Amphetamine also possesses the ability to inhibit the enzymes monoamine oxidase A and B (MAO-A and MAO-B) in high doses. MAO-A is responsible for the break down of serotonin, dopamine, norepinephrine, and epinephrine. MAO-B is responsible for breaking down dopamine (more potently than MAO-A) and phenylethylamine (PEA), which has actions similar to amphetamine itself, and is thought to be involved in feelings of lust, confidence, obsession, and sexuality. Some of the first antidepressants successfully marketed are in fact Monoamine-Oxidase inhibitors. However, MAO inhibition seen with amphetamine is not substantial enough in duration and quantity to entail the need for a tyramine-limited diet, unlike the more potent and long lived MAO-inhibiting antidepressants.
Amphetamine's ability to cause the inhibition of MAO results in the accumulation of monoamines: amphetamine directly stimulates the release of these neurochemicals, resulting in a potent elevation in monoamine neurotransmission. In sum, the effect of amphetamines is to increase neurotransmitter availability in the synapse, by both releasing more neurotransmitters, as well as prolonging their availability in the synapse by slowing their removal.
possible mechanisms of action of adderall: dopamine reuptake inhibition
Dextroamphetamine induces more euphoria, whereas levoamphetamine induces more depression
dextroamphetamine = S(+) isomer
"Amphetamines are believed to exert their effects by binding to the monoamine transporters and increasing extracellular levels of the biogenic amines dopamine, norepinephrine, and serotonin."
"It is hypothesized that D-amphetamine acts primarily on the dopaminergic (DA) systems, while L-amphetamine is comparatively norepinephrinergic (NE). The primary reinforcing and behavioral-stimulant effects of amphetamine, however, are linked to enhanced dopaminergic activity, primarily in the mesolimbic dopaminergic pathway. Amphetamine binds to the dopamine transporter (DAT) and blocks the transporter's ability to clear DA from the synaptic space. In addition, amphetamine is transported into the cell, which leads to dopamine efflux (DA is transported out of the cell and into the synaptic space via reverse transport of the DAT)."
mesolimbic dopaminergic pathway
http://en.wikipedia.org/wiki/Mesolimbic_pathway
"The mesolimbic pathway is one of the dopaminergic pathways in the brain. The pathway begins in the ventral tegmental area of the midbrain and connects to the limbic system via the nucleus accumbens, the amygdala, and the hippocampus as well as to the medial prefrontal cortex. It is known to be involved in modulating behavioral responses to stimuli that activate feelings of reward (motivation) and reinforcement through the neurotransmitter dopamine.[1]"
The mesolimbic dopaminergic pathway begins in the ventral tegmental area of the midbrain and connects to the limbic system via the nucleus accumbens, amygdala, hippocampus, medial prefrontal cortex.
"Studies have shown that rats that had their ventral tegmental area and nucleus accumbens destroyed do not lose their learning capabilities, but rather lack the motivation to work for a reward." [5]
[5] # ^ a b Berridge KC. 2007. The debate over dopamine's role in reward: the case for incentive salience. Psychopharmacology 191:391-431
mesolimbic dopaminergic pathway:
ventral tegmental area: *ventral-tegmental-area
nucleus acumbens:
location: ventral striatum
characteristics:
- medium spiny neurons
- # ^ Zhang TA, Maldve RE, Morrisett RA. 2006. Coincident signaling in mesolimbic structures underlying alcohol reinforcement. Biochemical Pharmacology 72:919-27
- # ^ Purves D et al. 2008. Neuroscience. Sinauer 4ed. 754-56
shell: #limbic region
core: #motor region
medium spiny neurons:
receive-input-from:
dopaminergic neurons of the VTA
glutamatergic neurons of the hippocampus
glutamatergic neurons (?) of the amygdala
glutamatergic neurons of the medial prefrontal cortex
output-GABA-to:
ventral pallidium: #part of the basal ganglia
adderall
Adderall XR
- 1/4 dextroamphetamine saccharate
- 1/4 dextroamphetamine sulfate
- 1/4 (racemic dextro/levo-amphetamine) aspartate monohydrate
- 1/4 (racemic dextro/levo-amphetamine) sulfate
http://en.wikipedia.org/wiki/Racemic "In chemistry, a racemic mixture, or racemate, is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule. The first known racemic mixture was "racemic acid," which Louis Pasteur found to be a mixture of the two enantiomeric isomers of tartaric acid."
