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Amphetamines incl METH and Cocaine elevate Dopamine levels within the cell body and terminal regions

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Freebase Cocaine: Crack, Rock. PSYCHOLOGICAL EFFECTS: ... at very high doses and frequencies, neurotoxicity does occur in mice and rats. [ Jonsson 1982] ... – PowerPoint PPT presentation

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Title: Amphetamines incl METH and Cocaine elevate Dopamine levels within the cell body and terminal regions


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Amphetamines (incl METH) and Cocaine elevate
Dopamine levels within the cell body and terminal
regions of VTA projections (NAC, PFC and BLA)
AMPH and METH
COC
3
redoxygen bluenitrogen whitehydrogen
4
redoxygen bluenitrogen whitehydrogen
5
History Dawn of time Sucking/chewing of leaf of
Erythroxylon coca plant 1850 Cocaine first
isolated from the Erythroxylon coca
plant 1850-1900s Medicinal and recreational use
increased 1914 Recreational use was banned in
the United States Present Medicinal use as a
topical anesthetic
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Erythroxylum coca plant.
freebase cocaine sodium bicarbonate
powdered cocaine solvents
7
Cocaine Coke, Snow, Nose Candy, Dust, White
Lady, Toot, Llello Freebase Cocaine Crack, Rock
8
PSYCHOLOGICAL EFFECTS Varies with dose and the
tolerance of the user. Smoking freebase cocaine
strong, short-lived peak of about 3-5
minutes Snorting cocaine powder lower high with
major effects lasting closer to 15 - 30 minutes.
Positive Psychological Effects Increases
alertness, wakefulness, elevates the mood, mild
to high degree of euphoria, increases athletic
performance, decreases fatigue, clearer thinking,
increases concentration, increases energy
Negative Psychological Effects Increased
irritability, insomnia, restlessness with high
doses may exhibit a pattern of psychosis with
confused and disorganized behavior, irritability,
fear, paranoia, hallucinations, may become
extremely antisocial and aggressive. PHYSICAL
EFFECTS Increases heart rate, blood pressure,
body temperature, and sweating. Increases speed
of respiration, dilates the pupils, decreased
sleep and appetite. Can decrease seizure
threshold and is associated with seizures,
strokes, and heart attacks in susceptible
individuals.
9
WITHDRAWAL SYMPTOMS No physical withdrawal
syndrome BUT (very) unpleasant withdrawal and
craving symptoms, including intense cravings for
more cocaine, hunger, irritability, apathy,
depression, paranoia, suicidal ideation, loss of
sex drive, insomnia or excessive sleep,
dizziness, shaking, and/or feeling cold.
OVERDOSE SYMPTOMS Agitation, hostility,
hallucinations, convulsions, high body
tempertature (hyperthermia), stroke, heart
attack, and possibly death. .
LONG-TERM USE Heavy, regular use of cocaine
causes restlessness, anxiety, hyperexcitability,
paranoia, irritability, insomnia, weight loss,
and a variety of other less acute psychological
symptoms. Snorting?damage to the cartiledge and
mucosa in the nose, eventually leading to a hole
in the septum (the soft structure separating the
nostils) Injecting? wide variety of problems
including life-threatening infections, shared
needle-related blood diseases, etc.
10
PET Brain Images Showing the Effects of
Intravenous Methylphenidate on Extracellular
Dopamine in the Striatum and on Regional Glucose
Metabolism in Cocaine-Addicted Subjects Extracell
ular dopamine in the striatum was assessed by
measuring 11Craclopride binding. Regional
brain glucose metabolism was assessed by
measuring 18Ffluorodeoxyglucose metabolism.
As shown in the scattergrams, although
methylphenidates increases in dopamine in the
striatum are associated with the "high," the
activation of the orbitofrontal cortex is
associated with drug craving.
