54 Factors that May Increase Dopamine

Modulation of Dopaminergic Pathways to Treat Erectile Dysfunction

54 Factors that May Increase Dopamine

Volume 119, Issue S3

The currently recommended first‐line treatments of erectile dysfunction (ED), phosphodiesterase type 5 inhibitors (PDE5i), for example sildenafil, are efficacious in many patients with ED of vascular origin, but this therapy is insufficient in approximately 30–40% of men with ED where there is also a neuronal affection. There is a demand of novel approaches to treat the condition. We review the possibility of modulating the dopaminergic pathways to improve erectile function. Dopamine D1 (D1, D5)‐ and D2 (D2–D4)‐ receptors in the paraventricular area, the medial pre‐optic area, the spinal cord, and in the erectile tissue are involved in erection, and several agonists developed for the treatment of Parkinson's disease are associated with increased libido. A therapeutic window for the treatment of ED was found by sublingual administration of the general dopamine receptor agonist apomorphine, but it failed mainly due to less efficacy on erectile function compared with PDE5i. To avoid the dose‐limiting side effects mediated by D2 receptors, nausea and emesis, dopamine D4 receptor agonists were developed, and they induce erection in rodents, but these drugs were never introduced clinically. The β‐lactamase inhibitor clavulanic acid increases dopamine and serotonin and was found to increase sexual arousal and erections, but the dose–response curve is bell‐shaped. Bupropion has selectivity for inhibition of the dopamine reuptake transporter and can be used to alleviate sexual symptoms caused by other antidepressant medication, hence providing an interesting approach to treat ED. In summary, modulation of the dopaminergic pathways provides a possibility to improve the treatment of ED.

Erection is a hemodynamic event where vasodilatation of intracavernous and helicine arteries is followed by increased arterial blood inflow to the corpora cavernosa. Erection involves different central and peripheral neural and/or humoral mechanisms 1.

Central neurotransmitters and neuropeptides can either facilitate, for example dopamine (DA), or inhibit (e.g. opioid peptides) penile erection by acting in several brain areas.

Serotonin can exert both facilitatory and inhibitory effects, depending on the receptor subtype involved 2.

Peripheral neurotransmitters released from sympathetic (noradrenaline, ATP) and parasympathetic (acetylcholine, nitric oxide, vasoactive intestinal peptide) nerves entering the corpora cavernosa, corpus spongiosum and glans penis regulate blood flow during erection and detumescence 1, 3, 4. In metabolic syndrome and diabetes, neuropathy as well as an imbalance between peripheral contractile and relaxant factors in the erectile tissue can contribute to erectile dysfunction (ED) 5.

Current guidelines recommend phosphodiesterase type 5 inhibitors (PDE5i), sildenafil, vardenafil, tadalafil and avanafil, as the first‐line treatment of ED; however, approximately 30–40% of men with ED do not respond to PDE5 inhibitor therapy 6, 7.

Patients suffering from neurological damage, diabetes mellitus or severe vascular disease may be resistant to PDE5 inhibitors 8. In addition to these diseases, medications of central nervous system (CNS) disorders, antidepressants, antipsychotics and anxiolytics, have also a negative impact on the erectile function 5.

Antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and venlafaxine, can negatively affect the male sexual function (desire/arousal–excitement–orgasm). Other antidepressants, bupropion, nefazodone and mirtazapine, also affect sexual function, although the incidence of sexual dysfunction is lower, compared with SSRI 9.

In addition to mood disorders, antidepressants are also used to treat neuropathic pain; therefore, sexual dysfunction induced by antidepressants affects a wider population.

In some clinical trials, sildenafil corrected ED induced by antidepressant medication; however, due to an increasing number of non‐responders to PDE5 inhibitors, there is a demand for novel approaches to the treatment of ED. An approach would be to target not only the peripheral pathways but also the central pathways of importance for erectile function.

As mentioned, a series of neurotransmitters are involved in erectile function both at central and peripheral levels and a series of recent reviews have addressed the regulation in detail 1, 2 and clinical studies related to sexual dysfunction and monoamines 10.

A comprehensive review which covers some of the most recent drugs under development for ED can also be recommended 11. For the treatment of Parkinson's disease, several drugs with dopaminergic effect were developed, and one of these drugs the general dopamine receptor agonist, apomorphine, was found to induce erection 12-15. Therefore, the focus of the present MiniReview is to consider the possibility of modulating the dopaminergic pathways to improve erectile function.

