Increase Brain Dopamine Levels Research Articles

Neurochemical Effects of the Adipokinetic Hormone/Red Pigment Concentrating Hormone Family of Peptides in MK-801-Induced Schizophrenia Rat Model

Objective: Adipokinetic hormone (AKH) plays a role in sugar and lipid metabolism in insects. Previous studies of AKH showed memory improvements in a schizophrenia rat model that displayed memory impairment and reduced depression in a rat olfactory bulbectomy model. In this study, we investigated the effects of the adipokinetic hormone/red pigment-concentrating hormone (AKH/RPCH) family of peptides on brain neurotransmitter levels and brain neurochemistry in a schizophrenia rat model. Materials and Methods: We administered AKH/RPCH peptides for 4 days sub-chronically, both in naive rats and also in the MK-801-induced schizophrenia rat model. Liquid chromatography-mass spectrometry apparatus was used for targeted and untargeted analysis of rat neurochemistry. Results: Increased brain glutamate levels characteristic of MK-801 peptide-treated rats were significantly reduced by AKH. Furthermore, AKH also increased brain dopamine levels in both naive and MK-801 rats. Metabolomic studies have shown that AKH affects lipid and glutamate metabolism, while hypertrehalosaemic hormone plays a role in sugar metabolism and inflammation. Conclusion: According to our results, AKH might affect dopaminergic and glutamatergic systems and reverse the effects of MK-801, possibly affecting NMDA receptors.

An inhibitory signal associated with danger reduces honeybee dopamine levels

Positive and negative experiences can alter animal brain dopamine levels.1 When first arriving at a rewarding food source or beginning to waggle dance and recruit nestmates to food, honeybees have increased brain dopamine levels, indicating a desire for food.2 We provide the first evidence that an inhibitory signal, the stop signal, which counters waggle dancing and is triggered by negative events at the food source, can decrease head dopamine levels and dancing, independent of the dancer having any negative experiences. The hedonic value of food can therefore be depressed simply by the receipt of an inhibitory signal. Increasing the brain dopamine levels reduced the aversive effects of an attack, increasing the time that bees spent subsequently feeding and waggle dancing and decreasing their stop signaling and time spent in the hive. Because honeybees regulate food recruitment and its inhibition at the colony level, these results highlight the complex integration of colony information with a basic and highly conserved neural mechanism in mammals and insects.2 VIDEO ABSTRACT.

Bile duct ligation increased dopamine levels in the cerebral cortex of rats partly due to induction of tyrosine hydroxylase.

Liver failure is associated with psychiatric alterations, partly resulting from the increased brain dopamine levels. We investigated the relationship between increased dopamine levels and mental abnormalities using bile duct ligation (BDL) rats and the mechanism by which liver failure increased dopamine levels in SH-SY5Y cells. Behavioural tests were carried out on day 13 and 27 following BDL, along with measurements of dopamine and metabolites, expressions of enzymes and transporters related to dopamine metabolism, and its transport into the cortex and the hippocampus. SH-SY5Y cells were used to investigate whether NH4 Cl, bile acids and bilirubin affected expression of tyrosine hydroxylase or not. Tyrosine hydroxylase (TH) expression in SH-SY5Y cells co-incubated with bilirubin and signal pathway inhibitors was measured. Open-field test results demonstrated BDL rats showed anxiety-like behaviour, accompanied by increased dopamine levels and expression of TH protein in the cortex. Membrane bound long form (MB)-COMT, slightly but significantly decreased. SH-SY5Y cells indicated that increased bilirubin levels was a factor in inducing TH expression. Both inhibitor of NF-κB pathway BAY 11-7082 and silencing NF-κB p65 reversed bilirubin-induced upregulation of TH protein. NF-κB activator TNF-α increased expression of TH protein. Roles of bilirubin in increases of TH protein expressions and dopamine levels were measured using hyperbilirubinemia rats. Anxiety-like behaviour, was associated with increased dopamine levels and TH protein expressions in hyperbilirubinemia rats. BDL significantly increased dopamine levels in rat cortex partly due to bilirubin-mediated TH induction. Increased bilirubin induced TH expression via activating NF-κB signalling pathway.

