharin solution. Finally, maintenance of rats on a 'Western' diet for twelve weeks produced a decrease in lick burst size for glucose in male rats, but an increase in lick burst size in females. Possible implications of these results for flavor-nutrient learning, maladaptive consequences of NAc insulin receptor subsensitivity, and the plausible involvement of distinct insulin-regulated mechanisms in NAc are discussed.
PMID: 35247443
ISSN: 1873-507x
CID: 5174832

Homeostatic Regulation of Reward via Synaptic Insertion of Calcium-Permeable AMPA Receptors in Nucleus Accumbens

Carr, Kenneth D
The incentive effects of food and related cues are determined by stimulus properties and the internal state of the organism. Enhanced hedonic reactivity and incentive motivation in energy deficient subjects have been demonstrated in animal models and humans. Defining the neurobiological underpinnings of these state-based modulatory effects could illuminate fundamental mechanisms of adaptive behavior, as well as provide insight into maladaptive consequences of weight loss dieting and the relationship between disturbed eating behavior and substance abuse. This article summarizes research of our laboratory aimed at identifying neuroadaptations induced by chronic food restriction (FR) that increase the reward magnitude of drugs and associated cues. The main findings are that FR decreases basal dopamine (DA) transmission, upregulates signaling downstream of the D1 DA receptor (D1R), and triggers synaptic incorporation of calcium-permeable AMPA receptors (CP-AMPARs) in the nucleus accumbens (NAc). Selective antagonism of CP-AMPARs decreases excitatory postsynaptic currents in NAc medium spiny neurons of FR rats and blocks the enhanced rewarding effects of d-amphetamine and a D1R, but not a D2R, agonist. These results suggest that FR drives CP-AMPARs into the synaptic membrane of D1R-expressing MSNs, possibly as a homeostatic response to reward loss. FR subjects also display diminished aversion for contexts associated with LiCl treatment and centrally infused cocaine. An encompassing, though speculative, hypothesis is that NAc synaptic incorporation of CP-AMPARs in response to food scarcity and other forms of sustained reward loss adaptively increases incentive effects of reward stimuli and, at the same time, diminishes responsiveness to aversive stimuli that have potential to interfere with goal pursuit.
PMID: 32092445
ISSN: 1873-507x
CID: 4324172

Modulatory Effects of Food Restriction on Brain and Behavioral Effects of Abused Drugs

Carr, Kenneth D
Energy homeostasis is achieved, in part, by metabolic signals that regulate the incentive motivating effects of food and its cues, thereby driving or curtailing procurement and consumption. The neural underpinnings of these regulated incentive effects have been identified as elements within the mesolimbic dopamine pathway. A separate line of research has shown that most drugs with abuse liability increase dopamine transmission in this same pathway and thereby reinforce self-administration. Consequently, one might expect shifts in energy balance and metabolic signaling to impact drug abuse risk. Basic science studies have yielded numerous examples of drug responses altered by diet manipulation. Considering the prevalence of weight loss dieting in Western societies, and the anorexigenic effects of many abused drugs themselves, we have focused on CNS and behavioral effects of food restriction in rats. Food restriction has been shown to increase the reward magnitude of diverse drugs of abuse, and these effects have been attributed to neuroadaptations in the dopamine-innervated nucleus accumbens. The changes induced by food restriction include synaptic incorporation of calcium-permeable AMPA receptors and increased signaling downstream of D1 dopamine receptor stimulation. Recent studies suggest a mechanistic model in which concurrent stimulation of D1 and GluA2-lacking AMPA receptors enables increased stimulus-induced trafficking of GluA1/GluA2 AMPARs into the postsynaptic density, thereby increasing the incentive effects of food, drugs, and associated cues. In addition, the established role of AMPA receptor trafficking in enduring synaptic plasticity prompts speculation that drug use during food restriction may more strongly ingrain behavior relative to similar use under free-feeding conditions.
PMID: 32013842
ISSN: 1873-4286
CID: 4301232

Interactions between insulin and diet on striatal dopamine uptake kinetics in rodent brain slices