"Adderall XR utilizes the Microtrol extended-release delivery system, incorporating two types of beads. The first dissolves immediately, releasing half of the medication, while the second type dissolves much more slowly releasing the remaining medication four hours later. Maximum plasma concentration is achieved in seven hours, compared to instant-release Adderall, which reaches maximum plasma concentration within three hours. As a result of its high bioavailability, Adderall XR's effectiveness is not altered by food absorption in the gastrointestinal tract. However, mean plasma concentration is prolonged by 2.5 hours (using a 900 calorie standard high-fat meal as the control). Medications that alter urinary pH will cause variations in amount and method of excretion and usage should be monitored when taken concurrently with Adderall."
Microtrol extended-release delivery system "Microtrol is an extended-release drug delivery system.[1] It is used in certain medications like Adderall and incorporates two types of beads. The first dissolves immediately, releasing half of the medication, while the second type dissolves much more slowly releasing the remaining medication four hours later. Maximum plasma concentration is achieved in seven hours, compared to instant-release which reaches maximum concentration in three hours.[citation needed] Microtrol is manufactured by Supernus Pharmaceuticals, Inc.[2]"
Supernus Pharmaceuticals, Inc. http://www.supernuspharma.com/
"The new product is formulated using patented Microtrol technology, based on the use of coated or uncoated 'multiparticulates' or beadlets that can be filled into capsules or compressed into tablets. These beads then release the therapeutic drug into the body at certain points, depending on pH. The same technology is used in the existing Adderall XR ADHD drug. "
"Supernus was founded by the former Shire Laboratories president and chief executive Jack Khattar and aims to develop products for its own portfolio and in partnership with other pharmaceutical companies. Mr Khattar said: "Our decision to acquire SLI's [Shire Laboratories] product formulation and development business was based on SLI's success and proven track record in developing advanced products? utilising its unique technology platforms and capabilities. "We will be applying those same technology platforms and capabilities to build our own pipeline of specialty products and to continue to support our partners." The main technologies that Supernus has under its belt are ProScreen and OptiScreen for lead selection and formulation optimisation, and the oral controlled release technologies Microtrol, Solutrol and EnSoTrol. "
Jack A. Khattar, CEO of Supernus, former Shire Laboratories president and chief executive
David Schappelle, human resources at Supernus
@ Rockville
Jim Barrett, Supernus board member
Michael Bigham, Supernus board member
"REDI, a public-private partnership spun off from the city of Rockville, was intent on keeping the jobs it saw as key to the area's growing biotechnology industry."
"It all came together when Khattar landed venture capital from New York-based OrbiMed and Baltimore-based New Enterprise Associates (NEA)"
http://nea.com/ http://abingworth.com/
Supernus Contacts Jack Khattar President & CEO Tel: 301 838-2500 1550 E Gude Drive Rockville, MD 20850 www.supernuspharma.com Woody Bryan VP Business Development Tel: 301 838-2681 Email Contact
phone: 301-838-2500
address: 1550 E Gude Drive, Rockville, MD 20850
http://maps.google.com/maps?f=q&source=s_q&hl=en&geocode=&q=1550+E+Gude+Drive,+Rockville,+MD+20850&sll=37.0625,-95.677068&sspn=32.939885,65.302734&ie=UTF8&ll=39.095351,-77.13244&spn=0.001969,0.003986&t=h&z=18
at inception, Supernus had 51 employees (down from 78 of the original).
East Gude Road office
levoamphetamine urinary pH stomach pH
Alkalinity increases bioavailability and acidity causes the drug to be excreted sooner.
Adderall XR utilizes the Microtrol extended-release delivery system, incorporating two types of beads. The first dissolves immediately, releasing half of the medication, while the second type dissolves much more slowly releasing the remaining medication four hours later. Maximum plasma concentration is achieved in seven hours, compared to instant-release Adderall, which reaches maximum plasma concentration within three hours.
The authors found that sustained-release dexamphetamine (the main isomeric-amphetamine component of Adderall) had a longer duration of action, though D-amphetamine was less effective in the first few hours. http://www.healthsystem.virginia.edu/internet/pediatrics/pharma-news/v8n3.pdf
Differential Effects of Amphetamine Isomers on Dopamine in the Rat Striatum and Nucleus Accumbens Core
Michael Yasick
http://shire.com/
http://adderallxr.com/
http://www.shirestudyresults.org/
An Interim Analysis of the Quality of Life, Effectiveness, Safety, and Tolerability (QU.E.S.T.) Evaluation of Mixed Amphetamine Salts Extended Release in Adults With ADHD. D.W. Goodman, L. Ginsberg, R.H. Weisler, et al. CNS Spectrums,2005;10(12,Suppl 20):26-34.