Effects of walnut (Juglans regia L.) kernel extract and juglone on dopamine levels and oxidative stress in rats

3,4-dihydroxyphenethylamine (dopamine) is a neurotransmitter that has vital functions in the nervous system. Dopamine metabolism and reactive oxygen species (ROS) production are highly related processes. The present study aims to evaluate the effects of walnut (Juglans regia L.) extract (WE) and 5-hydroxy-1,4 naphthoquinone (juglone) on dopamine levels and oxidative stress. For this purpose, WE and juglone were administered to rats. Serum and brain dopamine levels, total oxidant status (TOS), and total antioxidant status (TAS) were measured after 21 days. The oxidative stress index (OSI) was calculated. WE (300 mg/kg) significantly increased brain dopamine levels. WE and juglone reduced oxidative stress in liver and brain tissues compared to serum. Our results revealed that WE and juglone might have a neuroprotective effect. Further studies are needed to extensively investigate the molecular mechanism of the effects of herbal extracts and phenolic compounds on brain health.

Neuroprotective Effects of P-Coumaric Acid on Haloperidol-Induced Catalepsy Through Ameliorating Oxidative Stress and Brain Dopamine Level

Objective To evaluate the effect of p-coumaric acid (p-CA) on haloperidol-induced catalepsy in Swiss albino male mice. Methods To induce catalepsy, haloperidol (1 mg/kg i.p.) was administered for 21 consecutive days. p-CA (50, 75, and 100 mg/kg, PO) was administered 30 min before haloperidol injection for 21 consecutive days. For catalepsy, locomotor activity and motor coordination scores were recorded on the 17, 14, and 21 days of drug treatment, while the gait analysis score was recorded on day 21. After behavioral testing, animals were sacrificed, and various biochemical and histopathology tests of the brain were conducted. Dopamine, malondialdehyde, reduced glutathione (GSH), superoxide dismutase (SOD), and catalase activity were examined in the brain. Results Chronic administration of haloperidol significantly increased catalepsy in mice. It also produced hypolocomotion, motor coordination, and gait disturbance in mice. p-CA significantly inhibited haloperidol-induced catalepsy. Haloperidol significantly increased malondialdehyde levels in the brain. While dopamine levels in the brain dropped along with GSH, SOD, and catalase activity levels, which also had an impact on the histology of the brain. p-CA significantly reduced haloperidol-induced increases in brain oxidative stress, dopamine levels in the brain, and brain histology in mice. Discussion p-CA significantly reduced haloperidol-induced catalepsy, possibly through reducing oxidative stress and increasing brain dopamine levels. It can be a good candidate drug for extrapyramidal symptoms in Parkinson’s disease and adjuvant therapy with antipsychotic drugs.

Two-month administration of methylphenidate improves olfactory sensitivity and suppresses appetite in individuals with obesity.

Olfaction contributes to feeding behaviour and is modulated by changes in dopamine levels. Methylphenidate (MPH) increases brain dopamine levels and has been shown to reduce appetite and promote weight loss in patients with attention deficit hyperactivity disorder. The objectives of this study were to test the effect of MPH on olfaction, appetite, energy intake, and body weight (BW) on individuals with obesity. In a randomized, double-blind study, 12 participants (age 28.9 ± 6.7 years) with a body mass index (BMI) of 36.1 ± 4.5kg/m2 were assigned to MPH (0.5mg/kg) (n= 5) or placebo (n= 7) twice daily for 2months. Appetite (visual analog scale), odour threshold (Sniffin' Sticks®), energy intake (food menu), and BW (DEXA scan) were measured at day1 and day60. MPH intake significantly increased odour threshold scores (6.3 ± 1.4 vs. 9.4 ± 2.1 and 7.9 ± 2.3 vs. 7.8 ± 1.9, respectively; p= 0.029) versus placebo. There was a significantly greater suppression of appetite sensations (desire to eat (p= 0.001), hunger (p= 0.008), prospective food consumption (p= 0.003)) and an increase in fullness (p= 0.028) over time in the MPH versus placebo. MPH suppressed appetite and improved olfactory sensitivity in individuals with obesity. These data provide novel findings on the favourable effects of MPH on appetite and weight regulation in individuals living with obesity.