Patel, Jyoti C; Stouffer, Melissa A; Mancini, Maria; Nicholson, Charles; Carr, Kenneth D; Rice, Margaret E
Diet influences dopamine transmission in motor- and reward-related basal ganglia circuitry. In part, this reflects diet-dependent regulation of circulating and brain insulin levels. Activation of striatal insulin receptors amplifies axonal dopamine release in brain slices, and regulates food preference in vivo. The effect of insulin on dopamine release is indirect, and requires striatal cholinergic interneurons that express insulin receptors. However, insulin also increases dopamine uptake by promoting dopamine transporter (DAT) surface expression, which counteracts enhanced dopamine release. Here we determined the functional consequences of acute insulin exposure and chronic diet-induced changes in insulin on DAT activity after evoked dopamine release in striatal slices from adult ad-libitum fed (AL) rats and mice, and food-restricted (FR) or high-fat/high-sugar obesogenic (OB) diet rats. Uptake kinetics were assessed by fitting evoked dopamine transients to the Michaelis-Menten equation and extracting Cpeak and Vmax . Insulin (30 nM) increased both parameters in the caudate putamen and nucleus accumbens core of AL rats in an insulin receptor- and PI3-kinase-dependent manner. A pure effect of insulin on uptake was unmasked using mice lacking striatal acetylcholine, in which increased Vmax caused a decrease in Cpeak . Diet also influenced Vmax , which was lower in FR versus AL. The effects of insulin on Cpeak and Vmax were amplified by FR but blunted by OB, consistent with opposite consequences of these diets on insulin levels and insulin receptor sensitivity. Overall, these data reveal acute and chronic effects of insulin and diet on dopamine release and uptake that will influence brain reward pathways.
PMID: 29791756
ISSN: 1460-9568
CID: 3129832

Effects of diet and insulin on dopamine transporter activity and expression in rat caudate-putamen, nucleus accumbens, and midbrain

Jones, Kymry T; Woods, Catherine; Zhen, Juan; Antonio, Tamara; Carr, Kenneth; Reith, Maarten E A
Food restriction (FR) and obesogenic (OB) diets are known to alter brain dopamine transmission and exert opposite modulatory effects on behavioral responsiveness to psychostimulant drugs of abuse. Mechanisms underlying these diet effects are not fully understood. In the present study we examined diet effects on expression and function of the dopamine transporter (DAT) in caudate-putamen (CPu), nucleus accumbens (NAc), and midbrain regions. DA uptake by CPu, NAc or midbrain synapto(neuro)somes was measured in vitro with rotating disk electrode voltammetry or with [3 H]DA uptake and was found to correlate with DA transporter (DAT) surface expression, assessed by maximal [3 H]CFT binding and surface biotinylation assays. FR and OB diets were both found to decrease DAT activity in CPu with a corresponding decrease in surface expression but had no effects in the NAc and midbrain. Diet treatments also affected sensitivity to insulin-induced enhancement of DA uptake, with FR producing an increase in CPu and NAc, likely mediated by an observed increase in insulin receptor (InsR) expression, and OB producing a decrease in NAc. The increased expression of InsR in NAc of FR rats was accompanied by increased DA D2 receptor (D2 R) expression, and the decreased DAT expression and function in CPu of OB rats was accompanied by decreased D2 R expression. These results are discussed as partial mechanistic underpinnings of diet-induced adaptations that contribute to altered behavioral sensitivity to psychostimulants that target the DAT
PMID: 27973691
ISSN: 1471-4159
CID: 2363532

Food Restriction Induces Synaptic Incorporation of Calcium-Permeable AMPA Receptors in Nucleus Accumbens

Ouyang, Jiangyong; Carcea, Ioana; Schiavo, Jennifer K; Jones, Kymry T; Rabinowitsch, Ariana; Kolaric, Rhonda; de Vaca, Soledad Cabeza; Froemke, Robert C; Carr, Kenneth D
Chronic food restriction potentiates behavioral and cellular responses to drugs of abuse and D-1 dopamine receptor agonists administered systemically or locally in the nucleus accumbens (NAc). However, the alterations in NAc synaptic transmission underlying these effects are incompletely understood. AMPA receptor trafficking is a major mechanism for regulating synaptic strength, and previous studies have shown that both sucrose and d-amphetamine rapidly alter the abundance of AMPA receptor subunits in the NAc postsynaptic density (PSD) in a manner that differs between food-restricted and ad libitum fed rats. The present study examined whether food restriction, in the absence of reward stimulus challenge, alters AMPAR subunit abundance in the NAc PSD. Food restriction was found to increase surface expression and, specifically, PSD abundance, of GluA1 but not GluA2, suggesting synaptic incorporation of GluA2-lacking Ca2+-permeable AMPARs (CP-AMPARs). Naspm, an antagonist of CP-AMPARs, decreased the amplitude of evoked EPSCs in Nac shell, and blocked the enhanced locomotor response to local microinjection of the D-1 receptor agonist, SKF-82958, in food-restricted, but not ad libitum fed, subjects. Although microinjection of the D-2 receptor agonist, quinpirole, also induced greater locomotor activation in food-restricted than ad libitum fed rats, this effect was not decreased by Naspm. Taken together, the present findings are consistent with synaptic incorporation of CP-AMPARs in D-1 receptor expressing medium spiny neurons in NAc as a mechanistic underpinning of the enhanced responsiveness of food-restricted rats to natural rewards and drugs of abuse
PMID: 28112453
ISSN: 1460-9568
CID: 2418272

