Brain Glutamate Receptors and Cocaine Dependence



Status:Terminated
Conditions:Psychiatric, Pulmonary
Therapuetic Areas:Psychiatry / Psychology, Pulmonary / Respiratory Diseases
Healthy:No
Age Range:20 - 55
Updated:10/8/2017
Start Date:July 14, 2009
End Date:March 19, 2013

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Cocaine Dependence, Metabotropic Glutamate Receptor Subtype 5 (mGluR5) Density, Genetics and Craving

Objective:

Cocaine addiction continues to be an important public health problem with over 1.7 million
users in the US alone. Cocaine addiction is characterized by compulsive drug use despite
adverse consequences and high rates of relapse during periods of abstinence. Cocaine
addiction may be mediated by neuroadaptations in reward-related learning and memory processes
in the mesocorticolimbic dopamine system and glutamatergic corticolimbic circuitry.
Metabotropic glutamate subtype 5 receptors (mGluR5) likely play essential roles in mediating
some of the actions of drugs of abuse. Animal studies have shown that mGluR5 knock-out or
blockade reduces self-administration of cocaine and cocaine-induced hyper-locomotion.
However, to what extent mGluR5 are involved in the pathophysiology of cocaine addiction in
humans is currently unknown, partly due to the lack of suitable methods to reliably quantify
mGluR5 in the living human brain.

This protocol aims to determine whether the density of mGluR5 in brain is altered in
participants with cocaine addiction compared to healthy controls using positron emission
tomography (PET) and the recently developed radiotracer for mGluR5, [18F]SP203. We also aim
to determine whether this density is related to genotype, history of cocaine use, and/or
craving for cocaine.

Study Population:

The study populations will consist of healthy adults with no history of substance abuse and a
matched group of healthy current primary cocaine dependent male and female participants
(20-50 years old.; N=40/group).

Design:

Density of mGluR5 will be measured in cocaine dependent participants and healthy adults
volunteers with PET and (18F)SP203, a radioligand with specificity for mGluR5. All
participants will undergo genotyping to identify normal or variant mGluR5 gene associated
with drug abuse. The intensity of craving for cocaine will be assessed while watching a video
about cocaine use.

Outcome measures:

Density of mGluR5 will be compared between cocaine dependent participants and healthy
controls. In addition, correlation among the genetic polymorphism, the craving response, and
the density of mGluR5 will be determined.

Objective:

Cocaine addiction continues to be an important public health problem with over 1.7 million
users in the US alone. Cocaine addiction is characterized by compulsive drug use despite
adverse consequences and high rates of relapse during periods of abstinence. Cocaine
addiction may be mediated by neuroadaptations in reward-related learning and memory processes
in the mesocorticolimbic dopamine system and glutamatergic corticolimbic circuitry.
Metabotropic glutamate subtype 5 receptors (mGluR5) likely play essential roles in mediating
some of the actions of drugs of abuse. Animal studies have shown that mGluR5 knock-out or
blockade reduces self-administration of cocaine and cocaine-induced hyper-locomotion.
However, to what extent mGluR5 are involved in the pathophysiology of cocaine addiction in
humans is currently unknown, partly due to the lack of suitable methods to reliably quantify
mGluR5 in the living human brain.

This protocol aims to determine whether the density of mGluR5 in brain is altered in
participants with cocaine addiction compared to healthy controls using positron emission
tomography (PET) and the recently developed radiotracer for mGluR5, [18F]SP203. We also aim
to determine whether this density is related to genotype, history of cocaine use, and/or
craving for cocaine.

Study Population:

The study populations will consist of healthy adults with no history of substance abuse and a
matched group of healthy current primary cocaine dependent male and female participants
(20-55 years old.; N=40/group).

Design:

Density of mGluR5 will be measured in cocaine dependent participants and healthy adults
volunteers with PET and (18(F)SP203, a radioligand with specificity for mGluR5. All
participants will undergo genotyping to identify normal or variant mGluR5 gene associated
with drug abuse. The intensity of craving for cocaine will be assessed while watching a video
about cocaine use.

Outcome measures:

Density of mGluR5 will be compared between cocaine dependent participants and healthy
controls. In addition, correlation among the genetic polymorphism, the craving response, and
the density of mGluR5 will be determined.

- INCLUSION CRITERIA:

Cocaine dependent participants must meet DSM-IV criteria for cocaine dependence at the time
of participation.

