National Institute on Drug Abuse
Director's Report to the National Advisory Council on Drug Abuse
February 1997
Research Findings
Intramural Research
Activation of Memory Circuits During Cue-Elicited Cocaine Craving
Evidence accumulated over more than 45 years has indicated that environmental
stimuli can induce craving for drugs of abuse in individuals who have addictive
disorders. However, the brain mechanisms that subserve such craving have
not been elucidated. Here, a positron emission tomographic study shows increased
glucose metabolism in cortical and limbic regions implicated in several
forms of memory when human volunteers who abuse cocaine were exposed to
drug-related stimuli. Correlations of metabolic increases in the dorsolateral
prefrontal cortex, medial temporal lobe (amygdala) and cerebellum with self-reports
of craving suggest that a distributed neural network, which integrates emotional
and cognitive aspects of memory, links environmental cues with cocaine craving.
Identifying patterns of brain activation correlated with cocaine craving
can direct future investigations in the mechanism of and therapeutic interventions
for craving associated with drug addiction. Grant, S., London, E.D., Newlin,
D.B., Villemagne, V.L., Liu, X., Contoreggi, C., Phillips, R.L., Kimes,
A.S., Margolin, A. Proc. Natl. Acad. Sci., 93: pp. 12040-12045, 1996.
Subjective and Cardiovascular Effects of Nicotine in Human Volunteers
The subjective and cardiovascular effects of intravenous nicotine were assessed
in smokers and nonsmokers. Both smokers and nonsmokers manifested significant
increases in systolic and diastolic blood pressure and heart rate 1 min
after administration of single doses of nicotine (0.75 or 1.5 mg). The most
prominent difference between groups was the increase in heart rate was greater
and more sustained in nonsmokers than in smokers. Nonsmokers and smokers
also differed in subjective self-reports. In response to items on visual
analogue scales indicative of positive effects (e.g., "good effects,"
"like drug," "use again," and "feel energetic"),
smokers, but not nonsmokers, reported high scores after nicotine injection.
In addition, responses on the MBG and LSD subscales of the Addiction Research
Center Inventory indicated that smokers experienced positive subjective
effects after the test doses, whereas nonsmokers experienced disorientation.
The fact that intravenous nicotine was not associated with positive subjective
effects in nonsmokers indicates that repeated exposure is required to establish
positive reinforcing effects of nicotine. Soria, R., Stapleton, J.S., Gilson,
S.F., Sampson-Cone, A., Henningfield, J.E., and London, E.D. Psychopharmacology
128: pp. 221-226, 1996.
PPBP[4-Phenyl-l-l(4-phenylbutyl) piperidine] Decreased Brain Injury Following
Transient Focal Ischemia in Rats.
Sigma-receptor ligands have been hypothesized to be therapeutically beneficial
in the setting of focal cerebral ischemia. Previous studies in the cat were
extended to the rat to test if intravenous administration of the potent
sigma receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) initiated
half-way through a 2 h period of transient focal ischemia and continuing
for 23 h would decrease postischemic brain infarction volume occurring over
22 h of reperfusion in unanesthetized animals. The infarction volume of
cerebral cortex (saline, 39Å6%; PPBP, 21Å7% of the ipsilateral
hemisphere) and striatum (saline, 68Å6%; PPBP, 33Å8% of the
ipsilateral striatum) was smaller in rats treated with PPBP than in rats
treated with saline. Thus, PPBP effectively decreases brain injury from
transient focal ischemia, when administered after the onset of ischemia
and during reperfusion, and suggests sigma-receptors may influence the progression
of injury in ischemic border regions. Takahashi, H., Kirsch, J.R., Hashimoto,
K., London, E.D., Koehler, R.C., Traystman, R.J. Stroke 27: pp. 2120-2123,
1996.
Methamphetamine-Induced Neurotoxicity
These papers show that METH can cause increase in AP-1 binding activity.
This activation is secondary to the production of superoxide radicals because
transgenic mice that overexpress superoxide dismutase show much less of
a response. These results are consistent with previous findings that showed
that AP-1 activation is dependent on cellular redox status. These papers
also identify a role for AP-1 in the neurodegeneration of the dopaminergic
system of mice. Methamphetamine-Induced Neurotoxicity is Associated with
Increased Striatal AP-1 DNA-binding Activity in Mice. Sheng, P., Ladenheim
B., Moran T.H., and Cadet J.L. Molecular Brain Res. 42: pp., 171-174, 1996;
AP-1 DNA Binding Activation by Methamphetamine Involves Oxidative Sress.
Sheng P., Wang X-B., Ladenheim B., Epstein C., and Cadet J.L. Synapse 24:
pp. 213-217, 1996.