Effects of food restriction on expression of place conditioning and biochemical correlates in rat nucleus accumbens

Jung, Caroline; Rabinowitsch, Ariana; Lee, Wei Ting; Zheng, Danielle; de Vaca, Soledad Cabeza; Carr, Kenneth D
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 alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (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 h post-morphine (20.0 mg/kg, s.c.). Half of the subjects were then switched to food restriction. Daily testing resumed 3 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 and 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.
PMID: 27376947
ISSN: 1432-2072
CID: 2211522

Nucleus Accumbens AMPA Receptor Trafficking Upregulated by Food Restriction: An Unintended Target for Drugs of Abuse and Forbidden Foods

Carr, Kenneth D
There is a high rate of comorbidity between eating disorders and substance abuse, and specific evidence that weight-loss dieting can increase risk for binge pathology, rebound excessive weight gain, and initiation and relapse to drug abuse. The present overview discusses basic science findings indicating that chronic food restriction induces dopamine conservation, compensatory upregulation of D-1 dopamine receptor signaling, and synaptic incorporation of calcium-permeable glutamatergic AMPA receptors in nucleus accumbens. Evidence is presented which indicates that these neuroadaptations account for increased incentive effects of food, drugs, and associated environments during food restriction. In addition, these same neuroadaptations underlie upregulation of sucrose- and psychostimulant-induced trafficking of AMPA receptors to the nucleus accumbens postsynaptic density, which may be a mechanistic basis of enduring maladaptive behavior.
PMID: 26744733
ISSN: 2352-1554
CID: 1901222

Insulin receptor activation in the nucleus accumbens reflects nutritive value of a recently ingested meal

Woods, C A; Guttman, Z R; Huang, D; Kolaric, R A; Rabinowitsch, A I; Jones, K T; de Vaca, S Cabeza; Sclafani, A; Carr, K D
With respect to feeding, insulin is typically thought of as a satiety hormone, acting in the hypothalamus to limit ingestive behavior. However, accumulating evidence suggests that insulin also has the ability to alter dopamine release in the striatum and influence food preferences. With increased access to high calorie foods, Western societies have a high prevalence of obesity, accompanied by insulin insensitivity. Little is known about how insulin is trafficked into the brain following food consumption and whether insulin insensitivity in the periphery is mirrored in the central nervous system. We investigated insulin receptor activation in the ventral striatum of rats receiving water or 16% glucose either orally or intragastrically. We also investigated whether glucose-induced insulin receptor activation was altered in food-restricted (FR) or diet-induced obesity (OB) rat models. Lastly, we examined whether insulin plays a significant role in flavor-nutrient preference learning. Glucose intake stimulated a rapid increase in insulin receptor activity in the ventral striatum of FR and ad libitum (AL) fed rats, but not OB rats. Similarly, both AL and FR, but not OB rats demonstrated significant flavor-nutrient preferences. However AL rats receiving brief inhibition of insulin activity during conditioning failed to acquire a significant flavor-nutrient preference. These findings suggest that impaired insulin receptor activation in the ventral striatum may result in inaccurate valuation of nutritive foods, which could lead to overconsumption of food or the selection of foods that don't accurately meet the body's current physiological needs.
PMID: 26988281
ISSN: 1873-507x
CID: 2032102

Cocaine and HIV infection

Chapter by: Cardozo, Timothy; Shmelkov, Sergey V; Carr, Kenneth; Rotrosen, John, Mateu-Gelabert, Pedro; Friedman, Samuel R
in: Biologics to treat substance use disorders : vaccines, monoclonal antibodies, and enzymes by Montoya, Ivan D (Ed)
Cham : Springer, 2016
pp. 75-103
ISBN: 3319231502
CID: 4842782