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DOI: Background: Monosodium glutamate MSG is a flavour enhancer which induces behavioural changes in animals. However the influence of sex on the behavioural response to MSG has not been investigated. Methods: Mice were assigned to three groups , based on the models used to assess behaviours. Animals in group 1 were for the elevated-plus maze and tail-suspension paradigms, group 2 for the open-field and forced-swim paradigms, while mice in group 3 were for observation in the conditioned place preference paradigm. At the end of the behavioural tests, the animals were sacrificed, and blood was taken for estimation of glutamate levels. The brains were also homogenised for estimation of glutamate levels. Postconditioning MSG-associated place-preference was significantly higher in females. Conclusion: Repeated MSG administration alters a range of behaviours in a sex-dependent manner in mice. Keywords: Anxiolytic , central inhibition , depression , glutamate , sex , stereotypy. Stock conference working group sex differences in obesity and the regulation of energy homeostasis. Obes Rev ; J Chem Neuroanat ; Sex differences in glutamate receptor gene expression in major depression and suicide. Mol Psychiatry ; Sex differences in aripiprazole sensitization from adolescence to adulthood. Pharmacol Biochem Behav ; Genetic basis for sex differences in obesity and lipid metabolism. Annu Rev Nutr ; Sex differences in obesity and mental health. Curr Psychiatry Rep ; Diabetes and gender. Diabetologia ; Narrative review: ketosis-prone type 2 diabetes mellitus. Ann Intern Med ; Sex differences in autism spectrum disorders. Curr Opin Neurol ; Sex hormones and macronutrient metabolism. Crit Rev Food Sci Nutr ; Sex differences in GABAergic gene expression occur in the anterior cingulate cortex in schizophrenia. Schizophr Res ; Sex differences in psychiatric disease: a focus on the glutamate system. Front Mol Neurosc ; Anesthesia increases circulating glutamate in neurosurgical patients. Acta Neurochir ; Regional variations and the effects of age and gender on glutamate concentrations in the human brain. Magn Reson Imaging ; Homeostasis of glutamate in brain fluids: an accelerated brain-to-blood efflux of excess glutamate is produced by blood glutamate scavenging and offers protection from neuropathologies. Neuroscience ; Chemical heterogeneity of the living human brain: a proton MR spectroscopy study on the effects of sex, age, and brain region. Neuroimage ; In vivo glutamate measured with magnetic resonance spectroscopy: behavioral correlates in aging. Neurobiol Aging ; Sex differences in gamma-aminobutyric acid and glutamate concentrations in discrete rat brain nuclei. Neurosci Lett ; Gender differences in spatial learning, synaptic activity, and long-term potentiation in the hippocampus in rats: molecular mechanisms. ACS Chem Neurosci ; 6: Umami: a delicious flavour formed by convergence of taste and olfactory pathways in the human brain. European J Neurosci ; Acute low dose monosodium glutamate retards novelty induced behaviours in male Swiss albino mice. J Neurosci Behav Health ; 3: Foraging enrichment modulates open field response to monosodium glutamate in mice. Ann Neurosci ; Pathophysiology ; AIMS Neuroscience ; 3: Monosodium glutamate-associated alterations in open field, anxiety-related and conditioned place preference behaviours in mice. Naunyn Schmiedebergs Arch Pharmacol ; Neonatal monosodium glutamate treatment alters both the activity and the sensitivity of the rat hypothalamo-pituitary-adrenocortical axis. J Endocrinol ; Chronic administration of monosodium glutamate under chronic variable stress impaired hypothalamic-pituitary-adrenal axis function in rats. Korean J Physiol Pharmacol ; Monosodium glutamate neurotoxicity increases beta amyloid in the rat hippocampus: a potential role for cyclic AMP protein kinase. NeuroToxicol ; Neonatal treatment with monosodium glutamate lastingly facilitates spreading depression in the rat cortex. Life Sciences ; Excitotoxicity triggered by neonatal monosodium glutamate treatment and blood-brain barrier function. Arch Med Res ; Sex differences in brain cholinergic activity in MSG-obese rats submitted to exercise. Can J Physiol Pharmacol ; The blood-brain barrier and glutamate. Activation of the gut-brain axis by dietary glutamate and physiologic significance in energy homeostasis. Monosodium glutamate, a food additive, induces depressive-like and anxiogenic-like behaviors in young rats. Life Sci Diphenyl diselenide ameliorates monosodium glutamate induced anxiety-like behavior in rats by modulating hippocampal BDNF-Akt pathway and uptake of GABA and serotonin neurotransmitters. Physiol Behav ; Monosodium glutamate and treadmill exercise: anxiety-like behavior and spreading depression features in young adult rats. Nutr Neurosci ; The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology ; Zinc deficiency induces behavioral alterations in the tail suspension test in mice. Effect of antidepressants. Pharmacol Rep ; Behavioural despair in mice: A primary screening test for antidepressants. Arch Int Pharmacodyn Ther ; Antidepressant-like properties of zinc in rodent forced swim test. Brain Res Bull ; Trends in place preference conditioning with a cross-indexed bibliography: Neurosci Biobehav Rev ; Sex-Specific and estrous cycle-dependent antidepressant-like effects and hippocampal akt signaling of leptin. Endocrinology ; An introduction to behavioral endocrinology. Sunderland: Sinauer Associates Strain, sex, and open-field behavior: factors underlying the genetic susceptibility to helplessness. Behav Brain Res ; Mouse estrous cycle identification tool and images. Sex differences in the regulation of body weight. Sex-based differences in phagocyte metabolic profile in rats with monosodium glutamate-induced obesity. Sci Rep ; 8: Friedman JM. Mol Metab ; Glutamate mediates the function of melanocortin receptor 4 on Sim1 neurons in body weight regulation. Cell Metab ; Glutamate and GABA in appetite regulation. Front Endocrinol ; 4: Neuroreport ; MSG intake suppresses weight gain, fat deposition, and plasma leptin levels in male Sprague-Dawley rats. Transport of glutamate and other amino acids at the blood-brain barrier. J Nutr ; SS. VI Determination of factors affecting glutamate concentrations in the whole blood of healthy human volunteers. J Neurosurg Anesthesiol ; Elevated plus maze and Y-maze behavioral effects of subchronic, oral low dose monosodium glutamate in Swiss albino mice. Influence of social isolation, gender, strain, and prior novelty on plus-maze behaviour