Control participants who provide appropriate matches for cocaine-dependent participants
will be recruited on the following characteristics: age, and when possible, parental
socio-economic status and/or years of parental education.

EXCLUSION CRITERIA:

Control Participants:

1. Psychiatric disease: DSM-IV criteria will be used (American Psychiatric Association,
1994). No subject with a current axis I diagnosis (except for nicotine dependence)
will be allowed. Claustrophobia is also exclusionary.

2. History of Drug Abuse: Volunteers reporting current or having a significant history of
illicit drug abuse will be excluded from the study. Subjects may use moderate amounts
of alcohol and caffeine and smoke an occasional marijuana cigarette, but must not be
dependent on alcohol, caffeine or marijuana. No alcohol or marijuana for at least 24
hours prior to scanning. No smoking after midnight on the night before a scan.

3. Current or Past Medication Use: Volunteers may not currently use chronic (daily for
more than 10 to 14 days in the last month) prescription or over the counter
medications, (including, but not limited to, anti-hypertensive, anti-allergy, pain).
Over the counter or prescription medications may be used on an occasional basis (for
treatment of self-limited conditions, such as occasional headache, musculoskeletal
discomfort, allergic symptoms or pain). All medications will be discontinued at least
5 days before the experimental session.

4. CNS disease: History of known structural brain abnormalities (e.g., neoplasm,
subarachnoid cysts), cerebrovascular disease, infectious disease (e.g., abscess),
history of head trauma (defined as documented loss of consciousness > 5 min), history
of seizures as an adult, sleep apnea, tic disorder.

5. Cardiovascular, pulmonary, or systemic disease: Repeated (measured on three separate
occasions) diastolic blood pressure >90 mm Hg, or systolic blood pressure >135 mm Hg,
known arrhythmia, symptomatic or known coronary artery disease; history of
endocarditis, cerebral embolism, obstructive pulmonary disease, Factive tuberculosis,
known endocrine disease (derangements in adrenal, thyroid, bone or reproductive
function), known chronic renal or hepatic dysfunction, HIV seropositive, known current
autoimmune disease involving the CNS.

6. Miscellaneous exclusionary criteria: Body weight greater than 300 lbs. Hematocrit <
39.0 for males or < 36.0 for females. Participants are also excluded if veins are
inaccessible.

7. Radiation exposure: Any subject who has participated in any research studies in which
he/she received a radiation exposure that would result in combination with the present
study, in a total effective radiation exposure (from research studies) exceeding 5.0
rem in a year.

8. Novocain allergy or lack of bilateral ulner and radial arterial patency in subjects
receiving arterial catheter as assessed by an Allen s test or Dopler test artery
patency for all subjects to be catheterized.

9. Presence in body of metallic implants or materials that could be moved by the magnet
of the MRI scanner: pacemakers, surgical implants, aneurism clips, dental braces,
bullet(s) or other metallic materials. A history of working with metal with consequent
possible metal fragments in the body.

10. Inability to lie flat for a few hours for the PET scans

11. Women who are pregnant or lactating and children under the age of 18 will be excluded
to avoid unnecessary exposure to radiation to these populations.

Cocaine Dependent Subjects:

In addition to the exclusion criteria listed above with the exception of item i. b),
subjects in this group will be excluded if:

1. They are actively seeking or engaged in substance abuse treatment. Justification:
Videos viewed during this study may produce drug craving, producing a significant risk
of relapse in a dependent individual attempting to remain abstinent. Any participant
seeking treatment will be referred to treatment, since delaying entry into treatment
to participate in a study unnecessarily increases exposure to the risks associated
with active cocaine dependence. Assessment tool(s): Clinical interview at screening
and repeat questioning at time of consent.

2. They are dependent on other substances except nicotine or cocaine at the time of
participation. Use of other abused substances will be allowed as long as they are not
currently dependent on any drug except nicotine and cocaine. Justification: Dependence
on other substances may result in unique CNS deficits that would increase the noise in
our data. Further, other dependence may contaminate neural processes examined.
Nicotine dependence will be allowed since nicotine use is not associated with a drug
high in normal usage and the prevalence of nicotine dependence in cocaine using
individuals may make it impractical to exclude them. Assessment tool(s): Substance Use
Disorders module of the SCID with confirmation by clinical interview and negative
urine drug screen. Positive screens for cocaine are allowed.
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