Discovery of a macromolecular complex mediating the hunger suppressive actions of cocaine: Structural and functional properties.

Cocaine not only increases brain dopamine levels but also activates the sigma1 receptor (σ1 R) that in turn regulates orexigenic receptor function. Identification of interactions involving dopamine D1 (D1 R), ghrelin (GHS-R1a ), and σ1 receptors have been addressed by biophysical techniques and a complementation approach using interfering peptides. The effect of cocaine on receptor functionality was assayed by measuring second messenger, cAMP and Ca2+ , levels. The effect of acute or chronic cocaine administration on receptor complex expression was assayed by in situ proximity ligation assay. In silico procedures were used for molecular model building. σ1 R KO mice were used for confirming involvement of this receptor. Upon identification of protomer interaction and receptor functionality, a unique structural model for the macromolecular complex formed by σ1 R, D1 R, and GHS-R1a is proposed. The functionality of the complex, able to couple to both Gs and Gq proteins, is affected by cocaine binding to the σ1 R, as confirmed using samples from σ1 R-/- mice. The expression of the macromolecular complex was differentially affected upon acute and chronic cocaine administration to rats. The constructed 3D model is consistent with biochemical, biophysical, and available structural data. The σ1 R, D1 R, and GHS-R1a complex constitutes a functional unit that is altered upon cocaine binding to the σ1 R. Remarkably, the heteromer can simultaneously couple to two G proteins, thus allowing dopamine to signal via Ca2+ and ghrelin via cAMP. The anorexic action of cocaine is mediated by such complex whose expression is higher after acute than after chronic administration regimens.

Nilotinib increases brain dopamine and lowers CSF tau and oligomeric alpha-Synuclein in Parkinson's disease

This is a single center phase II, randomized, double-blind, placebo-controlled study to evaluate the effects of nilotinib, a potentially disease modifying drug in Parkinson's disease (PD). Our preclinical evidence indicate that nilotinib increases brain dopamine levels and reduces toxic tau and alpha-Synuclein via autophagy in models of neurodegeneration. We predicted that nilotinib alters exploratory biomarkers via inhibition of Abl in the CSF after 12-month daily nilotinib treatment in 3 groups, including placebo (n=21), 150mg nilotinib (n=21) and 300mg nilotinib (n=20).

The role of dopamine in dynamic effort-reward integration

When deciding to act, the neurotransmitter dopamine is implicated in a valuation of prospective effort and reward. However, its role in dynamic effort-reward integration during action, a process central to everyday behaviour, remains unclear. In a placebo-controlled, within-subject, study, we probed the impact of increasing brain dopamine levels (150 mg of levodopa) and blocking dopamine receptors (1.5 mg of haloperidol) in the context of a novel dynamic effort task in healthy human subjects. We show that modulating homoeostatic dopamine balance distinctly alters implicit and explicit effort allocation as a function of instantaneous reward. Pharmacologically boosting dopamine enhanced motor vigour, reflected in an implicit increase in effort allocation for high rewards. Conversely, pharmacological blockade of dopamine attenuated sensitivity to differences in reward context, reflected in reduced strategic effort discounting. These findings implicate dopamine in an integration of momentary physical experience and instantaneous reward, suggesting a key role of dopamine in acting to maximise reward on the fly.