in mice. Strain and gender differences in the behavior of mouse lines commonly used in transgenic studies. Generalized anxiety disorder: comorbidity, comparative biology and treatment. J Neuropsychopharmacol ; 5: The loss of glutamate-GABA harmony in anxiety disorders. IntechOpen: London The role of glutamate in anxiety and related disorders. CNS Spectr ; Sex differences in stress response circuitry activation dependent on female hormonal cycle. J Neurosci ; Sex differences in cognitive regulation of psychosocial achievement stress: brain and behavior. Hum Brain Mapp ; Sex differences in anxiety disorders: Interactions between fear, stress, and gonadal hormones. Horm Behav ; Factor analysis shows that female rat behaviour is characterized primarily by activity, male rats are driven by sex and anxiety. Changes in open-field activity and novelty-seeking behavior in periadolescent rats neonatally treated with monosodium glutamate. Neurotox Res ; Modulation of locomotor activity by NMDA receptors in the nucleus accumbens core and shell regions of the rat. Brain Res ; Caffeine and sleep-deprivation mediated changes in open-field behaviours, stress response and antioxidant status in mice. Sleep Sci ; 9: Neonatal treatment with monosodium glutamate does not alter grooming behavior induced by novelty or adrenocorticotropic hormone. Behav Neural Biol ; A unique hormonal and behavioral hyporesponsivity to both forced novelty and d-amphetamine in periadolescent mice. Neuropharmacol ; Sex differences and the organisation of juvenile social play behaviour. J Neuroendocrinol ; Sex differences in juvenile mouse social behavior are influenced by sex chromosomes and social context. Genes Brain Behav ; Anxiogenic effect of central CCK administration is attenuated by chronic fluoxetine or ipsapirone treatment. Neuropharmacology ; Evidence for Pavlovian conditioning of cocaine-induced responses linked to emotional behavioral effects. Pharmacol Biochem Behav 80 : The clinical antidepressant effect of exogenous agmatine is not reversed by parachlorophenylalanine: a pilot study. Acta Neuropsychiatr ; Human Mol Genetic ; Psychopharmacol ; Sex differences in antidepressant response in recent antidepressant clinical trials. J Clin Psychopharmacol ; Sex differences in drug abuse. Frontiers in Neuroendocrinol ; Sex differences and ovarian hormones in animal models of drug dependence. Hormones and Behavior ; Females are more vulnerable to drug abuse than males: evidence from preclinical studies and the role of ovarian hormones. Curr Topin Behav Neurosci ; 8: Behavioral and neurochemical characterization of mice deficient in the phosphodiesterase-1B PDE1B enzyme. Glutamatergic mechanisms in addiction. Mol Psychiatry ; 8: Effect of glutamate receptor antagonists on place aversion induced by naloxone in single-dose morphine- treated rats. Br J Pharmacol ; Inhibition of vesicular glutamate transporters contributes to attenuate methamphetamine-induced conditioned place preference in rats. Addiction and the brain: the neurobiology of compulsion and its persistence. Nat Rev Neurosci ; 2: Neuroplasticity in the mesolimbic dopamine system and cocaine addiction. British J Pharmacol ; The nucleus accumbens: gateway for limbic structures to reach the motor system? Progress Brain Res ; Abstract: Background: Monosodium glutamate MSG is a flavour enhancer which induces behavioural changes in animals. Neuromodulation techniques, including transcranial magnetic stimulation TMS , transcranial direct current stimulation tDCS , transcranial alternating current stimulation tACS , magnetic seizure therapy MST , electroconvulsive therapy ECT , theta burst stimulation TBS , vagus nerve stimulation VNS , and deep brain stimulation DBS , have been widely employed in the therapeutic management of prevalent psychiatric conditions such Download Article. Graphical Abstract. Lovejoy JC, Sainsbury A. Link JC, Reue K. Hawkins RA. Nelson RJ. PLoS One ; 7e Shi H, Clegg DJ. Delgado TC. Kondoh T, Torii K. Smith QR. Adriani W, Laviola G. To CT, Bagdy G. Shopsin B. Belzung C, Barreau S. Becker JB, Hu M. Current Psychopharmacology. Close Print this page. Content: Citation Only. Citation and Abstract. Close About this journal. Neuromodulation for the treatment of psychiatric disorders Neuromodulation techniques, including transcranial magnetic stimulation TMS , transcranial direct current stimulation tDCS , transcranial alternating current stimulation tACS , magnetic seizure therapy MST , electroconvulsive therapy ECT , theta burst stimulation TBS , vagus nerve stimulation VNS , and deep brain stimulation DBS , have been widely employed in the therapeutic management of prevalent psychiatric conditions such Guest Editor s : Dr. Wei Zheng. Current Bioactive Compounds. Current Cancer Drug Targets. Current Cancer Therapy Reviews. Current Diabetes Reviews. Current Drug Safety. Current Drug Targets. Current Drug Therapy. View More. Interventional Pain Surgery. Endoscopy and Fetoscopy Techniques for the Brain and Neuroaxis. Article Metrics. Journal Information. About Journal Editorial Board Volumes. For Authors. For Editors. For Reviewers. Explore Articles. Open Access. Open Access Articles. For Visitors. 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Natural Rewards, Neuroplasticity, and Non-Drug Addictions

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Official websites use. Share sensitive information only on official, secure websites. Corresponding Author: Christopher M. Olsen, Ph. There is a high degree of overlap between brain regions involved in processing natural rewards and drugs of abuse. Like drug addiction, non-drug addictions manifest in symptoms including craving, impaired control over the behavior, tolerance, withdrawal, and high rates of relapse. These alterations in behavior suggest that plasticity may be occurring in brain regions associated with drug addiction. In this review, I summarize data demonstrating that exposure to non-drug rewards can alter neural plasticity in regions of the brain that are affected by drugs of abuse. Research suggests that there are several similarities between neuroplasticity induced by natural and drug rewards and that, depending on the reward, repeated exposure to natural rewards might induce neuroplasticity that either promotes or counteracts addictive behavior. Keywords: novelty seeking, addiction, motivation, reinforcement, behavioral addiction, plasticity. There are now myriad television shows documenting people who compulsively engage in behaviors that may otherwise be considered normal, but do so in a manner that has a serious negative impact on their