Neuroadaptive Changes Following Chronic Cocaine Administration
This paper shows that chronic cocaine self-administration causes increases
in the number of dopamine uptake sites in the striatum, nucleus accumbens,
and the ventral tegmental areas. The use of the cocaine analog GBR-12909
reduced self-administration. Moreover, GBR-12909 caused a reversal of the
biochemical changes caused by cocaine. These results indicate that GBR-12909
might be an important drug in the treatment arsenal being built against
cocaine addiction. Differential Reinforcing Effects of Cocaine and GBR-12909:
Biochemical Evidence for Divergent Neuroadaptive Changes in the Mesolimbic
Dopaminergic System. Tella S.R., Ladenheim B., Andrews A.M., Goldberg S.R.,
and Cadet J.L. Journal of Neuroscience, 16: pp. 7416-7427, 1996.
Neurotoxicity of 2'Nh3-MPTP
These studies show that superoxide radicals are involved in the neurotoxicity
of 2'Nh3-MPTP. These results extend the role of free radicals to the neurodegeneration
of serotonergic and noradrenergic systems in rodent brains. Transgenic mice
with high levels of superoxide dismutase activity are protected from the
neurotoxic effects of 2'-Nh3-MPTP on serotonergic and noradrenergic nerve
terminals. Andrews A.M., Ladenheim B., Epstein C.J., Cadet J.L., and Murphy
D.L. Molecular Pharmacology 50: pp. 1511-1519, 1996.
PD-128, 907--A Selective D3 Dopamine Receptor Agonist with an Atypical
Antipsychotic Profile
The Drug Development Group of the Behavioral Pharmacology and Genetics Section
of NIDA IRP was the first group to report a common subjective effect pattern
for cocaine and agonists selective for dopamine D3 receptors. D3 receptors
have also become a focus of drug abuse researchers due to the reports from
Koob's group that this site may be a target for cocaine abuse therapeutics.
In the process of discovery of a selective antagonist for the abused drug,
phencyclidine (PCP), we have found a selective D3 agonist with an atypical
antipsychotic profile like that of the prototype, clozapine. PD-128,907(4aR,10bR-(+)-trans,
3,4,4a,10b-tetrahydro-4-n-propyl-2H,5H[4,3-b]-1,4-oxazin-9-ol) blocked behavioral
effects of dizocilpine [(+)-MK-801], a PCP-like antagonist of the NMDA receptor-associated
ion channel. Blockade occurred at doses of PD-128,907 that did not affect
spontaneous locomotor activity. Like clozapine, PD-128,907 blocked the stereotyped
behavior produced by dizocilpine but had minimal effects against apomorphine-induced
stereotypies. The dizocilpine-blocking effects of PD-128,907 were not observed
with the inactive, minus isomer of PD-128,907. Importantly, PD-128,907,
like clozapine, lacked cataleptic effects, predicting an absence of chronic
neurological problems associated with typical antipsychotic drugs (e.g.,
haloperidol). These data are the first to document a common mode of action
of a D3 receptor ligand with PCP blockade and psychosis and suggest novel
treatment approaches in both areas. Blockade of dizocilpine-induced behaviors
may be a valuable preclinical screening device for novel pharmacological
therapies for schizophrenia. The comorbidity of psychosis and drug abuse
makes these findings additionally compelling. This work was presented at
the annual meeting of the American College of Neuropsychopharmacology in
December, 1996.
Marjolein Beekman from the University of Groningen, The Netherlands has
been a guest scientist working on this project for the past 5 months. She
comes from the medicinal chemistry group that synthesized the most selective
drug, to date for D3 receptors. Future research will be directed toward
definitive identification of D3 receptors as the target for this novel effect.
Based upon the linkage with psychosis and with our previous findings on
commonalities in the pharmacology of cocaine and D3 receptor ligands, further
work will be expanded to identify a role for these compounds in the control
of psychomotor stimulant (cocaine, methamphetamine) abuse and toxicity.
Genotype-Dependent Differences in Morphine Self-Administration
The objective of the behavior genetic work in the Behavioral Pharmacology
and Genetics Section of the Preclinical Pharmacology Laboratory has been
to characterize the behavioral and neural substrates that determine individual
differences in the efficacy of morphine as a reinforcer and vulnerability
to opioid-reinforced behavior. The specific hypothesis has been that a significant
relationship exists between individual differences in mesolimbic-opiate
receptor concentration and the efficacy of morphine as a primary reinforcer.