Commonly Abused Drugs Differentially Increase the Frequency and Amplitude of Accumbal Transient Dopamine Release Events

The rewarding and reinforcing effects of abused drugs are thought to be mediated by their ability to increase brain dopamine levels. The canon holds that all drugs of abuse increase dopamine release in a brain region called the nucleus accumbens (NAc) but, due to the temporal constraints of previously available neurochemical techniques, it remains unknown how distinct drugs of abuse alter dopamine release in real time. A real time assessment is important due to the nature by which dopamine neurons fire. In awake and behaving rats, dopamine neurons fire in two distinct patterns. At ‘rest,’ dopamine neurons fire in a low‐frequency pacemaker fashion that is thought to produce a tone on high‐affinity dopamine receptors in the NAc. When presented with motivationally relevant stimuli, dopamine neurons fire in high‐frequency bursts. The phasic bursts of dopamine neural activity contribute to the generation of subsecond release events in the NAc that are sufficient in concentration to occupy low‐affinity dopamine receptors. As the activation of these low‐affinity receptors is thought to be particularly important in strengthening action‐outcome associations, we are especially interested in investigating how drugs of abuse alter their patterns of release. Fast‐scan cyclic voltammetry (FSCV) allows for the detection of dopamine release events with a temporal resolution of milliseconds, making it an ideal tool with which to examine how drugs of abuse alter transient dopamine release events in real time. We obtain two primary dependent measures of dopamine release, the frequency at which they occur and the total concentration of each event.Here, we are using FSCV to compare how different drugs of abuse alter the frequency and amplitude of dopamine release events in the awake and behaving rat. Drugs of investigation include: ethanol, diazepam, zolpidem, WIN55,212‐2, methamphetamine, methylenedioxymethamphetamine (MDMA) and heroin. Preliminary data show that the sedative‐hypnotics ethanol, diazepam and zolpidem all increase the frequency but decrease the amplitude of dopamine release events; although the ethanol amplitude effect is biphasic. Heroin, the synthetic cannabinoid WIN55,212‐2, and the psychostimulant methamphetamine increase both the frequency and amplitude of dopamine release events. The psychostimulant and tryptamine psychedelic MDMA increases the amplitude of dopamine release events but not their frequency. Together, these data reveal that the effects of abused drugs on transient dopamine release events varies across drug classes.Support or Funding InformationFunding for this work was provided by NSF grant IOS‐1557755, NIH grant R03DA038734, Boettcher Young Investigator Award and NARSAD Young Investigator Award to EBOThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Diazepam Concurrently Increases the Frequency and Decreases the Amplitude of Transient Dopamine Release Events in the Nucleus Accumbens.

Benzodiazepines are commonly prescribed anxiolytics that pose abuse liability in susceptible individuals. Although it is well established that all drugs of abuse increase brain dopamine levels, and benzodiazepines are allosteric modulators of the GABAA receptor, it remains unclear how they alter dopamine release. Using in vivo fast-scan cyclic voltammetry, we measured diazepam-induced changes in the frequency and amplitude of transient dopamine release events. We found that diazepam concurrently increases the frequency and decreases the amplitude of transient dopamine release events in the awake and freely moving rat. The time course during which diazepam altered the frequency and amplitude of dopamine release events diverged, with the decreased amplitude effect being shorter lived than the increase in frequency, but both showing similar rates of onset. We conclude that diazepam increases the frequency of accumbal dopamine release events by disinhibiting dopamine neurons, but also decreases their amplitude. We speculate that the modest abuse liability of benzodiazepines is due to their ability to decrease the amplitude of dopamine release events in addition to increasing their frequency.

Neural Stem Cells Derived from Human Parthenogenetic Stem Cells Engraft and Promote Recovery in a Nonhuman Primate Model of Parkinson's Disease.