lives and those of their families. While the subjects of these television shows may seem like extreme and rare cases, these types of disorders are surprisingly common. More recently, there has been a trend toward thinking about these non-drug addictions to be more like substance abuse and dependence Rogers and Smit, ; Wang et al , b ; Volkow and Wise, ; Grant et al. In fact, non-drug addictions fit the classical definition of addiction that includes engaging in the behavior despite serious negative consequences Holden, ; Hyman et al , Within this category, a Behavioral Addictions category has been proposed, which would include pathological gambling and potentially internet addiction APA , ; O'Brien, ; Tao et al , Like substance addictions, non-drug addictions manifest in similar psychological and behavioral patterns including craving, impaired control over the behavior, tolerance, withdrawal, and high rates of relapse Marks, ; Lejoyeux et al , ; National Institute on Drug Abuse NIDA et al , ; Potenza, Similarities between drugs and non-drug rewards can also be seen physiologically. Functional neuroimaging studies in humans have shown that gambling Breiter et al , , shopping Knutson et al , , orgasm Komisaruk et al , , playing video games Koepp et al , ; Hoeft et al , and the sight of appetizing food Wang et al , a activate many of the same brain regions i. This article will review preclinical evidence that natural reinforcers are capable of leading to plasticity in behavior and neurotransmission that is often reminiscent of adaptations seen following exposure to drugs of abuse, especially psychostimulants. For the sake of the present review, plasticity will be broadly defined as any adaptation in behavior or neural function, similar to the usage of the term originally described by William James James, Synaptic plasticity will refer to an alteration at the level of the synapse, typically measured using electrophysiological methods e. Neurochemical plasticity will refer to altered neurotransmission synaptic or intracellular measured biochemically by differences in basal or evoked levels of transmitter, receptor, or transporter, or by an enduring change in phosphorylation state of any of these molecules. Behavioral plasticity will refer to any adaptation in behavior several examples are discussed in Section 1. Evidence for this hijacking is seen in several forms of plasticity in brain regions known to affect motivation, executive function, and reward processing Kalivas and O'Brien, ; Thomas et al , ; Frascella et al , ; Koob and Volkow, ; Pierce and Vanderschuren, ; Russo et al , Animal models have given us a snapshot of the profound changes that administration of drugs of abuse can impart. Adaptations range from altered neurotransmitter levels to altered cell morphology and changes in transcriptional activity Robinson and Kolb, ; Kalivas et al , ; Russo et al. Several groups have also reported drugs of abuse altering synaptic plasticity in key regions of the brain implicated in drug addiction for review, see Winder et al , ; Kauer and Malenka, ; Luscher and Bellone, ; Thomas et al. The majority of the neuroadaptations described have been in regions of the mesocorticolimbic system and the extended amygdala Grueter et al , ; Schramm-Sapyta et al , ; Kauer and Malenka, ; Kalivas et al. Based on known roles of these regions in regulation of mood, processing of natural rewards, and motivated behavior, it is widely believed that this plasticity underlies the maladaptive changes in behavior associated with addiction. In humans, some of these changes include impaired decision making, decreased pleasure from natural rewards anhedonia , and craving Majewska, ; Bechara, ; O'Brien, In animal models, these altered behaviors can be studied with neurobehavioral measures following a history of drug administration, and analogous brain regions are thought to mediate these measures Markou and Koob, ; Shaham et al , ; Bevins and Besheer, ; Winstanley, These measures provide the basis for preclinical testing of pharmacotherapies that may be useful in the treatment of addiction. Recent evidence suggests that non-drug addictions may lead to neuroadaptations similar to those reported with long-term drug use. While the majority of these examples of plasticity are emerging from animal studies, reports also include examples from human studies. In this review, we will explore the concept that natural rewards are capable of inducing neural and behavioral plasticity in ways analogous to drug addiction. In the field of drug addiction, several theories have emerged to explain how neural and behavioral plasticity contribute to addiction. One theory is that of incentive-sensitization Robinson and Berridge, , , According to this theory, in susceptible individuals, repeated drug exposure leads to a sensitization reverse tolerance of the incentive-motivational properties of drugs and drug-related cues. This alteration is at least in part mediated by sensitized nucleus accumbens NAc dopamine DA release following exposure to drug-related cues. Behaviorally, this is associated with increased wanting and craving of drugs when one is exposed to cues that are associated with intake i. In animal models, incentive sensitization can be modeled by measuring drug-seeking behaviors in response to cues paired with drug administration Robinson and Berridge, Locomotor sensitization also occurs with repeated administration of several drugs of abuse and may be an indirect measure of incentive sensitization, although locomotor and incentive sensitization are dissociable processes Robinson and Berridge, Notably, sensitization processes can also translate between drug and non-drug rewards Fiorino and Phillips, ; Avena and Hoebel, b ; Robinson and Berridge, In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in or compulsive engagement in non-drug rewards such as gambling, shopping, or sex Evans et al , ; Aiken, ; Lader, Another theory that has been developed to explain how drug-related plasticity contributes to addiction is the opponent process theory Solomon, ; Koob et al , ; Koob and Le Moal, Briefly, this theory of motivation states that there are two processes engaged during repeated experiences: the first involves affective or hedonic habituation, the second process is an affective or hedonic withdrawal Solomon and Corbit, An example provided by Solomon related to opiate use, where tolerance developed to the acute hedonic effects following repeated drug exposure, and negative symptoms of withdrawal would emerge which would further motivate drug use negative reinforcement Solomon, This early version