In collaboration with Dr. J.L. Cadet of the Molecular Neuropsychiatry Section
of the Neuroscience Branch, behavior genetic and neuroanatomical techniques
were used to investigate the relationship between regional -opiate receptor
concentration and morphine-reinforced behavior. Inherited differences in
regional -opiate receptor concentration (genetically engineered and naturally
occurring) was used as a means to manipulate regional concentrations of
the -opiate receptor. Intravenous morphine self-administration behavior
was investigated in two sets of genetically engineered mice that overexpress
the -opiate receptor, two commonly used recombinant inbred strains with
high and low opiate receptor concentration and two commonly available inbred
strains. Multivariate analysis of the relationship between -opiate receptor
concentration in specific neuroanatomical regions and self-administration
behavior suggest that -opiate receptor concentration in the amygdala can
account for 64% of the variance (r2) in self-administration behavior. When
-opiate receptor concentration in amygdala, the shell of the nucleus accumbens
and ventral tegmental area were considered jointly, these regions accounted
for 98% of the variance (r2) in self-administration behavior across genotype.
These results suggest that -opiate receptor concentration in one or more
regions of the mesolimbic system are predictive of genotype-dependent differences
in morphine self-administration behavior and provide a significant step
towards identifying specific neural regions involved in the neurobiological
substrates underlying vulnerability to opioid addiction.
Additive Interactions of Caffeine and Nicotine
Nicotine and caffeine are two of the most widely used licit drugs in society,
and they are repeatedly consumed together. Epidemiological reports indicate
a correlation between coffee drinking and tobacco smoking and a possible
explanation is provided by laboratory studies that indicate these two heavily
used drugs interact additively. In a series of studies in the Behavioral
Pharmacology and Genetics Section of the Preclinical Pharmacology Laboratory,
we have shown that acute or chronic caffeine exposure can alter the reinforcing
and other behavioral properties of nicotine. Rats consuming caffeine in
their drinking water acquired i.v. nicotine self-administration faster and
reached higher levels of intake than controls. Rats trained to discriminate
nicotine from saline failed to generalize to other psychomotor stimulant
drugs when they were chronically exposed to caffeine during training. Squirrel
monkeys showed increases in nicotine self-administration responding and
a marked potentiation of other behavioral effects of nicotine after acute
or chronic caffeine exposure. Thus, caffeine exposure can markedly alter
the reinforcing, discriminative and stimulant properties of nicotine. Such
an interaction could be part of the pharmacological basis for nicotine usage
and relapse to usage after cessation. Results of this research were presented
at the College on Problems of Drug Dependence meeting in June, 1996 and
the Society for Neuroscience meeting in November, 1996.
Methamphetamine-Associated Neurotoxicity
Investigators in the Behavioral Pharmacology and Genetics Section and and
the Molecular Neuropsychiatry Section of NIDA's IRP have been conducting
a series of studies on methamphetamine self-administration and associated
neurotoxicity in rats and monkeys. D-methylamphetamine (methamphetamine)
and its stereoisomer l-methylamphetamine have been shown to have amphetamine-like
abuse liability in rats and monkeys using operant drug-discrimination and
intravenous self-administration procedures. Both isomers of methylamphetamine,
and l-deprenyl (selegiline), whose major metabolite is l-methylamphetamine,
had dose-dependent, d-amphetamine-like, discriminative-stimulus properties
in rats and monkeys. Both d-and l-methylamphetamine maintained high rates
of self-administration behavior in monkeys and rats. In rats, after 97 d-methylamphetamine
self-administration sessions, with total intake of d-methylamphetamine over
the 97 sessions ranging from 68 to 116 mg/kg, there were neuroadaptive changes
in dopamine uptake sites in the caudate and a small decrease in dopamine
transporter levels with corresponding upregulation of dopamine D1 receptors
in the nucleus acumbens. There was an indication that opioid systems may
be important in the mediation of methamphetamine's reinforcing effects since
there was marked upregulation of -opioid receptors in the nucleus acumbens,
substantia nigra compacta, ventral tegmental area, prefrontal cortex, anterior
caudate and different hippocampus regions. Further studies in rats are underway
using yoked control groups of rats that passively receive injections of
either methamphetamine or saline whenever test rats self-administer injections
of methamphetamine.
Potential Utility of l-deprenyl in Treating Stimulant Abuse
l-deprenyl has been suggested as a potential treatment agent for various
types of psychomotor stimulant abuse. l-deprenyl failed to maintain self-administration
behavior in monkeys and treatment with l-deprenyl before experimental sessions
failed to alter either the discriminative-stimulus actions of d-amphetamine
or d-methylamphetamine in rats or monkeys or the self-administration of
either d-or l-methylamphetamine in monkeys. Thus, although l-deprenyl had
amphetamine-like, discriminative-stimulus properties, it did not appear
to have methamphetamine-like reinforcing properties in rats or monkeys and
was ineffective in altering established patterns of methamphetamine self-administration
behavior. It is possible, however, that l-deprenyl treatment would ameliorate
the neurotoxicity seen with extended administration or self-administration
of high doses of methamphetamine.