The central pathways involved in the control of erectile function include several brain areas such as the medial pre‐optic area (MPOA), the paraventricular nucleus (PVN) of hypothalamus, the ventral tegmental area, the hippocampus, the amygdala, the bed nucleus of the stria terminalis, the nucleus accumbens, the medulla oblongata and the spinal cord 2, where the PVN of hypothalamus and the ventral tegmental area are particularly important 2, 15. A series of neurotransmitters are involved in the central regulation of erection and they facilitate erectile function (dopamine, nitric oxide, glutamate, acetylcholine, oxytocin, hexarelin peptide, ACTH, MSH and pro‐VGF), inhibit erectile function (e.g. noradrenaline, enkephalins, GABA and endocannabinoids) or in case of serotonin both facilitate and inhibit erectile function 2. Dopamine is the main neurotransmitter in the CNS and facilitates sexual motivation, copulation and genital reflexes 1, 16. Dopamine, thought to be of importance for erectile function, is localized in the MPOA and the PVN of the hypothalamus and the nucleus accumbens. These three areas receive dopaminergic innervation from the incertohypothalamic system 17. In the PVN, dopamine leads to the activation of oxytocinergic neurons probably by increasing intracellular calcium followed by the activation of neuronal nitric oxide synthase (nNOS). Nitric oxide through a cyclic GMP‐independent pathway probably nitrosylation is thought to lead to the activation of the oxytocinergic neurons (fig. 1). Nitric oxide is formed by nNOS and castration and also exogenous testosterone, respectively, down‐and up‐regulate the expression of nNOS in the PVN 2.

Dopaminergic pathways involved in penile erection (drawn in black). Imagination, memory recall, olfactory, visual and tactile stimuli are processed in cortex and lead to increased dopamine levels in the paraventricular nucleus of hypothalamus followed by the activation of dopamine D2, D3, D4 receptors and increase in neuronal nitric oxide synthase (nNOS) activity in oxytocinergic neurons, which project to extra‐hypothalamic areas including the lumbosacral part of the spinal cord, where neurons are activated and through parasympathetic nerves lead to the activation of nNOS in erectile tissue. Activation of dopamine receptors in the lumbosacral part of the spinal cord and in the erectile tissue are also involved in the erection.

Furthermore, dopaminergic neurons have been identified that travel from the caudal hypothalamus to innervate the autonomic and somatic nuclei in the lumbosacral spinal cord 18, 19. Thus, dopamine can be expected to participate in the regulation of both the autonomic and somatic components of the penile reflexes.

The PVN oxytocinergic neurons project to the neurohypophysis and other brain areas, but also to medulla oblongata and the spinal cord, where it leads to the activation of the pro‐erectile lumbo‐sacral parasympathetic neurons innervating genitalia.

Apparently, a spinal dopaminergic pathway is also of importance for erectile function. Fibres immunoreactive to dopamine are present in the thoracolumbar sympathetic chain and also in the lumbosacral parasympathetic nucleus 20, 21.

Moreover, a strong dopamine D2 receptor expression was found in the lumbosacral parasympathetic neurons 22.

Further support for a dopaminergic pathway at spinal level comes from the observations that in rats with spinal cord lesions at the thoracic T8 segment, the dopaminergic agonist apomorphine infused systemically is able to induce erection in rats by a mechanism antagonized by dopamine D2 receptor antagonist (haloperidol, sulpiride) and facilitated by a dopamine D1 receptor antagonist (SCH23390) 23. These observations were also supported by the observations that intrathecal administration of apomorphine induces spontaneous erectile responses 24.

Penile erection is initiated by inhibition of the sympathetic nerves and activation of parasympathetic pelvic nerves leading to penile arterial dilatation and relaxation of the erectile smooth muscle cells of the corpora cavernosa.

This allows blood filling of the cavernous sinusoids and restriction of the venous out‐flow, with entrapment of pressurized blood in the corpora cavernosa.

Release of nitric oxide from the parasympathetic nerves plays an important role for the relaxation, and the increase in blood inflow to penis during the erection also stimulates the endothelial cell layer to release nitric oxide and other endothelium‐dependent vasodilators contributing to maintain erection 25-27.

