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Background: Alcohol addiction is a social problem leading to both loss of health and economic prosperity among addicted individuals. Common properties of anti‑addictive compounds include anti‑anxiety, anticonvulsants, anti‑depressant, and nootropic actions primarily through modulation of gamma‑aminobutyric acid (GABA) and serotonergic systems. Objective: Here, we screen ashwagandha and shilajit known ethnopharmacologically as nervine tonic and adaptogenic herbs for possible anti‑addictive potential. Materials and Methods: Effect of ashwagandha churna and shilajit was measured on ethanol withdrawal anxiety using elevated plus maze. Role of ashwagandha and shilajit on chronic ethanol consumption (21 days) was measured using two bottle choice protocol of voluntary drinking. We also measured the effect of the above herbs on corticohippocampal GABA, dopamine, and serotonin levels. Results: Both ashwagandha and shilajit were found to reduce alcohol withdrawal anxiety in a dose‑dependent manner. These herbs alone or in combination also decreased ethanol intake and increased water intake significantly after 21 days of chronic administration. Chronic administration of ashwagandha was found to significantly increase GABA and serotonin levels whereas shilajit altered cortico‑hippocampal dopamine in mice. Conclusion: These central nervous system active herbs alone or in combination reduced both alcohol dependence and withdrawal thus showing promising anti‑addictive potential.
Effect of ashwagandha and shilajit on ethanol withdrawal anxiety using elevated plus maze. (a) Ethanol abstinence significantly decreased (P < 0.001) time spend in open arm compared to ethanol‑treated animals. Ashwagandha treatment to abstinent animals significantly (50 mg/kg P < 0.01 and 100 mg/kg, 200 mg/kg, 500 mg/kg P < 0.001) increased the time spend in open arm compared to ethanol abstinent animals. (b) Ethanol abstinence significantly decreased (P < 0.001) the number of entries in open arm compared to animals on ethanol. Ashwagandha treatment (200 mg/kg and 500 mg/kg) significantly (P < 0.001) increased the number of open arm entries compared to abstinent animals. (c) Ethanol abstinence significantly decreased (P < 0.001) time spend in open arm compared to ethanol‑treated animals. Shilajit treatment to abstinent animals significantly (10 mg/kg, 25 mg/kg, 50 mg/kg P < 0.001) increased the time spend in open arm compared to ethanol abstinent animals. (d) Ethanol abstinence significantly decreased (P < 0.05) the number of entries in open arm compared to animals on ethanol. Shilajit treatment (25 mg/kg and 50 mg/kg) significantly (P < 0.01) increased the number of open arm entries compared to abstinent animals. Values (e) Ashwagandha (200 mg/kg) and shilajit (25 mg/kg) together significantly increased (P < 0.01) the time spend in open arm compared to ethanol abstinent animals. However, this increase was comparable (P > 0.05) with ashwagandha (200 mg/kg) and shilajit (25 mg/kg) treatments alone. Diazepam also significantly increased time spend in open arm over ethanol abstinent and ethanol‑treated groups (P < 0.001). (f ) Ashwagandha (200 mg/kg) and shilajit (25 mg/kg) together significantly increased (P < 0.01) the number of entries into the open arm when compared with ethanol abstinent animals. However, this increase was comparable (P > 0.05) with ashwagandha (200 mg/kg) and shilajit (25 mg/kg) treatments alone. Diazepam also significantly increased the number of open arm entries over ethanol abstinent and ethanol‑treated groups (P < 0.001). Values represent mean ± standard error of the mean n = 7
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Effect of ashwagandha and shilajit on central nervous system neurotransmitter levels. (a) Changes in serotonin levels before and after treatment. Ashwagandha (500 mg/kg) as well as combined ashwagandha and shilajit treatment (day 21–30) lead to significant increase (P < 0.01) increase in corticohippocampal serotonin compared to untreated animals on ethanol (30 days). However, treatment with shilajit (50 mg/kg) alone or diazepam failed to increase serotonin levels compared to alcohol treated group. (b) Changes in dopamine levels before and after treatment. Shilajit (50 mg/kg) as well as ashwagandha and shilajit combination treatment (day 21–30) led to significant increase (P < 0.01) in corticohippocampal dopamine compared to untreated animals on ethanol (30 days). However, treatment with ashwagandha (500 mg/kg) alone or diazepam failed to increase serotonin levels compared to alcohol treated group. (c) Changes in gamma‑aminobutyric acid levels before and after treatment. Ashwagandha (500 mg/kg) as well as combined ashwagandha and shilajit treatment (day 21–30) led to significant increase (P < 0.01) increase in corticohippocampal gamma‑aminobutyric acid levels compared to untreated animals on ethanol (30 days). However, treatment with shilajit (50 mg/kg) alone failed to increase serotonin levels compared to alcohol‑treated group. Diazepam treatment also showed a significant increase (P < 0.001) increase in corticohippocampal gamma‑aminobutyric acid levels. Values represent mean ± standard error of the mean n = 5
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... On the other hand, diabetic groups that received 100 & 200 mg/kg BW of ashwagandha demonstrated a significant rise in serum serotonin levels when compared with the DC group. This is in line with an earlier study by Bansal and Banerjee (2016) who found that chronic ashwagandha administration significantly increased serotonin levels. Also, Priyanka et al. (2020) pointed to the ability of ashwagandha in increasing serotonin concentrations. ...