of the theory was originally developed to explain behavior altered by exposure to both drug and non-drug rewards for review, see Solomon, An expansion of opponent process theory is the allostatic model of brain motivational systems Koob and Le Moal, , Briefly, this model includes the opposing concepts of reward and anti-reward, while the latter involves a failure to return to a homeostatic set point, leading to negative affect and reduction in natural reward, which increases motivation to relieve this state Koob and Le Moal, Evidence for neuroplasticity that regulates this altered affective state comes from several findings, including decreased basal NAc DA following drug withdrawal in rats Weiss et al , , decreased striatal D2 receptors in striatum and accumbens of human alcoholics and abstinent heroin addicts Volkow et al. In addition to alterations in mesolimbic DA signaling, central stress systems are also recruited. A particularly robust example is increased CRF signaling in the hypothalamus, central nucleus of the amygdala, and bed nucleus of the stria terminalis following withdrawal of many drugs of abuse Koob and Le Moal, A third theory to describe neuroplasticity contributing to addiction is the recruitment of habit-based neurocircuitry throughout repeated drug exposure Everitt et al , ; Everitt et al , ; Graybiel, ; Ostlund and Balleine, ; Pierce and Vanderschuren, For example, non-human primates self-administering cocaine show changes in glucose metabolism and levels of dopamine D2 receptor and dopamine transporter that initially affect the ventral striatum, but with increasing exposure expand into the dorsal striatum Porrino et al , a ; Porrino et al , b. This progressive plasticity from ventral to dorsal striatum parallels an older literature on the transition from goal- to habit-based learning Balleine and Dickinson, and has an anatomical correlate that supports the ability of extended reward-based learning to engage progressively more dorsal aspects of the striatum Haber et al , Perhaps the most extensively studied reward is that of food. Food is the quintessential reward in many rodent studies and has been used as a reinforcer in procedures such as operant self-administration tasks, runway tests, maze learning, gambling tasks, and place conditioning Skinner, ; Ettenberg and Camp, ; Kandel et al , ; Kelley, ; Tzschentke, ; Zeeb et al , In rats that were trained to press a lever to receive intravenous self-administration of drugs, highly palatable foods such as sugar and saccharin were shown to reduce self-administration of cocaine and heroin Carroll et al , ; Lenoir and Ahmed, , and these natural reinforcers have been demonstrated to outcompete cocaine in choice self-administration in the majority of rats tested Lenoir et al , ; Cantin et al , This would suggest that sweet foods have a higher reinforcing value than cocaine, even in animals with an extensive history of drug intake Cantin et al. While this phenomenon could appear as a weakness in current models of cocaine addiction, a minority of rats prefer cocaine to sugar or saccharin Cantin et al. This notion is explored more in the Discussion Section 6. Work from many laboratories has demonstrated examples of plasticity in reward-related circuits following access to palatable food. Neurobehavioral adaptations following a history of palatable food intake have been likened to those observed following drugs of abuse, prompting several scientists to propose that dysregulation of food intake may be similar to addiction Hoebel et al , ; Le Magnen, ; Wang et al. The laboratory of Bartley Hoebel has extensive data demonstrating behavioral plasticity following a history of intermittent sugar access, which has led he and his colleagues to propose that sugar consumption that meets criteria for addiction Avena et al , This notion is supported by the fact that several examples of plasticity seen following repeated drug exposure are also observed following intermittent access to not only sugar, but also fat. During repeated access to sugar, escalation of intake is observed Colantuoni et al , , a phenomenon previously associated with cocaine and heroin self-administration Ahmed and Koob, ; Roberts et al , Escalation is an increase in intake that occurs during the initial phase e. Following removal of sugar or fat access, withdrawal symptoms including anxiety- and depressive-like behaviors emerge Colantuoni et al , ; Teegarden and Bale, In fact, when given a re-exposure to sugar after a period of abstinence, animals consume a much greater amount of sugar than during previous sessions Avena et al. This deprivation effect was originally described for alcohol Sinclair and Senter, , and is thought to be another preclinical model of craving and relapse McBride and Li, ; Spanagel and Holter, Finally, following intermittent exposure to a high fat diet, food-seeking was continued despite adverse consequences Teegarden and Bale, ; Johnson and Kenny, , which has been proposed as a animal corollary for risky acquisition of drugs seen in human addicts Deroche-Gamonet et al , Cross-sensitization is a phenomenon that occurs following previous exposure to an environmental or pharmacological agent such as a stressor or psychostimulant, respectively that results in an enhanced response typically locomotor to a different environmental or pharmacological agent Antelman et al , ; O'Donnell and Miczek, ; Kalivas et al , ; Vezina et al , Sensitization processes involving psychostimulants involve mesolimbic DA neurons, and cross-sensitization is believed to occur from common mechanisms of action between two stimuli Antelman et al. During conditioning sessions, the animals are confined to one of the chambers and paired with a reward e. These sessions are repeated and interleaved with conditioning sessions that involve pairing of another chamber of the apparatus with the control condition e. The test phase is done under the same conditions as the pre-test and CPP is demonstrated when animals show a significant preference for the chamber that was paired with the drug or non-drug reward. Davis et al. Withdrawal is a phenomenon also seen following repeated exposure to highly palatable foods. Somatic signs of withdrawal commonly associated with naloxone precipitated opiate withdrawal can be also be precipitated by naloxone or food restriction following intermittent sugar Colantuoni et al. Elevated thresholds for brain stimulation reward, which are commonly observed following withdrawal from cocaine, alcohol, amphetamine, and nicotine Simpson and Annau, ; Cassens et al , ; Markou and Koob, ; Schulteis et al , ; Wise and