In contrast to the role of dopamine in the CNS, the role of dopamine in the peripheral erectile tissue is less clear. Infusion of dopamine induces erection in cats 28, and an antagonist of dopamine D1 receptors, SCH23390, markedly inhibits the increase in intracavernosal pressure induced by stimulating the cavernous nerve in rats 29.

Dopamine D1 and D2 receptors are expressed in erectile tissue from rats and man 30, 31, and patch clamp of isolated smooth muscle cells from corpus cavernosum suggested that dopamine and dopaminergic agonists induce relaxation by opening of large‐conductance calcium‐activated potassium channels 32.

There is evidence for the expression of the dopamine transporter in the endothelial cells of systemic arteries 33, 34, but this has still not been examined in endothelial cells of erectile tissue.

Despite dopamine can be formed in sympathetic nerve terminals, the source of dopamine in erectile tissue remains to be clarified, and also whether the dopamine involved in erection derives from the endothelium or other structures in the erectile tissue.

In summary, dopaminergic pathways in CNS and in the lumbosacral part of the spinal cord are involved in the erectile function, and in the erectile tissue there is probably also a dopaminergic pathway. This suggests that modulation of the dopaminergic pathways can aim at all three levels or hydrophilic drugs targeting only the peripheral dopaminergic pathways can be attempted.

The first drug with dopaminergic effect found to induce erection was the general dopaminergic receptor agonist, apomorphine 12, and most of the evidence related to pro‐erectile effects has been obtained for dopaminergic receptor agonists.

There are five main subtypes of dopamine receptors D1–D5 grouped as D1‐ (D1, D5), and D2‐ (D2, D3 and D4) receptors.

Binding affinities are described for the dopamine receptor agonists in table 1, although that does not necessarily correspond to the functional effects of the drugs on the respective receptors.

Some of the drugs are only partial agonists at the receptors meaning that high concentrations may antagonize the endogenous ligand dopamine. Moreover, homo‐ and heterodimers of dopamine receptors have been described, and that may also change both affinity and effect of the respective agonists 35.

D1 GαS cAMP↑, Ca2+↑ D2 Gi/Go cAMP↓, K+↑ D3 Gi/Go cAMP↓, K+↑ D4 Gi/Go cAMP↓, K+↑ D5 GαS cAMP↑
Apomorphine5.3–6.27.6 (PA)6.1–7.68.4 (PA)6.4–7.8 (PA)
Bromocriptine6.2 (PA)7.37.1 (PA)6.3 (PA)
Cabergoline6.79.0–9.2 (PA)9.17.3 (PA)7.7
Lisuride7.29.2–9.59.3 (PA)8.3
PD168,0778.8 (PA)
ABT 724

Source: https://onlinelibrary.wiley.com/doi/full/10.1111/bcpt.12653

Dopamine deficiency: Symptoms, causes, and treatment

54 Factors that May Increase Dopamine

Dopamine is a chemical found naturally in the human body. It is a neurotransmitter, meaning it sends signals from the body to the brain.

Dopamine plays a part in controlling the movements a person makes, as well as their emotional responses. The right balance of dopamine is vital for both physical and mental wellbeing.

Vital brain functions that affect mood, sleep, memory, learning, concentration, and motor control are influenced by the levels of dopamine in a person’s body. A dopamine deficiency may be related to certain medical conditions, including depression and Parkinson’s disease.

A dopamine deficiency can be due to a drop in the amount of dopamine made by the body or a problem with the receptors in the brain.

Share on PinterestA dopamine deficiency is associated with depression, but researchers are still investigating this complex link.

The symptoms of a dopamine deficiency depend on the underlying cause. For example, a person with Parkinson’s disease will experience very different symptoms from someone with low dopamine levels due to drug use.

Some signs and symptoms of conditions related to a dopamine deficiency include:

  • muscle cramps, spasms, or tremors
  • aches and pains
  • stiffness in the muscles
  • loss of balance
  • constipation
  • difficulty eating and swallowing
  • weight loss or weight gain
  • gastroesophageal reflux disease (GERD)
  • frequent pneumonia
  • trouble sleeping or disturbed sleep
  • low energy
  • an inability to focus
  • moving or speaking more slowly than usual
  • feeling fatigued
  • feeling demotivated
  • feeling inexplicably sad or tearful
  • mood swings
  • feeling hopeless
  • having low self-esteem
  • feeling guilt-ridden
  • feeling anxious
  • suicidal thoughts or thoughts of self-harm
  • low sex drive
  • hallucinations
  • delusions
  • lack of insight or self-awareness

Share on PinterestDopamine deficiency may be influenced by a number of factors. Existing conditions, drug abuse, and an unhealthy diet may all be factors.