Experiment Findings
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Evaluation of the efficacy of ashwagandha root extract to ameliorate the oxidative stress and depression resulting from diabetes in male rats was conducted in the current study. Thirty-six male albino rats were randomly grouped into two main groups: normal (n=18) and diabetic (n=18), diabetes was induced by a single dose of 150 mg/kg BW alloxan injected intraperitoneally. After six weeks, both normal and diabetic groups were further subdivided into six subgroups ; normal control, 100 & 200 mg/kg BW ashwagandha treated normal, diabetic control, 100 and 200 mg/kg BW ashwagandha treated diabetic groups, for another six weeks. The forced swim test was used to assess depression, and serum serotonin levels were measured. In brain tissue homogenates, the glutathione reduced content, superoxide dismutase, and catalase activity were measured, as well as the total antioxidant capacity, total oxidative capacity, and malondialdehyde levels. Moreover, histo-pathological examination of the brain (cerebral cortex and cerebellum) were conducted. The obtained results revealed that the administration of ashwagandha extract to diabetic rats reduced immobility time during the forced swim test while increasing the serotonin levels significantly when compared with the diabetic group. Similar to this, brain total antioxidant capacity, glutathione reduced content, superoxide dismutase, and cata-lase activity increased significantly, while brain total oxidative capacity, oxidative stress index, and malondi-aldehyde levels decreased significantly when compared with the diabetic group. Furthermore, the histopatho-logical changes in brain sections were reversed by ashwagandha root extract. In conclusion, ashwagandha root extract can be used to ameliorate the brain oxidative stress and depression brought on by diabetes mellitus at doses of 100 and 200 mg/kg BW.
... Another study reported that in chronic alcohol exposure Ashwagandha churna causes reduction in both withdrawal anxiety and intake of ethanol. Dominantly, the mechanism involved in anti-addiction is via modulation of GABAergic and serotonergic system (Bansal and Banerjee, 2016). In view of several above studies, Ashwagandha is found to be effective in reversing addiction. ...
Article
Ethnopharmacological relevance: Withania somnifera (Family: Solanaceae), commonly known as Ashwagandha or Indian ginseng is distributed widely in India, Nepal, China and Yemen. The roots of plant consist of active phytoconstituents mainly withanolides, alkaloids and sitoindosides and are conventionally used for the treatment of multiple brain disorders. Aim of the review: This review aims to critically assess and summarize the current state and implication of Ashwagandha in brain disorders. We have mainly focussed on the reported neuroactive phytoconstituents, available marketed products, pharmacological studies, mechanism of action and recent patents published related to neuroprotective effects of Ashwagandha in brain disorders. Materials and methods: All the information and data was collected on Ashwagandha using keywords “Ashwagandha” along with “Phytoconstituents”, “Ayurvedic, Unani and Homeopathy marketed formulation”, “Brain disorders”, “Mechanism” and “Patents”. Following sources were searched for data collection: electronic scientific databases such as Science Direct, Google Scholar, Elsevier, PubMed, Wiley On-line Library, Taylor and Francis, Springer; books such as AYUSH Pharmacopoeia; authentic textbooks and formularies. Results: Identified neuroprotective phytoconstituents of Ashwagandha are sitoindosides VII–X, withaferin A, withanosides IV, withanols, withanolide A, withanolide B, anaferine, beta-sitosterol, withanolide D with key pharmacological effects in brain disorders mainly anxiety, Alzheimer's, Parkinson's, Schizophrenia, Huntington's disease, dyslexia, depression, autism, addiction, amyotrophic lateral sclerosis, attention deficit hyperactivity disorder and bipolar disorders. The literature survey does not highlight any toxic effects of Ashwagandha. Further, multiple available marketed products and patents recognized its beneficial role in various brain disorders; however, very few data is available on mechanistic pathway and clinical studies of Ashwagandha for various brain disorders is scarce and not promising. Conclusion: The review concludes the results of recent studies on Ashwagandha suggesting its extensive potential as neuroprotective in various brain disorders as supported by preclinical studies, clinical trials and published patents. However vague understanding of the mechanistic pathways involved in imparting the neuroprotective effect of Ashwagandha warrants further study to promote it as a promising drug candidate.