http://www.shirestudyresults.org/documents/
http://www.google.com/patents?id=uLoUAAAAEBAJ&dq=microtrol+%22Shire+Laboratories%22+OR+%22Shire+Labs%22
Inventors: Richard A. Couch, Beth A. Burnside, Rong-Kun Chang
Obetrol http://en.wikipedia.org/wiki/Obetrol
Obetrol contained (Per 10mg tablet)[1]:
- 2.5mg methamphetamine Saccharate
- 2.5mg methamphetamine hydrochloride
- 2.5mg (racemic dextro/levo-amphetamine) sulfate
- 2.5mg dextroamphetamine sulfate
Rasmussen, Nicolas (2008-03-01). "On Speed: The Many Lives of Amphetamine". New York University Press. pp. p.148 Fig. 33. http://hist-phil.arts.unsw.edu.au/staff/staff.php?first=Nicolas&last=Rasmussen. Retrieved on 2009-01-27
patent # 2748052
http://www.google.com/patents?id=5OtKAAAAEBAJ&printsec=abstract&zoom=4&dq=patent:2748052&as_drrb_ap=q&as_minm_ap=0&as_miny_ap=&as_maxm_ap=0&as_maxy_ap=&as_drrb_is=q&as_minm_is=0&as_miny_is=&as_maxm_is=0&as_maxy_is=&num=100&source=gbs_summary_r&cad=0_0
Inventor: Armin Rosner
http://www.shire.com/shire/Products/products.jsp?country=us
dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, USP, amphetamine sulfate USP
gelatin capsules, hydroxypropyl methylcellulose, methacrylic acid copolymer, opadry beige, sugar spheres, talc, and triethyl citrate. Gelatin capsules contain edible inks, kosher gelatin, and titanium dioxide. The 5 mg, 10 mg, and 15 mg capsules also contain FD&C Blue #2. The 20 mg, 25 mg, and 30 mg capsules also contain red iron oxide and yellow iron oxide.
Manufactured for Shire US Inc., Wayne, PA, 19087.
Enantiomeric amphetamine compositions (R.A. Couch) http://www.google.com/patents?id=6WafAAAAEBAJ&dq=ENANTIOMERIC+AMPHETAMINE+COMPOSITIONS+FOR+THE+TREATMENT+OF+ADHD&num=100
Richard A. Couch, Alex Michaels, Paul Hodgkins
AM Michaels http://cogres.com/ShowPage.asp?page=GaryKay.asp
Simulated Driving Changes in Young Adults With ADHD Receiving Mixed Amphetamine Salts Extended Release and Atomoxetine
Paul S Hodgkins Some Metabotropic Glutamate Receptor Ligands Reduce Kynurenate Synthesis in Rats by Intracellular Inhibition of Kynurenine Aminotransferase II.
kynurenic acid (tryptophan metabolism?)
http://www.bcbsms.com/index.php?id=155&articleid=621482 "Elevated brain levels of a compound called kynurenic acid are associated with problem-solving deficits in people with schizophrenia, according to U.S. researchers." (John P. Bruno)
"Kynurenic acid is present in all human brains and has useful functions. However, an excessive amount of the compound interferes with other chemical processes involved in the ability to pay attention and think strategically under changing circumstances, said Bruno and colleagues, who conducted their research in rats."
""So, we've already got problems with these neurotransmitters, and then to make matters worse, we've got all this extra kynurenic acid antagonizing the alpha-7 receptors, which just throws gasoline on the fire," Bruno said. "If we can design drugs that are able to inhibit the enzymes that are responsible for overproducing kynurenic acid, we may improve cognitive performance in these patients.""
Stimulation of cortical acetylcholine release following blockade of ionotropic glutamate receptors in nucleus accumbens
"In vivo microdialysis techniques were used to determine the ability of glutamate receptors within the nucleus accumbens to trans-synaptically modulate the basal forebrain cortical cholinergic system. Rats were implanted with a dialysis probe in the medial prefrontal cortex to measure changes in cortical acetylcholine efflux and in the ipsilateral nucleus accumbens to locally manipulate glutamate receptor activity. Intra-accumbens perfusion of the broad spectrum ionotropic glutamate receptor antagonist kynurentate (1.0, 5.0 mm) led to a dose-dependent increase (maximum of 200%) in cortical acetylcholine efflux. This stimulated efflux was reproduced with the intra-accumbens perfusion of the AMPA/kainate antagonist DNQX (0.1, 0.25, 2.5 mm; maximum increase of 200%) or the NMDA antagonist D-CPP (10.0, 100.0, 200 µM; maximum increase of 400%). These results reveal a significant glutamatergic tone within the accumbens of awake rats and support the hypothesis that accumbens efferents to basal forebrain modulate the excitability of the basal forebrain cortical cholinergic system."
Hyperdopaminergic Mutant Mice Have Higher "Wanting" But Not "Liking" for Sweet Rewards
"These results indicate that chronically elevated extracellular dopamine facilitates "wanting" and learning of an incentive motivation task for a sweet reward, but elevated dopamine does not increase "liking" reactions to the hedonic impact of sweet tastes."