Low dopamine is linked to numerous mental health disorders but does not directly cause these conditions.

The most common conditions linked to a dopamine deficiency include:

In Parkinson’s disease, there is a loss of the nerve cells in a specific part of the brain and loss of dopamine in the same area.

It is also thought that drug abuse can affect dopamine levels. Studies have shown that repeated drug use could alter the thresholds required for dopamine cell activation and signalling.

Damage caused by drug abuse means these thresholds are higher and therefore it is more difficult for a person to experience the positive effects of dopamine. Drug abusers have also been shown to have significant decreases in dopamine D2 receptors and dopamine release.

Diets high in sugar and saturated fats can suppress dopamine, and a lack of protein in a person’s diet could mean they do not have enough l-tyrosine, which is an amino acid that helps to build dopamine in the body.

One interest study found that people who are obese and have a certain gene are more ly to be dopamine deficient too.

There is no reliable way to directly measure levels of dopamine in a person’s brain.

There are some indirect ways to determine a dopamine level imbalance in the brain. Doctors can measure the density of dopamine transporters that correlate positively with nerve cells that use dopamine. This test involves injecting a radioactive material that binds to dopamine transporters, which doctors can measure using a camera.

A doctor will look at a person’s symptoms, lifestyle factors, and medical history to determine if they have a condition related to low levels of dopamine.

Share on PinterestOmega-3 fatty acid supplements may help to boost dopamine levels naturally.

Treatment of dopamine deficiency depends on whether an underlying cause can be found.

If a person is diagnosed with a mental health condition, such as depression or schizophrenia, a doctor may prescribe medications to help with the symptoms. These drugs may include anti-depressants and mood stabilizers.

Ropinirole and pramipexole can boost dopamine levels and are often prescribed to treat Parkinson’s disease. Levodopa is usually prescribed when Parkinson’s is first diagnosed.

Other treatments for a dopamine deficiency may include:

  • counseling
  • changes in diet and lifestyle
  • physical therapy for muscle stiffness and movement problems

Supplements to boost levels of vitamin D, magnesium, and omega-3 essential fatty acids may also help to raise dopamine levels, but there needs to be more research into whether this is effective.

Activities that make a person feel happy and relaxed are also thought to increase dopamine levels. These may include exercise, therapeutic massage, and meditation.

Dopamine and serotonin are both naturally occurring chemicals in the body that have roles in a person’s mood and wellbeing.

Serotonin influences a person’s mood and emotions, as well as sleep patterns, appetite, body temperature, and hormonal activity, such as the menstrual cycle.

Some researchers believe that low levels of serotonin contribute to depression. The relationship between serotonin and depression and other mood disorders is complex and unly to be caused by a serotonin imbalance alone.

Additionally, dopamine affects how a person’s moves, but there is no clear link to the role of serotonin in movement.

Dopamine deficiency can have a significant impact on a person’s quality of life, affecting them both physically and mentally. Many mental health disorders are linked to low levels of dopamine. Other medical conditions, including Parkinson’s disease, have also been linked to low dopamine.

There is limited evidence that diet and lifestyle can affect the levels of dopamine a person creates and transmits in their body. Certain medications and some therapies may help relieve symptoms, but a person should always speak to a doctor first if they are concerned about their dopamine levels.

Source: https://www.medicalnewstoday.com/articles/320637

Prolonged High Fat Diet Reduces Dopamine Reuptake without Altering DAT Gene Expression

54 Factors that May Increase Dopamine

The development of diet-induced obesity (DIO) can potently alter multiple aspects of dopamine signaling, including dopamine transporter (DAT) expression and dopamine reuptake.

However, the time-course of diet-induced changes in DAT expression and function and whether such changes are dependent upon the development of DIO remains unresolved. Here, we fed rats a high (HFD) or low (LFD) fat diet for 2 or 6 weeks.

Following diet exposure, rats were anesthetized with urethane and striatal DAT function was assessed by electrically stimulating the dopamine cell bodies in the ventral tegmental area (VTA) and recording resultant changes in dopamine concentration in the ventral striatum using fast-scan cyclic voltammetry.

We also quantified the effect of HFD on membrane associated DAT in striatal cell fractions from a separate group of rats following exposure to the same diet protocol. Notably, none of our treatment groups differed in body weight.