Munn, ; Epping-Jordan et al , ; Rylkova et al , , are observed in rats following 40 days access to a cafeteria diet in addition to regular chow, and this effect persisted at least 14 days following withdrawal of the high fat food Johnson and Kenny, This measure has commonly been used to describe a state of relative anhedonia characterized by lower tone of endogenous brain reward systems Kenny, ; Wise, ; Bruijnzeel, ; Carlezon and Thomas, and is thought to regulate continued intake of drugs and perhaps food to relieve this state a phenomenon known as negative reinforcement Cottone et al , ; Koob, In addition to behavioral plasticity, excessive intake of certain types of food has also been associated with neurochemical plasticity. In particular, dopamine and opioid signaling appears to be susceptible to adaptations following intermittent access to high sugar or high fat foods. In the NAc, intermittent feeding episodes with access to sugar and chow increase D1 and D3 receptor content either mRNA or protein , while decreasing D2 receptors in the NAc and dorsal striatum Colantuoni et al. This effect was also observed with extended access to a high fat diet in rats, with the greatest decrease in D2 occurring in the heaviest rats Johnson and Kenny, These adaptations in accumbal and striatal dopamine receptors parallel those seen in rodents repeatedly administered cocaine or morphine Alburges et al , ; Unterwald et al , a ; Spangler et al , ; Conrad et al , Further, reductions in striatal D2 receptors are also seen in human psychostimulant users and alcoholics Volkow et al , ; Volkow et al , ; Volkow et al , ; Zijlstra et al. Endogenous opioid signaling is also affected profoundly by diet Gosnell and Levine, Neurochemical plasticity in mesolimbic DA and opioid signaling has also been demonstrated to occur in the offspring of female mice fed high fat food during pregnancy Vucetic et al , Interestingly, these alterations were associated with epigenetic modification hypomethylation of the promoter elements for all of the proteins affected. CRF in the amygdala was increased following a 24 hour withdrawal from a high fat diet, while animals maintained on this diet had unaltered amygdala CRF Teegarden and Bale, As a result, CRF antagonists are being proposed for the treatment of alcoholism and drug addiction Sarnyai et al , ; Koob et al , ; Lowery and Thiele, Transcription factors are another class of molecule implicated in mediating enduring effects of drugs of abuse by directly affecting gene expression McClung and Nestler, In support of the idea that food is capable of inducing neural plasticity, several transcription factors are also altered by diet. NAc phospho-CREB was reduced 24 hours following withdrawal from a high carbohydrate diet and both 24 hours and 1 week following withdrawal from a high fat diet, while the transcription factor delta FosB is increased during access to high fat diet Teegarden and Bale, or sucrose Wallace et al , In the NAc, decreased phospho-CREB is also seen during periods of withdrawal from amphetamine and morphine McDaid et al , a ; McDaid et al , b , and delta FosB is also increased following withdrawal from these drugs as well as cocaine, nicotine, ethanol, and phencyclidine McClung et al , ; McDaid et al. Similar to their proposed role in increasing drug seeking behavior, these neuroadaptations may also affect subsequent feeding behavior, as overexpression of delta FosB in the ventral striatum increases motivation to obtain food Olausson et al , and sucrose Wallace et al. Synaptic plasticity in addiction-related circuitry has been linked with in vivo administration of numerous drugs of abuse. In the VTA, several classes of addictive, but not non-addictive psychoactive drugs induce synaptic plasticity Saal et al , ; Stuber et al , a ; Wanat et al , a. To date, there is very little data directly measuring the effects of food on synaptic plasticity in addiction-related neurocircuitry. When cocaine was self-administered, the effect lasted up to three months, and this effect was not seen with passive administration of cocaine Chen et al. Miniature EPSP frequency in the VTA was also increased for up to three months following cocaine self-administration, and up to three weeks following sucrose but not chow self-administration, suggesting that glutamatergic signaling is strengthened pre- and post-synaptically Chen et al. These data suggest that some measures of synaptic plasticity in the mesolimbic system e. This is supported by the fact that Pavlovian learning associated with food reward occluded VTA LTP during acquisition day 3 of conditioning Stuber et al , b. Although evidence of plasticity was observed on day 3, it was absent two days later, suggesting that self-administration distinctly leads to more enduring plasticity in these circuits Stuber et al. This appears to also be the case for plasticity associated with cocaine self-administration, as repeated non-contingent cocaine-induced plasticity in the VTA is also short-lived Borgland et al , ; Chen et al. The nature of these operant studies does not, however, discount the fact that extended access to palatable food may lead to protracted synaptic plasticity. During typical operant conditioning studies, animals are allowed much less access to food reward than during free-feeding or scheduled access. Future studies will need to be conducted to determine the effects of extended access to highly palatable food on synaptic plasticity. Sex is a reward that, much like food, is critical for the survival of a species. Like food and several drugs of abuse, sexual behavior elevates mesolimbic DA Meisel et al , ; Mermelstein and Becker, It is also a behavior that has been measured in terms of reinforcing value by operant Beach and Jordan, ; Caggiula and Hoebel, ; Everitt et al , ; Crawford et al , and place conditioning methods Paredes and Vazquez, ; Martinez and Paredes, ; Tzschentke, Considering these adaptations in behavior, it is reasonable to imagine significant neuroadaptations occurring within mesocorticolimbic circuitry. As seen with repeated sugar exposure, repeated sexual encounters in male rats cross-sensitized with amphetamine in a locomotor assay Pitchers et al , a. Repeated sexual encounters also increase sucrose consumption and place preference for low dose amphetamine, suggesting cross-sensitization between sexual experience and drug reward Wallace et al. Also similar to the sensitizing effects of drugs of abuse Segal and Mandell, ; Robinson and Becker, ; Robinson and Berridge, , repeated sexual encounters sensitize the NAc DA response to a later sexual encounter Kohlert and