... Another study reported that in chronic alcohol exposure Ashwagandha churna causes reduction in both withdrawal anxiety and intake of ethanol. Dominantly, the mechanism involved in anti-addiction is via modulation of GABAergic and serotonergic system (Bansal and Banerjee, 2016). In view of several above studies, Ashwagandha is found to be effective in reversing addiction. ...
Article
Full-text available
Ethnopharmacological relevance Withania somnifera (Family: Solanaceae), commonly known as Ashwagandha or Indian ginseng is distributed widely in India, Nepal, China and Yemen. The roots of plant consist of active phytoconstituents mainly withanolides, alkaloids and sitoindosides and are conventionally used for the treatment of multiple brain disorders. Aim of the review: This review aims to critically assess and summarize the current state and implication of Ashwagandha in brain disorders. We have mainly focussed on the reported neuroactive phytoconstituents, available marketed products, pharmacological studies, mechanism of action and recent patents published related to neuroprotective effects of Ashwagandha in brain disorders. Materials and methods All the information and data was collected on Ashwagandha using keywords “Ashwagandha” along with “Phytoconstituents”, “Ayurvedic, Unani and Homeopathy marketed formulation”, “Brain disorders”, “Mechanism” and “Patents”. Following sources were searched for data collection: electronic scientific databases such as Science Direct, Google Scholar, Elsevier, PubMed, Wiley On-line Library, Taylor and Francis, Springer; books such as AYUSH Pharmacopoeia; authentic textbooks and formularies. Results Identified neuroprotective phytoconstituents of Ashwagandha are sitoindosides VII–X, withaferin A, withanosides IV, withanols, withanolide A, withanolide B, anaferine, beta-sitosterol, withanolide D with key pharmacological effects in brain disorders mainly anxiety, Alzheimer's, Parkinson's, Schizophrenia, Huntington's disease, dyslexia, depression, autism, addiction, amyotrophic lateral sclerosis, attention deficit hyperactivity disorder and bipolar disorders. The literature survey does not highlight any toxic effects of Ashwagandha. Further, multiple available marketed products and patents recognized its beneficial role in various brain disorders; however, very few data is available on mechanistic pathway and clinical studies of Ashwagandha for various brain disorders is scarce and not promising. Conclusion The review concludes the results of recent studies on Ashwagandha suggesting its extensive potential as neuroprotective in various brain disorders as supported by preclinical studies, clinical trials and published patents. However vague understanding of the mechanistic pathways involved in imparting the neuroprotective effect of Ashwagandha warrants further study to promote it as a promising drug candidate.
... [42][43][44][45] Withania somnifera is also often used by practitioners of Ayurveda for combating addiction, obsession, and diverse so-called "lifestyle disorders" [46] and numerous preclinical and clinical studies conducted with its different types of extract have continued to justify such traditionally known medicinal uses of different parts of the plant. [28,30,31,[47][48][49][50] However, the therapy relevant questions concerning their doses and treatment regimen necessary for prevention and cure of such disorders still remain unanswered or speculative only. ...