We found a deficit in the rate of dopamine reuptake in HFD rats relative to LFD rats after 6 but not 2 weeks of diet exposure. Additionally, the increase in evoked dopamine following a pharmacological challenge of cocaine was significantly attenuated in HFD relative to LFD rats.

Western blot analysis revealed that there was no effect of diet on total DAT protein. However, 6 weeks of HFD exposure significantly reduced the 50 kDa DAT isoform in a synaptosomal membrane-associated fraction, but not in a fraction associated with recycling endosomes. Our data provide further evidence for diet-induced alterations in dopamine reuptake independent of changes in DAT production and demonstrates that such changes can manifest without the development of DIO.

Citation: Cone JJ, Chartoff EH, Potter DN, Ebner SR, Roitman MF (2013) Prolonged High Fat Diet Reduces Dopamine Reuptake without Altering DAT Gene Expression. PLoS ONE 8(3): e58251. https://doi.org/10.1371/journal.pone.0058251

Editor: Sidney Arthur Simon, Duke University Medical Center, United States of America

Received: October 26, 2012; Accepted: February 5, 2013; Published: March 13, 2013

Copyright: © 2013 Cone et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: The project described was supported by National Institutes of Health (NIH) grants DA025634 (MFR)and T32-MH067631 from the Biomedical Neuroscience Training Program (JJC).

Additional support was provided by the National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH, through grant UL1RR029877 (JJC) and by the Chicago Biomedical Consortium with support from the Searle Funds at The Chicago Community Trust (JJC).

The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the Chicago Biomedical Consortium. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

The overweight and obese represent an increasingly larger percentage of the United States and worldwide populations [1], [2]. While there are many pathways to obesity, perhaps one of the biggest threats to healthy body weight is the prevalence and consumption of highly palatable, densely caloric foods [3].

Indeed, the energy density (kcal/g) of food potently contributes to overweight and obesity in adults [4], [5]. Palatable foods evoke dopamine release in the striatum of both humans and non-human animals [6], [7], [8], [9] and subjective ratings of fattiness in food are positively correlated with the strength of neural responses in the ventral striatum [10].

Thus, dopamine and the striatum appear to contribute to preferences for energy dense foods. Recently, it was shown that differences in diet can cause simultaneous changes in striatal circuitry and food-directed behavior [11].

However, perhaps less appreciated is the growing evidence that differences in ingested foods, especially with respect to fat, can feedback on and alter striatal dopamine signaling.

Striatal dopamine signaling is regulated by several factors including dopamine production by the enzyme tyrosine hydroxylase, pre- and postsynaptic dopamine receptors, and presynaptic dopamine transporters (DATs), all of which have been implicated in obesity [12], [13].

Alterations in DAT number or function can alter the sphere of influence of released dopamine and consequently striatal function [14], [15]. Insulin, released in response to ingested food, has been shown to influence DAT function [16], [17].

Thus, the DAT is one of the ly candidates for the effects of diet.

Recently, correlations between obesity and DAT availability as well as diet-induced alterations of DAT function have been explored. Body mass index (BMI) is negatively correlated with DAT availability in the human striatum [18]. DAT binding, and hence availability, is reduced in high fat diet (HFD) fed mice [19].

HFD -induced obesity (DIO) is associated with a reduced rate of dopamine reuptake by the DAT in rats [20]. Taken together, these studies suggest that obesity established by HFD consumption can potently influence critical presynaptic regulators of dopamine signaling – especially the DAT.

However, the time course of diet-induced alterations in dopamine signaling and whether the development of DIO is requisite for changes to manifest remains unknown. We assayed DAT function by evoking dopamine release in the ventral striatum and quantifying its rate of reuptake in rats using fast-scan cyclic voltammetry.

To determine if decreased dopamine reuptake was caused by reduced DAT gene expression, we measured DAT mRNA in the ventral tegmental area and substantia nigra using real-time qRT-PCR. Additionally, we used a biochemical fractionation procedure and Western blot analysis to assay striatal DAT levels in crude synaptosomal and endosomal membranes.

Rats had either 2 or 6 weeks of high or low fat diet, but all measurements were made in the absence of DIO. Our results suggest that prolonged consumption of HFD, independent of DIO, decreases the rate of dopamine reuptake in the ventral striatum without decreasing DAT expression.