Meisel, Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA Fiorino and Phillips, As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience Hedges et al. The MAP kinase signaling pathway is another plasticity-related pathway that is engaged during repeated sexual experience Bradley et al , Increases in NAc pERK are induced by several drugs of abuse, but not by non-addictive psychoactive drugs, suggesting that NAc ERK activation may be associated with plasticity associated with addiction Valjent et al , Further, a recent study found that pERK was induced by sexual activity in the same neurons of the NAc, basolateral amygdala, and anterior cingulate cortex that were previously activated by methamphetamine Frohmader et al , This unique selectivity suggests that activation of this signaling cascade in NAc and other mesocorticolimbic regions may specifically lead to plasticity that promotes future appetitive behavior Girault et al , Neural structure in the mesocorticolimbic system is also altered following sexual experience. This expands on other data demonstrating that sexual experience can alter dendritic morphology in a manner analogous to repeated drug exposure Fiorino and Kolb, ; Robinson and Kolb, ; Meisel and Mullins, Access to a running wheel for exercise serves as a reinforcer in laboratory rodents Belke and Heyman, ; Belke and Dunlop, ; Lett et al , Like drugs of abuse and other natural rewards, exercise in rodents is associated with increased DA signaling in the NAc and striatum Freed and Yamamoto, ; Hattori et al , Exercise also elevates brain and plasma levels of endogenous opioids in humans and rodents Christie and Chesher, ; Janal et al , ; Schwarz and Kindermann, ; Asahina et al , One target of these opioids is the mu opiate receptor, a substrate of opiate drugs of abuse such as heroin and morphine. This overlap also appears to extend to behavioral responses to drugs of abuse. Unlike the natural rewards discussed thus far, most studies have found that exposure to exercise attenuates the effects of drugs of abuse. For example, self-administration of morphine, ethanol, and cocaine are all reduced following exercise Cosgrove et al , ; Smith et al , ; Ehringer et al , ; Hosseini et al , Exercise prior to self-administration training was also able to reduce drug seeking and reinstatement, although in this study self-administration of cocaine was not affected Zlebnik et al , In a similar study, cocaine seeking and cue reinstatement were reduced in rats that exercised during a period of drug abstinence Lynch et al , In animals with a history of running wheel experience, withdrawal of wheel access leads to drug withdrawal-like symptoms including, increased anxiety and aggression, and susceptibility to naloxone-precipitated withdrawal Hoffmann et al , ; Kanarek et al , In addition to altered behavioral responses to drugs of abuse, there is neurochemical plasticity reflected by increased dynorphin in the striatum and NAc following running, a phenomenon also seen in human cocaine addicts and in animals following administration of cocaine or ethanol Lindholm et al , ; Werme et al , ; Wee and Koob, Also reminiscent of drug associated neural plasticity, the transcription factor delta FosB is induced in the NAc of animals with wheel running experience Werme et al , Conversely, exercise during drug abstinence is also associated with a reduction in reinstatement-induced activation of ERK in the PFC Lynch et al. This is an especially relevant finding considering the role of ERK in many aspects of addiction Valjent et al. Striatal levels of the dopamine D2 receptor have also been reported to increase following exercise MacRae et al , ; Foley and Fleshner, , an effect that is opposite to that observed following psychostimulant self-administration in rodents, primates, and humans Volkow et al. Support for this idea comes from studies mentioned earlier in this section demonstrating reduced drug self-administration, seeking, and reinstatement in animals allowed to exercise. Exercise also has effects within the hippocampus, where it influences plasticity reflected in elevated LTP and improved spatial learning and increases neurogenesis and the expression of several plasticity-related genes Kanarek et al. Decreased hippocampal neurogenesis has been linked with depressive-like behaviors in preclinical studies Duman et al , ; Sahay and Hen, , and consistent with an ability to increase hippocampal neurogenesis, exercise has been demonstrated to have an antidepressant effect in a depressive line of rats Bjornebekk et al , , and to improve depressive symptoms in human patients Ernst et al , Considering a recently reported link between suppression of hippocampal neurogenesis and increased cocaine intake and seeking behaviors in the rat Noonan et al , along with previous evidence that exposure to stress a treatment that reduces hippocampal neurogenesis , increases drug intake Covington and Miczek, , it is important to consider effects of exercise on hippocampal function in addition to those on mesolimbic function. Because exercise leads to plasticity in both depression-related circuitry i. Consistent with the effects of exercise on drug rewards, there is also evidence that running can decrease preference for natural reinforcers. Under conditions of limited food access, rats with constant access to running wheel will actually cease to eat to the point of death Routtenberg and Kuznesof, ; Routtenberg, This extreme phenomenon is observed only when periods of food access occur with continued access to a running wheel, although it may suggest that exposure to exercise may reduce motivation in a general manner for both drug and non-drug reinforcers. A final consideration of the effects of exercise is that a running wheel housed within the animal cage may act as a form of environmental enrichment. While it is difficult to completely dissociate environmental enrichment from exercise EE housed animals exercise more , dissociable effects of EE and exercise have been reported van Praag et al. Novel stimuli, sensory stimulation, and enriched environments are all reinforcing to animals, including rodents Van de Weerd et al , ; Besheer et al , ; Bevins and Bardo, ; Mellen and Sevenich MacPhee, ; Dommett et al , ; Cain et al , ; Olsen and Winder, Novel environments, sensory stimuli, and environmental enrichment EE have all been shown to activate the mesolimbic DA system Chiodo et al , ; Horvitz et al , ; Rebec et al , a ; Rebec et al , b ; Wood and Rebec, ; Dommett et al. In human populations, sensation and novelty seeking have been linked to susceptibility, intake, and severity