Article
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Background: The objective of the study is to compare stress resistance-promoting effect of triethylene glycol (TEG) and root extract of Ashwagandha (Withaniasomnifera) i.e. withanolide-free root extract of Withaniasomnifera (WFWS). Materials and methods: Mice groups treated orally with 10 mg/kg TEG or WFWS (3.3, 10, 33.3, or 100 mg/kg) for 12 consecutive days were subjected to foot shock stress-triggered hyperthermia test on the 1st, 5th, 7th and 10th day and to marble-burying test on the following 2 days. Effects of treatment on stress-triggered alteration in body weight, core temperature, blood glucose, insulin and cortisol level were quantified and statistically analyzed. Results: WFWS doses up to 10 mg/kg/day were as effective as TEG in affording protection against stress-triggered alteration in body weight, core temperature and marble-burying behavior. Protection against stress-triggered alteration in blood glucose and insulin level, as well as antidepressants or anxiolytic-like activities in the behavioral test, were observed in the higher two WFWS doses (33.3 and 100 mg/kg) treated groups only. Conclusion: Ashwagandha metabolites other than withanolides contribute to its stress resistance increasing effects. The observations suggest that modulation of physiological functions of gut microbiota may be involved in the mode of action of Withaniasomnifera root extracts.
... However, under stressful condition there is depletion of GABA receptor binding in the CNS [43,44] which leads to the activation of the HPA axis. Studies have shown that extracts and active compounds of ashwagandha have GABA-like activity and also increase the production of GABA in brain [45][46][47]. Therefore, it is suggested that IC might induce higher levels of GABA or exert GABA like action in brain under the stressful condition and thereby suppress the activation of the HPA axis and the subsequent increase in serum level of corticosterone which is to be substantiated by future studies. ...
Article
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Objective: To find out whether an isolated compound (IC) from the ethanolic extract of roots of ashwagandha prevents stress-induced hyperglycemia by direct interference with the action of increased concentration of corticosterone on hepatocytes or by preventing hyper-secretion of corticosterone or both.Methods: A group of rats served as controls, and those in another group were subjected to restraint (1 h) and forced swimming exercise (15 min), after a gap of 4 h daily for 4 w. The third group of rats received orally IC (5 mg/kg bw/rat) 1 h prior to exposure to stressors. After the last treatment period, a blood sample was collected and serum was separated for the estimation of corticosterone and glucose. In in vitro experiment, hepatocytes were treated with different concentrations of corticosterone (100, 200, 300, 400 and 500 ng/ml). In another set of experiment, hepatocytes were treated with different doses of IC (1, 10, 100, 1000 and 10 000 μg/ml of medium) along with corticosterone (400ng/ml). The concentration of glucose and activities of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) were determined after the treatment.Results: Stress exposure caused a significant increase in serum concentration of corticosterone and glucose whereas, administration of IC did not result in similar changes. Further, treatment of corticosterone in in vitro significantly increased the activities of PEPCK and G6Pase and concentration of glucose in a dose-dependent manner in hepatocytes. However, treatment with IC did not interfere with the corticosterone-induced an increase in the activities of PEPCK and G6Pase as well as the concentration of glucose in hepatocytes.Conclusion: The in vivo and in vitro results put together reveal that IC does not directly interfere with the action of corticosterone on hepatocytes. However, it prevents stress-induced hyperglycemia by suppressing hyper-secretion of corticosterone.
... Both epidemiological and animal studies have shown obesity to be a risk factor for mood disorders including depression. [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] Diabetic rats have also been shown to develop signs of depression. 40,41 However, how obesity or diabetes may lead to depression is not very well characterized. ...