This study was carried out in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The protocol was approved by the Animal Care Committee at the University of Illinois, Chicago. All surgery was performed under urethane anesthesia, and all efforts were made to minimize suffering.

Standard male Sprague–Dawley rats (n = 67), approximately 2 months old and weighing 225–275 g upon arrival were used. Animals were individually housed in plastic cages (26.

5×50×20 cm) in a temperature- (22°C) and humidity- (30%) controlled environment on a 12∶12 h light:dark cycle (lights on at 07∶00 h).

Rats acclimated to the facility for one week with ad libitum access to standard lab chow and water.

After acclimation, rats were weighed and randomly assigned to 1 of 4 groups that were counterbalanced for initial body weight. Two groups were maintained on low fat diet (LFD; Research Diets, New Brunswick, NJ; D12450B; 10% kilocalories from fat (3.85 kcal/g)). The other 2 groups were maintained on HFD (Research Diets; D12492; 60% kilocalories from fat (5.24 kcal/g)).

For each diet, rats were maintained for either 2 or 6 weeks (wks). Thus, the 4 groups were: LFD-2 wk (n = 18), HFD-2 wk (n = 16), LFD-6 wk (n = 16) and HFD-6 wk (n = 17). All groups had ad libitum access to water.

Food intake and body weight measurements were made three times/wk and data are reported separately for rats undergoing voltammetric recordings or DAT protein/message analysis.

Following diet exposure, a subset of rats that did not differ in body weight were prepared for voltammetric recordings (LFD-2 wk (n = 8), HFD-2 wk (n = 6), LFD-6 wk (n = 6), and HFD-6 wk (n = 7)) under urethane (1.5 g/kg) anesthesia [as in 9,21]. A guide cannula (Bioanalytical Systems, West Lafayette, IL) was positioned above the ventral striatum (1.3 mm anterior, 1.

5 mm lateral from bregma), a chlorinated silver wire (Ag/AgCl) reference electrode was implanted in the contralateral cortex and both were secured to the skull with stainless steel screws and dental cement. A micromanipulator containing a carbon-fiber electrode (CFE) was inserted into the guide cannula and the electrode was lowered into the ventral striatum.

The CFE and reference electrode were connected to a headstage and the potential of the CFE was scanned from −0.4 to +1.3 V (vs. Ag/AgCl) and back (400 V/s; 10 Hz). A bipolar stimulating electrode (Plastics One, Roanoke, VA) was then gradually lowered into the ventral tegmental area/substantia nigra pars compacta (VTA/SNpc; 5.2 mm posterior, 1.0 mm lateral and initially 7.

0 mm ventral from bregma) in 0.2 mm increments. At each increment, a train of current pulses (60 pulses, 4 ms per pulse, 60 Hz, 400 µA) was delivered.

When the stimulating electrode is positioned in the VTA/SNpc and the CFE is in the striatum, stimulation reliably evokes dopamine release – extracted from voltammetric data using principal component analysis [9], [22]; and converted into concentration after each CFE is calibrated in a flow injection system following each experiment [23].

The position of the stimulating electrode was optimized for maximal release. The CFE was then allowed to equilibrate for 10 min before starting the experiment. Dopamine release was evoked by electrical stimulation of the VTA/SNpc (same parameters as above), and the resultant changes in dopamine concentration were calculated from −5 s to 10 s relative to stimulation.

Immediately following stimulation, rats were injected with cocaine hydrochloride dissolved in 0.9% saline (10 mg/kg i.p.) and, 10 min later, the stimulation was repeated. Applied voltages, data acquisition, and analysis were performed using software written in LabVIEW (National Instruments, Austin, TX, USA) [22].

Dopamine reuptake was modeled using Demon Voltammetry Analysis Software (24; Wake Forest University, Winston-Salem NC). Here we report the decay constant tau as our measure of the rate of dopamine reuptake.

Tau is derived from an exponential curve fit that encompasses the majority of the dopamine clearance curve and is highly correlated (r = .9899) with Km, the apparent affinity of dopamine for the DAT [24].

To determine the effect of cocaine on peak dopamine concentration we compared values obtained before and after administration (% change).

After each recording, a stainless steel electrode (A-M Systems #571500, Sequim, WA) was lowered to the same depth as the CFE and a lesion (10 µA, 4 s) was made to mark the recording location.

Brains were removed and stored in 10% formalin. Light microscopy was used to identify the lesion location on coronal sections (50 µm) through the striatum.