of drug abuse Cloninger, ; Kelly et al , ; for review, see Zuckerman, In rodents, response to novelty has also been correlated with subsequent drug self-administration Piazza et al , ; Cain et al , ; Meyer et al , , suggesting that these two phenotypes covary. Based on these and neurochemical data, there is thought to be overlap in mesocorticolimbic circuitry that underlies response to novelty and drugs of abuse Rebec et al. Sensory stimuli especially visual and auditory stimuli have been studied for their reinforcing properties Marx et al , ; Stewart, ; Cain et al. Plasticity following discrete exposure to novelty or sensory stimuli within parameters that would not be aversive is limited, although there is extensive evidence for neural plasticity following strong activation or deprivation of sensory systems Kaas, ; Rauschecker, ; Uhlrich et al , ; Smith et al , However, there is a wealth of data on neural plasticity associated with housing in an enriched environment which includes aspects of other topics discussed, including novelty and exercise; for more in-depth reviews, see Kolb and Whishaw, ; van Praag et al , a ; Nithianantharajah and Hannan, Hebb's renowned theory of learning was influenced by results he obtained demonstrating that rats housed in an enriched environment his own house performed better at learning tasks than littermates housed in the laboratory Hebb, Subsequent studies have identified drastic changes in brain weight, angiogenesis, neurogenesis, gliogenesis, and dendritic structure in response to environmental enrichment EE Bennett et al , ; Greenough and Chang, ; Kolb and Whishaw, ; van Praag et al , b. More recent data from microarray studies have shown that EE housing induces expression of gene cascades involved with NMDA-dependent plasticity and neuroprotection Rampon et al , The same group found that exposure to the EE environment for only 3 hours i. Compared to animals in impoverished conditions, EE produced a rightward shift in the dose-response curve of locomotor activation by morphine, as well as attenuated morphine- and amphetamine-induced locomotor sensitization Bardo et al , ; Bardo et al , A similar trend was observed following psychostimulant treatment, where EE attenuated the locomotor activating and sensitization effects of nicotine and reduced cocaine self-administration and seeking behavior although EE increased cocaine CPP Green et al , ; Green et al , Interestingly, EE did not lead to differences in NAc or striatal DA synthesis or mu opiate receptor binding in several mesocorticolimbic areas investigated Bardo et al. This resulting increase in prefrontal DA signaling could impact mesolimbic activity, impulsivity, and drug self-administration Deutch, ; Olsen and Duvauchelle, , ; Everitt et al. EE also affects transcriptional activity induced by drugs of abuse. Induction of the immediate early gene zif in the NAc by cocaine is reduced, as is cocaine-induced expression of delta FosB in the striatum although EE itself was found to elevate striatal delta FosB Solinas et al , The degree of plasticity induced by EE is so great that it is continuing to be studied in terms of protecting and improving recovery from several neurological diseases van Praag et al. As discussed in regards to exercise, conclusions regarding the effects of EE on drug self-administration should be made while considering the potential anti-depressive effects of enriched housing. Like exercise, EE has been demonstrated to increase hippocampal neurogenesis van Praag et al. As research in non-drug addiction progresses, knowledge gained from the fields of drug addiction, motivation, and obsessive-compulsive disorder will contribute to the development of therapeutic strategies for non-drug addictions. There is emerging clinical evidence that pharmacotherapies used to treat drug addiction may be a successful approach to treating non-drug addictions. For example, naltrexone, nalmefine, N-acetyl-cysteine, and modafanil have all been reported to reduce craving in pathological gamblers Kim et al , ; Grant et al , b ; Leung and Cottler, Opiate antagonists have also shown promise in small studies in the treatment of compulsive sexual behavior Grant and Kim, , and topirimate has shown success in reducing binge episodes and weight in obese patients with binge eating disorder McElroy et al , The success of these treatments for non-drug addictions further suggests that there are common neural substrates between drug and non-drug addictions. Animal models of motivated and compulsive behavior will also help provide insight into neural mechanisms underlying non-drug addictions Potenza, ; Winstanley et al , Some types of non-drug addictions are more easily modeled in rodents than others. For example, paradigms using access to highly palatable foods have provided an excellent framework for the study of the transition to compulsive or excessive food intake. These treatments can increase future motivation for food reward Wojnicki et al , and lead to alterations in neural plasticity in the mesolimbic dopamine system Hoebel et al , Food self-administration models have further found that food-associated cues and stressors can lead to relapse to food seeking Ward et al. Thus, these types of models have high construct validity and may result in neuroadaptations that give us insight into human conditions such as compulsive food intake or relapse to excessive eating habits following a beneficial change in diet. Another area of recent progress has been in the development of rodent models of gambling and risky choice van den Bos et al , ; Rivalan et al , ; St Onge and Floresco, ; Zeeb et al. Studies have demonstrated that rats are capable of performing the Iowa gambling task IGT Rivalan et al. One study found that rats that performed suboptimally on the IGT had higher reward sensitivity and higher risk taking Rivalan et al. Mechanistic studies using sensory stimuli as a reinforcer have found overlap of the molecular mechanisms that modulate self-administration of sensory reinforcers and drugs of abuse Olsen and Winder, ; Olsen et al. While research in this field is in its infancy, these and future experiments may give insight into potential therapeutic strategies for the treatment of compulsive internet use or video gaming. While these and other advancements in behavioral models are beginning to give us potential insight into processes underlying non-drug addictions, there are several challenges and limitations when attempting to model such behavior. One limitation is that in most models, there is no significant consequence of maladaptive decision-making or excessive