Article
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Metabolic syndrome (MetS) is associated with high blood glucose, insulin resistance, dyslipidemia, central obesity, and hypertension. There is clinical evidence of the coexistence of depression and MetS, however, pathways associating these diseases are far from clear. In the present study, we evaluate and determine the pathogenesis of depression in MetS animals. Methods: Diet induced (High-fat diet long with 20% fructose water; HFHC diet for 4 weeks) MetS was developed in swiss albino mice. Fasting blood glucose levels, Lipids and blood pressure (BP) was measured in these animals. Development of depression in these animals was determined using forced swim and tail suspension tests. This was followed by measurement of GABA, dopamine, serotonin and norepinephrine levels in these animals. We also evaluated the effect of various antidepressants, on MetS associated depression. Results: MetS was induced using high fat and high carbohydrate (HFHC) diet in Swiss albino mice with high fasting blood glucose levels (>250 mg/dl), significantly increased LDL (p<0.001) and triglyceride (p<0.01) and reduced HDL levels (p<0.05) and significant increase in systolic BP; p<0.001) compared to normal controls. MetS animals showed signs of depression with significantly higher (p<0.001) immobility time in forced swim and tail suspension tests. These animals showed significantly lower corticohippocampal norepinephrine (NE) levels (p<0.01) compared to controls. Nortryptaline, showed a dose dependent decrease in immobility time in MetS animals (p<0.001) in both forced swim and tail suspension tests thus reversing MetS induced depression. Conclusion: The above results suggest that MetS may lead to depression in mice which is primarily mediated by NE system. © 2018, Association of Pharmaceutical Teachers of India. All rights reserved.
Chapter
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Substance use disorders are a growing concern for all ages, including adolescents. Even though there is an increase in recreational substance use and a wider variety of drugs is available to this young population, treatment options remain scarce. Most medications have limited evidence in this population. Few specialists treat individuals struggling with addiction along with mental health disorders. As the evidence grows, these treatments are usually included in complementary and integrative medicine. This article discusses available evidence for many complementary and integrative treatment approaches while briefly describing existing psychotherapeutic and psychotropic medications.
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Evidence suggests that alcohol affects brain function by interacting with multiple neurotransmitter systems, thereby disrupting the delicate balance between inhibitory and excitatory neurotransmitters. Short-term alcohol exposure tilts this balance in favor of inhibitory influences. After long-term alcohol exposure, however, the brain attempts to compensate by tilting the balance back toward equilibrium. These neurological changes occur as the development of tolerance to alcohol's effects. When alcohol consumption is abruptly discontinued or reduced, these compensatory changes are no longer opposed by the presence of alcohol, thereby leading to the excitation of neurotransmitter systems and the development of alcohol withdrawal syndrome. Long-term alcohol intake also induces changes in many neurotransmitter systems that ultimately lead to the development of craving and alcohol-seeking behavior.
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The effect of Shilajit was investigated for putative nootropic and anxiolytic activity, and its effect on rat brain monoamines using Charles Foster strain albino rats. Nootropic activity was assessed by passive avoidance learning and active avoidance learning acquisition and retention. Anxiolytic activity was evaluated by the elevated plus-maze technique. Rat brain monoamines and monoamine metaboliteswere estimated bya HPLC technique. The results indicated that Shilajit had significant nootropic and anxiolytic activity. The biochemical studies indicated that acute treatment with Shilajit had insignificant effects on rat brain monoamine and monoamine metabolite levels. However, following subacute (5days) treatment, there was decrease in 5-hydroxytryptamine and 5-hydroxyindole acetic acid concentrations and an increase in the levels of dopamine, homovanillic acid and 3.4-dihydroxyphenyl-acetic acid concentrations, with insignificant effects on noradrenaline and 3-methoxy-4- hydroxyphenylethylene glycol levels. The observed neurochemical effects induced by Shilajit, indicating a decrease in rat brain 5-hydroxytryptamine turnover, associated with an increase in dopaminergic activity, helps to explain the observed nootropic and anxiolytic effects of the drug.