All recordings reported here were made in the ventral striatum [25].

Rats (LFD-2 wk, HFD-2 wk, LFD-6 wk, and HFD-6 wk; n = 10/group; no difference in body weight) were killed by decapitation. Biochemical fractionation was performed using the protocol described in [26], with minor modifications.

Brains were rapidly removed, frozen in isopentane and sliced on a cryostat (HM505E, Microm, Walldorf, Germany, −20°C) until reaching the striatum. Bilateral 1-mm3 punches through the ventral striatum (average tissue weight: 15.2 mg) were homogenized for 20 s in 0.8 ml ice-cold TEVP (10 mM Tris base, 5 mM NaF, 1 mM Na3VO4, 1 mM EDTA, 1 mM EGTA, pH 7.

4) +320 mM sucrose buffer. A 100 µl aliquot of total homogenate (H) was saved. The remainder of H was centrifuged at 800×g for 10 min at 4°C. The pellet (P1, nuclei and large debris) was resuspended in 0.2 ml TEVP buffer and saved. The supernatant (S1) was removed and placed in a clean tube on ice.

S1 was centrifuged at 9200×g for 15 min at 4°C to generate a pellet (P2, crude synaptosomal membranes) and a supernatant (S2). P2 was rinsed once in TEVP +35.6 mM sucrose buffer and then resuspended in 0.25 ml of TEVP +35.6 mM sucrose buffer, vortexed gently for 3 s and hypo-osmotically lysed by keeping the sample on ice for 30 min.

Supernatant (S2) was collected and spun at 165,000×g for 2 h to generate a pellet (P3, light membranes, recycling endosomes) that was resuspended in TEVP (0.1 ml) and saved. All samples were kept at −80°C until polyacrylamide gel electrophoresis.

Protein content was determined using the Bio-Rad DC Protein Assay kit (Hercules, CA), and the concentration of each sample was adjusted to 0.3 mg/ml protein. NuPAGE LDS (lithium dodecyl sulfate) sample buffer (Invitrogen, Carlsbad, CA) and 50 mM dithiothreitol were added to each sample prior to heating at 70°C for 10 min.

To load equivalent amounts of protein for each fraction, 3 µg of each sample were loaded into NuPAGE Novex 4–12% Bis-Tris gels (Invitrogen) for separation by gel electrophoresis. Proteins were subsequently transferred to polyvinylidene fluoride membrane (PVDF) (PerkinElmer Life Sciences, Boston, MA).

Nonspecific binding sites were blocked for 2 hr at room temperature in blocking buffer (5% nonfat dry milk in PBS and 0.02% Tween 20 [PBS-T]).

Blots were then incubated in primary antibody (1∶3000 mouse monoclonal anti-NR2B [#05–920, Millipore], 1∶5000 rabbit anti-DAT [#AB2231, Millipore], and 1∶1000 mouse monoclonal anti-transferrin receptor (TfR) [#13–6800, Invitrogen]. Blots were cut into 3 parts: high (>97 kDa), medium (46–97 kDa), and low (

Source: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0058251

Concerta Addiction and Abuse

54 Factors that May Increase Dopamine

Concerta (methylphenidate) is a prescription stimulant in the same class as Ritalin. In fact, Concerta and Ritalin have essentially the same chemical make-up, but Concerta is the extended-release version, lasting up to 12 hours.

The chemical makeup of Concerta is similar to other stimulants cocaine and amphetamine, and the drug is similarly addictive.

Those who use the drug recreationally—without a prescription—and those who take more than their prescribed dosage are at risk for developing a Concerta addiction.

A person with an addiction to Concerta will experience uncomfortable withdrawal symptoms if they stop taking the drug, such as paranoia, fatigue and depression. Other signs of Concerta addiction include:

  • Needing higher doses to feel the drug’s effects (tolerance)
  • Experiencing strong urges to use Concerta
  • Finding new ways to obtain the drug—legally or illegally—in order to abuse it
  • Using Concerta even if it’s causing issues with loved ones or responsibilities

Those struggling with a Concerta addiction are advised not to quit taking the drug without medical supervision. A medical provider can set up a tapering program for the user where the drug will be administered in increasingly smaller doses. A medical professional can also help users manage and treat withdrawal symptoms.

When abused by older teens or adults – especially if it’s crushed or poured from capsules then snorted or injected – the drug is more other forms of amphetamine, including methamphetamine, that have damaging and addictive psychological and physical effects.