11
(a) Images for 11Ccocaine and for
11Cmethylphenidate at the level of the basal
ganglia at different times after radiotracer
administration. The colors reflect the
concentration of the radiotracer and correspond
to redgtyellowgtgreengtbluegtpurple. (b)
Time-activity curves for 11Ccocaine and for
11Cmethylphenidate plotted with the
corresponding temporal patterns for the
subjective experience of 'high' after
pharmacological doses of intravenous cocaine and
of intravenous MP. The peak corresponds to the
normalized maximum for the self-report of 'high'
reported by each subject. Note the rapid uptake
of these two drugs into the brain but the much
faster clearance for cocaine than for MP. Note
the parallelism between the 'high' after cocaine
and the kinetics of 11Ccocaine in basal
ganglia. Note the dissociation between the 'high'
from MP, which falls rapidly after peaking and
the slow clearance of 11Cmethylphenidate from
basal ganglia.
12
                       (a) Regional brain
metabolic images in a cocaine abuser during a
neutral and a cocaine interview. (b) Regional
brain metabolic measures for whole brain (global)
and for OFC in cocaine abusers tested during a
neutral interview and tested during a cocaine
interview. Note the increases in OFC metabolism
during the cocaine interview.
13
History 1887 Amphetamine was first synthesized
by German chemist L. Edeleano (originally named
phenylisopropylamine) 1930s Amphetamines were
first marketed as 'benzedrine' in an
over-the-counter inhaler to treat congestion Late
1930's Amphetamines was prescribed for the
treatment of narcolepsy and ADHD (attention
deficit hyperactivity disorder) 1940s
Amphetamine use grew rapidly when amphetamines
were distributed to soldiers during World War II.
1971 scheduled II in the United States
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Slang AMPH Amphetamines, Speed Dex Adderall
Dexamphetamine Bennies Dexies Black Beauty
Jollies The Experience speeding, tweaking
(tweaked), spinning (spun), up 1887
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Psychological Effects of AMPH/METH use Positive
Effects Attention / Wakefulness In low doses
and used infrequently, amphetamine increases
wakefulness and attentiveness in users. It is
used by truckers, the military, and others who
need to stay awake for long periods of time.
Wakefulness can be important for safety when
operating machinery. Reduced Appetite Although
still prescribed to aid in weight loss, the
recognized cardiovascular risks of using
amphetamines now make their prescription for
weight loss far less common than in the past. The
prevalence of "weight loss only" non-prescription
use of amphetamines is impossible to
gauge. Negative Effects Agitation, Inability
to Concentrate In some users, increasing with
dose, amphetamine causes agitation, restlessness,
and inability to concentrate or focus. Paranoia
Using recreational (higher) doses of amphetamines
more than once per day or for several days in a
row can cause mild to moderate paranoid ideation
in some users. The paranoid thinking can cause
lasting problems and the paranoia can sometimes
last for days or weeks after use ceases. Regular
amphetamine use (and lack of sleep) can cause
paranoid, delusional thinking and sometimes
auditory and visual hallucinations (usually
barely audible or on the periphery of vision).
Chronic, high dose use may lead to long term
mental health problems. Poor Sleep Quality and
Sleep Deprivation Mild sleep disruptions are
very common and include difficulty falling asleep
and poor sleep quality. Repeated dosing can lead
to lack of sleep for days on end, resulting in
cognitive impairment, poor judgment, confusion,
hallucinations, and paranoia. Stress Oxidative
Damage Methamphetamine causes stress to the body
and mind and causes an increase in oxidative
stress in blood and tissues. At very high doses
and frequencies of use, organ damage and
premature aging may occur. Frequency
uncommon. Physiological Heath
Risks Cardiovascular Stress Increased heart
rate and blood pressure. Tachycardia (fast heart)
and palpitations are common at high doses. Heart
Attack Hypertensive Crisis With higher doses
and for vulnerable individuals, Cardiovascular
Stress can precipitate severe hypertensive crises
and Heart Attacks. Stroke Increases risk of
stroke as dose increases. Overheating High doses
can cause overheating (hyperthermia) which can be
dangerous in certain environments or for
vulnerable people. Death Usually resuling from
cardiac arrest, stroke, or hyperthermia. Acute
renal failure associated with rhabdomyolysis,
acidosis, and ischemic renal failure also is
associated with methamphetamine fatalities.