Article
Withania somnifera (Ashawagandha) is very revered herb of the Indian Ayurvedic system of medicine as a Rasayana (tonic). It is used for various kinds of disease processes and specially as a nervine tonic. Considering these facts many scientific studies were carried out and its adaptogenic / anti-stress activities were studied in detail. In experimental models it increases the stamina of rats during swimming endurance test and prevented adrenal gland changes of ascorbic acid and cortisol content produce by swimming stress. Pretreatment with Withania somnifera (WS) showed significance protection against stress induced gastric ulcers. WS have anti-tumor effect on Chinese Hamster Ovary (CHO) cell carcinoma. It was also found effective against urethane induced lung-adenoma in mice. In some cases of uterine fibroids, dermatosarcoma, long term treatment with WS controlled the condition. It has a Cognition Promoting Effect and was useful in children with memory deficit and in old age people loss of memory. It was also found useful in neurodegenerative diseases such as Parkinson’s, Huntington’s and Alzeimer’s diseases. It has GABA mimetic effect and was shown to promote formation of dendrites. It has anxiolytic effect and improves energy levels and mitochondrial health. It is an anti-inflammatory and antiarthritic agent and was found useful in clinical cases of Rheumatoid and Osteoarthritis. Large scale studies are needed to prove its clinical efficacy in stress related disorders, neuronal disorders and cancers. Key words: Withania somnifera, rejuvenator, adaptogen / anti-stress, anti-tumor, neuroregenerative, anti-arthritic. doi: 10.4314/ajtcam.v8i5S.9
Article
Objective: To evaluate the effect of Ashwagandha (ASW) in attenuation of alcohol withdrawal in ethanol withdrawal mice model. Methods: Alcohol dependence was induced in mice by the oral, once-daily administration of 10% v/v ethanol (2 g/kg) for one week. Once the animals were withdrawn from alcohol, the efficacy of ASW (200mg/kg and 500mg/kg) in comparison with diazepam (1 mg/kg) in the attenuation of withdrawal was studied using, pentylenetetrazole (PTZ) kindling test for seizure threshold, forced swim test (FST) for depression and locomotor activity (LCA) in open field test (OFT). 6 hours after the last ethanol administration, seizure threshold was measured in all the groups by administering the convulsant drug, PTZ with a subconvulsive dose of 30 mg/kg i.p). In FST, mice were forced to swim and the total duration of immobility (seconds) was measured during the last 4 min of a single 6-min test session. In OFT, number of crossings of the lines marked on the floor was recorded for a period of 5 min. Results: Compared to ethanol group, ASW (500 mg/Kg) has suppressed the PTZ kindling seizures in ethanol withdrawal animals [0% convulsion], FST has shown decreased immobility time and OFT has exhibited increase in the number of line crossing activity by mice which may be the consequence of anxiolytic activity of ASW similar to that of diazepam. Conclusions: The present study provides satisfactory evidence to use ASW as a safe and reliable alternative to diazepam in alcohol withdrawal conditions.
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A large body of literature has emerged concerning the role of the neurotransmitter serotonin (5-hydroxytryptamine, or 5-HT) in the regulation of alcohol intake and the development of alcoholism. Despite the wealth of information, the functional significance of this neurotransmitter remains to be fully elucidated. This paper, part one of a two-part review, summarizes the available clinical research along two lines: the effects of alcohol on serotonergic functioning and the effects of pharmacological manipulation of serotonergic functioning on alcohol intake in normal (nonalcohol dependent) and alcohol-dependent individuals. It is concluded that considerable evidence exists to support the notion that some alcoholic individuals may have lowered central serotonin neurotransmission.
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Article
Introduction: Debate continues over the precise causal contribution made by mesolimbic dopamine systems to reward. There are three competing explanatory categories: 'liking', learning, and 'wanting'. Does dopamine mostly mediate the hedonic impact of reward ('liking')? Does it instead mediate learned predictions of future reward, prediction error teaching signals and stamp in associative links (learning)? Or does dopamine motivate the pursuit of rewards by attributing incentive salience to reward-related stimuli ('wanting')? Each hypothesis is evaluated here, and it is suggested that the incentive salience or 'wanting' hypothesis of dopamine function may be consistent with more evidence than either learning or 'liking'. In brief, recent evidence indicates that dopamine is neither necessary nor sufficient to mediate changes in hedonic 'liking' for sensory pleasures. Other recent evidence indicates that dopamine is not needed for new learning, and not sufficient to directly mediate learning by causing teaching or prediction signals. By contrast, growing evidence indicates that dopamine does contribute causally to incentive salience. Dopamine appears necessary for normal 'wanting', and dopamine activation can be sufficient to enhance cue-triggered incentive salience. Drugs of abuse that promote dopamine signals short circuit and sensitize dynamic mesolimbic mechanisms that evolved to attribute incentive salience to rewards. Such drugs interact with incentive salience integrations of Pavlovian associative information with physiological state signals. That interaction sets the stage to cause compulsive 'wanting' in addiction, but also provides opportunities for experiments to disentangle 'wanting', 'liking', and learning hypotheses. Results from studies that exploited those opportunities are described here. Conclusion: In short, dopamine's contribution appears to be chiefly to cause 'wanting' for hedonic rewards, more than 'liking' or learning for those rewards.