engagement in the behaviors. For example, rodent gambling tasks use smaller rewards or increased delay between rewards in response to poor decisions, but the animal doesn't risk losing his home after a losing streak. Another limitation is that excessive engagement in behaviors such as food or drug self-administration in laboratory conditions may be a consequence of animals not having access to other non-drug rewards Ahmed, This unique situation has been proposed to model risk-prone individuals in human populations Ahmed, , although it still represents a caveat for these types of studies. Continued study of excessive, compulsive, or maladaptive performance in eating, gambling, and other non-drug behaviors will be key in advancing our understanding of non-drug addictions. One question that remains is whether the same populations of neurons are activated by drug and natural rewards. While there is ample evidence that there is overlap in the brain regions affected by natural rewards and drugs of abuse Garavan et al , ; Karama et al , ; Childress et al , , there is conflicting data regarding overlap in neural populations that are affected by natural rewards and drugs. Single unit recordings from rat and non-human primate ventral striatum indicate that different neural populations are engaged during self-administration of natural rewards food, water, and sucrose vs. There is also evidence that drugs of different classes engage distinct neural ensembles within the mesocorticolimbic system. Single unit recordings from the medial PFC and NAc of rats self-administering cocaine or heroin revealed that different populations of neurons were differentially engaged during both the anticipatory and post-infusion periods Chang et al , The distinction between natural and drug reward may not be so absolute, however, as there is also evidence for the contrary. Following timed exposure to methamphetamine and sexual experience, there was significant coincidence of neurons activated by these two rewards in the NAc, anterior cingulate cortex, and basolateral amygdala Frohmader et al. Thus, recruitment of neural populations by particular drugs of abuse may overlap with that of some natural rewards, but not others. Future studies using more comprehensive batteries of natural and drug rewards will be needed to address this issue. Another question that arises is to what degree the study of natural reward processing can help us understand drug and non-drug addiction. For example, sugar and saccharin can reduce self-administration of cocaine and heroin Carroll et al. In a retrospective analysis of animals across studies, Cantin et al. Thus, in the majority of animals sugar and saccharin appear to be more reinforcing than cocaine. Thus, comparing individual animals' preferences for drug versus natural rewards may yield insight into vulnerability factors associated with drug addiction. A final question is whether the pursuit of natural rewards can help prevent or treat drug addiction. Environmental enrichment has been proposed as both a preventative and a treatment measure for drug addiction based on preclinical studies with several drugs of abuse Bardo et al , ; Deehan et al , ; Solinas et al , ; Solinas et al. These results are promising and suggest that environmental enrichment could potentially improve neuroadaptations associated with chronic drug use. Similar to environmental enrichment, studies have found that exercise reduces self-administration and relapse to drugs of abuse Cosgrove et al. There is also some evidence that these preclinical findings translate to human populations, as exercise reduces withdrawal symptoms and relapse in abstinent smokers Daniel et al , ; Prochaska et al , , and one drug recovery program has seen success in participants that train for and compete in a marathon as part of the program Butler, There are many parallels between non-drug addictions and drug addictions, including craving, impaired control over the behavior, tolerance, withdrawal, and high rates of relapse Marks, ; Lejoyeux et al. As I have reviewed, there is a glut of evidence that natural rewards are capable of inducing plasticity in addiction-related circuitry. This should not come as a surprise, as 1 drugs of abuse exert actions within the brain that are similar to, albeit more pronounced than natural rewards Kelley and Berridge, , and 2 learned associations between things such as food or sexual opportunities and the conditions which maximize availability is beneficial from a survival standpoint and is a natural function of the brain Alcock, In some individuals, this plasticity may contribute to a state of compulsive engagement in behaviors that resembles drug addiction. Extensive data suggests that eating, shopping, gambling, playing video games, and spending time on the internet are behaviors that can develop into compulsive behaviors that are continued despite devastating consequences Young, ; Tejeiro Salguero and Moran, ; Davis and Carter, ; Garcia and Thibaut, ; Lejoyeux and Weinstein, As with drug addiction, there is a transition period from moderate to compulsive use Grant et al. One potential approach to make this distinction is to test patients using DSM criteria for substance dependence. Using this approach, reports have been made that these DSM criteria can be met when applied to patients that compulsively engage in sexual activity Goodman, , gambling Potenza, , internet usage Griffiths, , and eating Ifland et al , In other fields, this type of nomenclature has helped to raise awareness that disorders such as autism and fetal alcoholism have numerous levels of severity. Future studies will continue to reveal insights into how the pursuit of natural rewards can become compulsive in some individuals and how best to treat non-drug addictions. I would like to thank Kelly Conrad, Ph. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. As a library, NLM provides access to scientific literature. Published in final edited form as: Neuropharmacology. Find articles by Christopher M Olsen. Issue date Dec. All rights reserved. The publisher's version of this article is available at Neuropharmacology. Open in a new tab. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel. Colantuoni et al. Vezina et al. Carroll et al. Shippenberg and Heidbreder, ; Davis et al. Stewart, ; Lynch et al. Robinson and Becker, ; Kohlert and Meisel, ; Leri et al. Packard and Knowlton, ; Porrino et al. Hammer, ; Unterwald et al. McDaid et al. Nestler et al. Mesocorticolimbic Synaptic Plasticity. Saal et al. NC operant sucrose pellets, limited access.

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