Disseminated Intravascular Coagulation also
reported. Lan 1998. Rhabdomyolysis and Kidney
Damage Breakdown of muscle fibers usually caused
by overheating and overstimulation. High-dose use
can result in rhabdomyolysis, causing large
amounts of proteins to be released into the
blood. Urine becomes dark as the rhabdomyolysis
increases and the kidneys can suffer mild to
severe damage. Chan 1994, Lan 1998. Dry Mucus
Membranes Dried mucus membranes can lead to
bloody noses, painful sinus dryness, and
increased likelihood of sinus infections. Dry
Skin, Picking at the Skin Regular amphetamine
use is associated with a drying of the skin and
increased itchyness. Obsessively picking or
pulling at the skin (sometimes until it bleeds)
is reported in many people after higher dose,
frequent use of methamphetamine. Damage to Teeth
and Gums Jaw tension can lead to teeth grinding
(bruxia/bruxism) and permanent wear and cracking.
Long-term use of amphetamines can result in tooth
rot (dental caries) and loss of teeth. Shaner
2002 Regular amphetamine use can lead to
gingivitis (inflammation of the gums). This may
be the result of prolonged dry mouth which can
cause the gums to become inflamed, worsening oral
health. Hasan 2004.
17
Physiological Effects of AMPH/METH
use Rhabdomyolysis and Kidney Damage Breakdown
of muscle fibers usually caused by overheating
and overstimulation. High-dose use can result in
rhabdomyolysis, causing large amounts of proteins
to be released into the blood. Urine becomes dark
as the rhabdomyolysis increases and the kidneys
can suffer mild to severe damage. Cardiovascular
Stress Increased heart rate and blood pressure.
Tachycardia (fast heart) and palpitations are
common at high doses. Heart Attack Hypertensive
Crisis With higher doses and for vulnerable
individuals, Cardiovascular Stress can
precipitate severe hypertensive crises and Heart
Attacks. Stroke Increases risk of stroke as
dose increases. Overheating High doses can cause
overheating (hyperthermia) which can be dangerous
in certain environments or for vulnerable
people. Death Usually resuling from cardiac
arrest, stroke, or hyperthermia. Acute renal
failure associated with rhabdomyolysis, acidosis,
and ischemic renal failure also is associated
with methamphetamine fatalities. Disseminated
Intravascular Coagulation also reported.
Neurotoxicity (D/L-Amphetamine) Neurotoxicity
with D/L amphetamine (most of what is prescribed
as medications) is not as well documented, but at
very high doses and frequencies, neurotoxicity
does occur in mice and rats. Jonsson
1982 Neurotoxicity (Methamphetamine) At high
doses, methamphetamine causes damage to dopamine
and serotonin neurons in the brain Seiden 1976,
Thompson 2004. Long term use may lead to
noticeable neurological and behavioral problems.
This effect is well documented with
methamphetamine in mice and now largely confirmed
in humans behavioral/clinical effects of this
damage is not well documented in humans Hanson
2004.
18
Typical Subject Pool for METH Brain Imaging
Studies
19
SERT levels Figure 1. Voxel-based
trans-1,2,3,5,6,10-beta-hexahydro-6-4-(methylthio
)phenylpyrrolo-2,1-aisoquinoline
(11C()McN-5652) distribution volume images
from a control subject and a methamphetamine
abuser. These absolute parametric images were
normalized to the standard stereotaxic brain
atlas using transformation parameters for early
integrated images of 11C()McN-5652 (0-20
minutes after injection). The 11C()McN-5652
distribution volumes in broad areas of the brain
of the methamphetamine abuser were lower than
those of the control subject.
20
Figure 2. Mean regional brain trans-1,2,3,5,6,10-b
eta-hexahydro-6-4-(methylthio)phenylpyrrolo-2,1
-aisoquinoline (11C()McN-5652) distribution
volumes (DVs) in control subjects and
methamphetamine abusers. Methamphetamine abusers
had significantly decreased 11C()McN-5652 DVs
in the global regions compared with controls
(Wilks    0.001 P  .003, by multivariate
analysis of variance). Univariate analysis of
variance revealed that methamphetamine users had
significantly lower 11C()McN-5652 DVs than
controls in all regions studied (Plt.001 for all).