Cell therapy has attracted considerable interest as a promising therapeutic alternative for patients with Parkinson's disease (PD). Clinical studies have shown that grafted fetal neural tissue can achieve considerable biochemical and clinical improvements in PD. However, the source of fetal tissue grafts is limited and ethically controversial. Human parthenogenetic stem cells offer a good alternative because they are derived from unfertilized oocytes without destroying potentially viable human embryos and can be used to generate an unlimited supply of neural cells for transplantation. We have previously reported that human parthenogenetic stem cell-derived neural stem cells (hpNSCs) successfully engraft, survive long term, and increase brain dopamine (DA) levels in rodent and nonhuman primate models of PD. Here we report the results of a 12-month transplantation study of hpNSCs in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned African green monkeys with moderate to severe clinical parkinsonian symptoms. The hpNSCs manufactured under current good manufacturing practice (cGMP) conditions were injected bilaterally into the striatum and substantia nigra of immunosuppressed monkeys. Transplantation of hpNSCs was safe and well tolerated by the animals with no dyskinesia, tumors, ectopic tissue formation, or other test article-related serious adverse events. We observed that hpNSCs promoted behavioral recovery; increased striatal DA concentration, fiber innervation, and number of dopaminergic neurons; and induced the expression of genes and pathways downregulated in PD compared to vehicle control animals. These results provide further evidence for the clinical translation of hpNSCs and support the approval of the world's first pluripotent stem cell-based phase I/IIa study for the treatment of PD (Clinical Trial Identifier NCT02452723).

Baicalin may have a therapeutic effect in attention deficit hyperactivity disorder

Baicalin is a flavonoid purified from Scutellaria baicalensis Georgi. It possesses a variety of pharmacological properties, such as anti-inflammatory, antioxidant, antiapoptotic, and neuro-protective properties, and provides protection against cerebral hemorrhage. However, it is seldom considered a therapeutic in mental disorders. Recent studies showed that baicalin protects cerebral functions against ischemia and has sedative and anxiolytic-like effects. Animal experiments showed that it protects dopaminergic neurons in the striatum, hippocampus and substantia nigra. It also has effects such as anti-depressive and anti-epileptic and offers resistance to Parkinson’s disease. Attention deficit hyperactivity disorder (ADHD) pathogenesis is closely related to dopamine deficiency. However, the therapeutic effect of baicalin in ADHD has not been studied. We hypothesize that baicalin may protect dopaminergic neurons and increase brain dopamine levels, thus serving as an effective novel treatment for ADHD.

Methylphenidate decreases fat and carbohydrate intake in obese teenagers

Dopamine is a neurotransmitter that mediates the reward value of food. Methylphenidate (MPH) selectively binds and inhibits the dopamine transporter, thus increasing brain dopamine levels shortly after oral administration. This investigation studied whether a single dose of MPH decreases energy intake (EI) in obese teenagers compared to placebo (P). This study used a single-blind, placebo-controlled, within subject design. Teenagers with body mass index (BMI) ≥95th percentile underwent two identical meal tests (P or MPH) after a 10 h fast in random order. Food was weighed before and after the meals, and EI was calculated as energy content/gram of consumed foods. Total and macronutrient EI (mean ± SD) were analyzed by Mann-Whitney U and Wilcoxon tests. Twenty-two subjects (15 females, 7 males) completed the study. Participants were 13.4 ± 2.2 years old and had BMI 34.9 ± 10.7 kg/m². EI from fat (167 vs. 203 kcal, P = 0.03) and carbohydrates (311 vs. 389 kcal, P = 0.04) was decreased for MPH compared to P meals, with a trend in decreased total EI (545 vs. 663 kcal, P = 0.06). A single dose of MPH decreases EI from fat and carbohydrates in obese adolescents. This effect underscores the importance of central dopamine signaling on eating behavior.