– Dr. Lawrence Diller, The Sacramento Bee, 2015

Understanding Concerta (Methylphenidate)

Concerta pills are cylindrical in shape and either red, gray, yellow or white, depending on the potency. They are formulated in 18 mg, 27 mg, 36 mg and 54 mg strengths. Concerta is a brand name of the drug methylphenidate. Other brand names of methylphenidate include:

  • Aptensio XR
  • Metadate CD
  • Metadate ER
  • Ritalin
  • Ritalin LA
  • Ritalin SR

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Street names for Concerta include kibbles & bits, kiddy cocaine, pineapple, kiddie coke, smarties and skittles. Concerta is a Schedule II regulated stimulant.

Concerta is primarily used as a stimulant medication to increase attention span and decrease hyperactivity and impulsive behavior.

Concerta and other stimulants have a calming effect for individuals with ADHD and similar conditions and increase focus, so they are widely used to treat attention deficit hyperactivity disorder (ADHD).

However, if individuals who do not have ADHD take these medications, the result will be hyperactivity and overstimulation.

The drug also slowly raises the user’s dopamine levels in the brain, achieving a therapeutic effect for those with proper ADHD (and similar) diagnoses.

Some people abuse Concerta by taking more pills than prescribed or by crushing and snorting large doses of it for a more powerful high. The drug can also be abused intravenously.

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Concerta Effects and Abuse

Getting or using Concerta without a prescription is considered abuse of the drug. For those with a prescription, increasing the dose and/or frequency without the prescribing doctor’s recommendation is also considered Concerta abuse.

Concerta affects chemicals in the brain and nervous system that contribute to hyperactivity and impulse control. It is often prescribed to treat ADHD and narcolepsy. Although many people take Concerta to treat these conditions, others abuse the drug for its stimulant properties.

People may abuse Concerta to:

  • As a stimulant, Concerta increases focus and concentration as well as alertness and energy level. College-age students commonly abuse stimulants as study aids.

  • Stimulants are appetite suppressants, so people abuse Concerta in order to lose weight.

  • Because Concerta activates the reward system in the brain, the drug can provide a high when taken by someone who is not being treated for ADHD. Increased dopamine levels are associated with attention and pleasure.

Taking too much Concerta can lead to overdose, which can be life-threatening.

A Concerta overdose can affect the individual both physically and psychologically. Physical Concerta overdose symptoms include:

  • Vomiting
  • Twitching
  • Convulsions
  • Headache
  • Increased or irregular heart rate
  • Increased blood pressure
  • Sinus arrhythmia
  • Dry mouth
  • Uncontrollable tremors
  • Flushed skin
  • Abdominal cramps
  • Fever
  • Overactive reflexes
  • Rapid breathing
  • Restlessness

Psychological symptoms of Concerta overdose include:

  • Manic- state
  • Psychoses
  • Aggression
  • Compulsive behaviors
  • Hallucinations
  • Delusions
  • Paranoia
  • Disorientation
  • Mental confusion
  • Feeling panic/panic attacks

Concerta abuse can cause enormous strain on the user’s heart and cardiovascular system. In the most severe cases, Concerta abuse may result in cardiac arrhythmia, heart attack, excessively high or low blood pressure, stroke, circulation failure, convulsions, seizure, coma, or fatal drug poisoning.

Common Concerta Drug Combinations

Concerta is sometimes taken in combination with other drugs, such as alcohol—especially among college students. Mixing Concerta with alcohol can have dangerous consequences.

As a stimulant, Concerta can override the depressant effects of alcohol. Users may not feel the effects of alcohol they normally would, leading them to drink more. This increases the risk of alcohol poisoning, which can be fatal.

Combining the drug with alcohol can also intensify the negative side effects of Concerta, such as nausea, headaches and dizziness. It can also cause anxiety and impaired concentration in the user.

Concerta Abuse Statistics



Approximately 6.4 million children four to 17 years of age have been diagnosed with ADHD.


college students

Approximately one-third of college students have abused stimulants Concerta.


ER visits

There were 15,585 emergency room visits related to ADHD treatment medications Concerta reported in 2010.

Overcoming a Concerta addiction can be difficult, but professional treatment can help with the process. Please contact us now for help finding a Concerta addiction treatment program.

Source: https://www.addictioncenter.com/stimulants/concerta/