Error bars represent SE.
21
D2 Dopamine Receptor (found on terminals and cell
bodies) Images obtained with 11Craclopride (to
measure DA D2 receptor availability) at the level
of the basal ganglia in subjects addicted to
different types of drugs of abuse including
alcohol and the images for age- and
gender-matched controls. Note the decreases in DA
D2 receptors in drug abusers when compared with
controls. The scale is to the right and the
different colors reflect the levels of DA D2
receptor availability. METH corresponds to
methamphetamine.
22
SERT Levels (red means area lower in METH
users) Figure 4. Results of the whole-brain
voxel-based statistical parametric mapping
analysis of the trans-1,2,3,5,6,10-beta-hexahydro-
6-4-(methylthio)phenylpyrrolo-2,1-aisoquinolin
e (11C()McN-5652) distribution volumes (DVs).
A, Locations of methamphetamine abuser and
control differences in 11C()McN-5652 DVs. B,
Locations of clusters with significant negative
correlations between Aggression Questionnaire
scores and 11C()McN-5652 DVs in
methamphetamine abusers (Plt.05, corrected for
voxel level). Each top row shows 3-dimensional
glass brain views each bottom row, detected area
superimposed onto normal template magnetic
resonance images.
23
REDerrors associated with atrophy
Hippocampal Brain Damage Figure 2. Hippocampal
atrophy in MA abusers is linked with poorer
auditory vigilance performance. Each hippocampus
was traced in coronal MRI sections and converted
to a mesh surface representation in which the
radial size of the hippocampus was measured from
a centerline and plotted on the surface. These
meshes were averaged across MA subjects, and
atrophy relative to the control mean was computed
at each surface grid point as described before
(Thompson et al 2004b). Hippocampal regions (in
ICBM space) where CPT error rate log (1 percent
errors) was significantly associated with radial
atrophy in the MA abuser group are shown in red.
The Top section is viewed from the anterior and
superior position while the view from Bottom is
from the posterior and inferior position. MA,
methamphetamine MRI, magnetic resonance imaging
ICBM, International Consortium for Brain Mapping
CPT, continuous performance task.
24
Figure 1. Locations of methamphetamine (MA) and
control group differences in relative regional
cerebral glucose metabolic rate (rCMRglc).
Statistical parametric maps were generated using
SPM99 (Wellcome Department of Cognitive
Neurology, London, England) for the contrast of
relative rCMRglc in the control group (n 18)
greater than in the MA abuser group (n 17) and
also for the contrast of relative rCMRglc in the
MA abuser group greater than in the control
group. Colors superimposed on the gray-scale
structural magnetic resonance template indicate
areas where the height threshold for the contrast
(whole brain) was t  1.69 (P .049). Locations
where clusters exhibited Plt.05 for spatial extent
(corrected for search volume of the relevant
region of interest but not the number of regions)
are noted (Table 4). Coordinates are in MNI space
(Montreal Neurological Institute, Toronto,
Ontario). igACC indicates infragenual anterior
cingulate cortex pgACC, perigenual anterior
cingulate cortex.
25
Poor Diet Reduced appetite and reduced enjoyment
of eating can lead to poor diet which, over time,
can lead to poor general health, oral health and
skin tone, and increased physical and mental
stress.
Dry Mucus Membranes Dried mucus membranes can
lead to bloody noses, painful sinus dryness, and
increased likelihood of sinus infections. Dry
Skin, Picking at the Skin Regular amphetamine
use is associated with a drying of the skin and
increased itchyness. Obsessively picking or
pulling at the skin (sometimes until it bleeds)
is reported in many people after higher dose,
frequent use of methamphetamine. Damage to Teeth
and Gums Jaw tension can lead to teeth grinding
(bruxia/bruxism) and permanent wear and cracking.
Long-term use of amphetamines can result in tooth
rot (dental caries) and loss of teeth. Shaner
2002 Regular amphetamine use can lead to
gingivitis (inflammation of the gums). This may
be the result of prolonged dry mouth which can
cause the gums to become inflamed, worsening oral
health. Hasan 2004.
http//www.pbs.org/wgbh/pages/frontline/meth/body/
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