Prolactinoma-associated obesity treated with bupropion and methylphenidate

Obesity has been strongly associated with dopaminergic deficiency and dysfunctional reward processing [Wang et al. 2001; Johnson and Kenny, 2010]. Dopamine is proposed to regulate food intake by modulating food-related reward signals within the mesolimbic circuity of the brain [Martel and Fantino, 1996] as well as peripherally regulating adipocyte function [Ben-Jonathan and Hnasko, 2001]. Increased food intake has been interpreted in terms of compensation for an underlying dopaminergic deficiency including reduced phasic reward signals to food stimuli. Consistently, patients receiving D2-receptor blocking compounds report increased appetite and weight gain [Baptista, 1999]. Conversely, drugs increasing brain dopamine levels promote reductions, both in weight and appetite. [Towell et al. 1988; Foltin et al. 1990]. Prolactin-secreting pituitary adenomas may serve as a mechanistically plausible example to investigate the role of dopamine in obesity. Prolactinomas suppress the dopaminergic tone and, consistently, have been shown to be associated with body weight gain and obesity [Greenman et al. 1998]. Similar brain lesions that lead to obesity have also been shown to be associated with a reduced dopaminergic tone, e.g. hypothalamic tumors such as craniopharyngioma [Elfers and Roth, 2011]. Still, the exact mechanism of the association of prolactinoma and obesity is insufficiently understood and studies on obesity after normalization of prolactin levels show inconsistent results [Greenman et al. 1998; Delgrange et al. 1999; dos Santos Silva et al. 2011]. However, both standard pharmacological treatments for prolactinoma and cognitive–behavioural treatment often fail to reduce patients’ weight [Doknic et al. 2002; dos Santos Silva et al. 2011]. Overall, there is a considerable need for effective clinical options to address obesity associated with pituitary tumours and to elucidate the relationship between central and peripheral dopamine effects on adipogenesis including the role of prolactin. The above-mentioned observations suggest the exploration of novel dopaminergic strategies.

Cutaneous Vasculopathy Associated with Levamisole-Adulterated Cocaine

We report a case of cutaneous vasculopathy associated with the use of levamisole-adulterated cocaine. This recently described clinical entity is characterized by a purpuric rash with a predilection for the ears, leukopenia, and anti-neutrophilic cytoplasmic antibody (ANCA) positivity. It is estimated that more than 70% of the current United States cocaine supply is contaminated with levamisole. Levamisole is a widely available, inexpensive, white powder used as a "cutting agent" in cocaine to expand volume and increase profits. It may also increase the euphoric and stimulatory effects of cocaine by increasing brain dopamine levels and producing amphetamine-like metabolites. Our patient exhibited a characteristic rash with involvement of the ears, leukopenia, and cocaine metabolites were detected in serum and urine. The presence of levamisole was confirmed in the urine utilizing gas chromatography-mass spectrometry. ANCA positivity was also present. Punch biopsy of the skin demonstrated vascular thrombosis and necrosis without true vasculitis. We review the literature for reported cases of cocaine-levamisole cutaneous vasculopathy syndrome, highlight the salient immunologic abnormalities, and contrast the features of this entity with idiopathic systemic vasculitis.

The Latest Evidence in the Neuroscience of Solvent Misuse: An Article Written for Service Providers

This work reviews preclinical and clinical studies published during the past two decades on the cellular and behavioral effects of commonly misused solvents. In animals, acute solvent exposure produces motor impairment and antidepressant- and anxiolytic-like effects. Human intoxication from misusing solvents is similar to that of ethanol; however, hallucinations and sudden sniffing death may occur at high solvent concentrations. Among chronic misusers, there is evidence of impaired memory, increased prevalence of psychiatric disorders, and neurological damage. Solvents facilitate inhibitory neurotransmission and block excitatory mechanisms. Toluene, in particular, increases brain dopamine levels and its effects occur at concentrations that do not dissolve cell membranes; therefore, neuronal damage is not an immediate, unavoidable consequence of solvent misuse.

Dopaminergic regulation of sleep and cataplexy in a murine model of narcolepsy.