Mice with Chronically Elevated Dopamine Exhibit Enhanced Motivation, but not Learning, for a Food Reward
"The increase in dopamine is associated with elevated levels of dynorphin and Fos B expression in the dorsal caudate-putamen and the core but not the shell subregion of the nucleus accumbens"
http://researchnews.osu.edu/archive/kynacid.htm
"Excess levels of kynurenic acid inhibit the work of the alpha-7 receptors, meaning they suppress the release of these neurotransmitters even more."
"“So we’ve already got problems with these neurotransmitters, and then to make matters worse, we’ve got all this extra kynurenic acid antagonizing the alpha-7 receptors, which just throws gasoline onto the fire,†Bruno said. “If we can design drugs that are able to inhibit the enzymes that are responsible for overproducing kynurenic acid, we may improve cognitive performance in these patients.â€"
Coauthors on the studies are Ohio State researchers and graduate students
Amy Zmarowski, Katie Alexander, Ã…sa Konradsson, Clelland Gash and Julie Brooks, as well as Robert Schwarcz and Hui-Qiu Wu of the University of Maryland School of Medicine.
Amy Zmarowski
Katie Alexander
Ã…sa Konradsson
Clelland Gash
Julie Brooks
Robert Schwarcz
Hui-Qiu Wu
Contact: John Bruno, (614) 292-1770; Bruno.1@osu.edu
http://faculty.psy.ohio-state.edu/bruno/
"We are also studying nicotinic receptor agonists as a means of potentiating the release of ACh in cortex."
"In the rat striatum, S-ESBA produced a 35% reduction in extracellular KYNA, which was accompanied by a 270% increase in extracellular DA."
"KYNA synthesis was dose-dependently reduced by L-leucine or L-phenylalanine, two amino acids that compete with L-kynurenine for cellular uptake, and by aminooxyacetate, a non-specific aminotransferase inhibitor."
alpha 7 nicotinic acetylcholine receptor
CHRNA7
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1139&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSum
regulation of the expression of CHRNA7 ?
alpha-bungarotoxin inhibits a7NAChRs
"Excess levels of kynurenic acid inhibit the work of the alpha-7 receptors, meaning they suppress the release of these neurotransmitters even more."
"In the mammalian brain, KYNA can be produced by several kynurenine aminotransferases (KATs), of which KAT II appears to be the most functionally relevant (Guidetti et al., 2007a). This enzyme is almost exclusively localized in astrocytes (Guidetti et al., 2007b), which promptly release newly formed KYNA into the extracellular millieu (Turski et al., 1989)
[avoid: alpha-bungarotoxin] [avoid: tryptophan]
- L-leucine
- L-phenylalanine
- S-ESBA (S-ethylsulfonylbenzoylalanine)
indicates indo-3-pyruvate and cysteine as efficient inhibitors for hKAT-I,
L-α-aminoadipate aminotransferase; EC 2.6.1.39;
2-Oxoacids Regulate Kynurenic Acid Production in the Rat Brain: Studies In Vitro and In Vivo.
"This study was designed to examine the role of 2-oxoacids in the enzymatic transamination of L-kynurenine to the excitatory amino acid receptor antagonist, kynurenate, in the rat brain. In brain tissue slices incubated in Krebs-Ringer buffer with a physiological concentration of L-kynurenine, pyruvate, and several other straight- and branched-chain 2-oxoacids, substantially restored basal kynurenate production in a dose-dependent manner without increasing the intracellular concentration of L-kynurenine. All 2-oxoacids tested also reversed or attenuated the hypoglycemia-induced decrease in kynurenate synthesis, but only pyruvate and oxaloacetate also substantially restored intracellular L-kynurenine accumulation. Thus, 2-oxoacids increase kynurenate formation in the brain primarily by functioning as co-substrates of the transamination reaction. This was supported further by the fact that the nonspecific kynurenine aminotransferase inhibitors (aminooxy)acetic acid and dichlorovinylcysteine prevented the effect of pyruvate on kynurenate production in a dose-dependent manner. Moreover, all 2-oxoacids tested attenuated or prevented the effects of veratridine, quisqualate, or L-[alpha]-aminoadipate, which reduce the transamination of L-kynurenine to kynurenate. Finally, dose-dependent increases in extracellular kynurenate levels in response to an intracerebral perfusion with pyruvate or [alpha]-ketoisocaproate were demonstrated by in vivo microdialysis. Taken together, these data show that 2-oxoacids can directly augment the de novo production of kynurenate in several areas of the rat brain. 2-Oxoacids may therefore provide a novel pharmacological approach for the manipulation of excitatory amino acid receptor function and dysfunction."