To determine if the dopaminergic system modulates cataplexy, sleep attacks and sleep-wake behavior in narcoleptic mice. Hypocretin/orexin knockout (i.e., narcoleptic) and wild-type mice were administered amphetamine and specific dopamine receptor modulators to determine their effects on sleep, cataplexy and sleep attacks. Hypocretin knockout (n = 17) and wild-type mice (n = 21). Cataplexy, sleep attacks and sleep-wake behavior were identified using electroencephalogram, electromyogram and videography. These behaviors were monitored for 4 hours after an i.p. injection of saline, amphetamine and specific dopamine receptor modulators (D1- and D2-like receptor modulators). Amphetamine (2 mg/kg), which increases brain dopamine levels, decreased sleep attacks and cataplexy by 61% and 67%, suggesting that dopamine transmission modulates such behaviors. Dopamine receptor modulation also had powerful effects on sleep attacks and cataplexy. Activation (SKF 38393; 20 mg/kg) and blockade (SCH 23390; 1 mg/kg) of D1-like receptors decreased and increased sleep attacks by 77% and 88%, without affecting cataplexy. Pharmacological activation of D2-like receptors (quinpirole; 0.5 mg/kg) increased cataplectic attacks by 172% and blockade of these receptors (eticlopride; 1 mg/kg) potently suppressed them by 97%. Manipulation of D2-like receptors did not affect sleep attacks. We show that the dopaminergic system plays a role in regulating both cataplexy and sleep attacks in narcoleptic mice. We found that cataplexy is modulated by a D2-like receptor mechanism, whereas dopamine modulates sleep attacks by a D1-like receptor mechanism. These results support a role for the dopamine system in regulating sleep attacks and cataplexy in a murine model of narcolepsy.

The putative antidepressant DOV 216,303, a triple reuptake inhibitor, increases monoamine release in the prefrontal cortex of olfactory bulbectomized rats

The first line of antidepressant treatment nowadays are selective serotonin reuptake inhibitors. Although they are relatively safe to use, selective serotonin reuptake inhibitors (SSRIs) can induce severe side effects. New promising antidepressants may be the triple monoamine reuptake inhibitors, which not only enhance serotonin and norepinephrine neurotransmission, but also increase brain dopamine levels. Recently it has been shown that one of the triple reuptake inhibitors, DOV 216,303 has antidepressant-like effects in the olfactory bulbectomy (OBX) model of depression, but the alterations in monoaminergic neurotransmission in these animals are still unknown. In the present study we investigated not only the effect of acute, but also chronic treatment of DOV 216,303 in OBX rats on monoamine and metabolite levels. The main results are decreased baseline dopamine levels in the prefrontal cortex one day after OBX, while 38 days after OBX no difference could be observed in monoamine levels after vehicle treatment. Treatment with DOV 216,303 leads to increased extracellular levels of serotonin and norepinephrine neurotransmission, but also increased dopamine levels in OBX animals as well as their controls. This increase could be observed after one single administration, but also after chronic treatment. However, a DOV 216,303 challenge in chronically treated animals resulted in lower monoamine concentrations than the same challenge in untreated animals. More research is needed to investigate this seemingly hyporesponsivity to chronic DOV 216,303 treatment.

Citicoline affects appetite and cortico‐limbic responses to images of high‐calorie foods

Cytidine-5'-diphosphocholine (citicoline) has a variety of cognitive enhancing, neuroprotective, and neuroregenerative properties. In cocaine-addicted individuals, citicoline has been shown to increase brain dopamine levels and reduce cravings. The effects of this compound on appetite, food cravings, and brain responses to food are unknown. We compared the effects of treatment with Cognizin citicoline (500 mg/day versus 2,000 mg/day) for 6 weeks on changes in appetite ratings, weight, and cortico-limbic responses to images of high-calorie foods using functional magnetic resonance imaging (fMRI). After 6 weeks, there was no significant change in weight status, although significant declines in appetite ratings were observed for the 2,000 mg/day group. The higher dose group also showed significant increases in functional brain responses to food stimuli within the amygdala, insula, and lateral orbitofrontal cortex. Increased activation in these regions correlated with declines in appetite ratings. These preliminary findings suggest a potential usefulness of citicoline in modulating appetite, but further research is warranted.