Development of Compound that Binds Irreversibly to the Dopamine Transporter
The Psychobiology Section of NIDA's IRP has developed a drug that binds
irreversibly to the dopamine transporter. The drug was derived from a compound
that binds to the dopamine transporter and inhibits dopamine uptake but
does not have cocaine-like behavioral effects. It is believed that the parent
compound acts primarily through a low-affinity binding site on the dopamine
transporter, although that is highly speculative. The characterization of
the in vitro pharmacology of the compound that binds irreversibly is currently
in progress. Studies will more fully characterize the drug in order to assess
its suitability for functional characterization of the roles of the high-and
low-affinity sites on the dopamine transporter.
Human Pharmacokinetics of Intravenous, Sublingual and Buccal Buprenorphine
Buprenorphine is a potent opioid analgesic used in the treatment of moderate
to severe pain. At higher doses it has demonstrated potential for treating
heroin dependence. Collaborative efforts between scientists from NIDA's
IRP and the Armed Forces Institute of Pathology were undertaken to investigate
buprenorphine pharmacokinetics by different routes of administration at
dosages approximating those used in opioid dependence studies. Six healthy
male subjects who were non-dependent but had a history of heroin use were
administered buprenorphine in a cross-over design study by intravenous (1.2
mg), sublingual (4.0 mg) and buccal (4.0 mg) routes of administration. Plasma
samples were collected up to 96 hours and assayed for buprenorphine and
norbuprenorphine by negative chemical ionization tandem mass spectrometry.
Plasma concentrations of buprenorphine and norbuprenorphine were analyzed
by nonlinear regression analysis with standard non-compartmental methods.
Buprenorphine bioavailability by the sublingual and buccal routes was estimated
as 51.4% and 27.8%, respectively, although there was considerable inter-subject
variability by both routes of administration. The terminal elimination half-lives
were longer for the sublingual and buccal routes than the intravenous route.
The extended elimination half-lives may be due to a shallow depot effect
by sequestration of buprenorphine in the oral mucosa. Norbuprenorphine mean
peak plasma concentrations were less than 1 ng/mL and were highly variable
between different routes of administration and subjects. The terminal elimination
half-life of norbuprenorphine was longer than buprenorphine.
Cocaine Disposition in Meconium from Newborns of Cocaine-Abusing Mothers
and Urine of Adult Drug Users
The analysis of meconium for cocaine and other metabolites has proven to
be a reliable method for the detection of fetal cocaine exposure. Better
sensitivity and a larger gestational window of detection have been demonstrated
for meconium testing as compared to neonatal urine testing. Cocaine and
cocaine metabolites have been identified in meconium including benzoylecgonine,
ecgonine methyl ester, cocaethylene, norcocaine, benzoylnorecgonine, and
m-hydroxybenzoylecgonine. The origin of these metabolites, whether maternal
or fetal, has not been established. This study was conducted to compare
the disposition of cocaine and metabolites in meconium from cocaine exposed
fetuses to that of urine from cocaine abusers. Meconium specimens were obtained
from 6 neonates of mothers positive for cocaine use by urinalysis and/or
self-report during pregnancy. Urine specimens were obtained from 17 adult
female and 17 adult male cocaine users enrolled in a treatment program.
Specimens were analyzed by GC-MS for cocaine and 12 related analytes. The
following analytes were identified and measured in meconium and urine: anhydroecgonine
methyl ester; ecgonine methyl ester; ecgonine ethyl ester; cocaine; cocaethylene;
benzoylecgonine; norcocaine; norcocaethylene; benzoylnorecgonine; m- and
p-hydroxy-cocaine; and m- and p-hydroxybenzoylecgonine. In addition, both
m- and p-hydroxy-benzoylecgonine were found to exhibit approximately equal
crossreactivity with benzoylec-gonine in the EMIT and TDx assays. The presence
of p-hydroxybenzoylecgonine in meconium suggested that this newly identified
metabolite, like m-hydroxybenzoylecgonine, might serve as a valuable marker
of fetal cocaine exposure during pregnancy. The presence of cocaine and
anhydroecgonine methyl ester in meconium was attributed to transfer across
the placenta from the mother. However, the origin of the hydrolytic and
oxidative metabolites of cocaine could not be established since they were
also identified in urine specimens of adult, female cocaine users and could
have arisen in meconium from either fetal or maternal metabolism.
Melanin and Lipids on Cocaine Binding to Caucasoid and Africoid Hair
Although the mechanism(s) of drug deposition in hair are unknown, there
is evidence which suggests that the amount and type of melanin present is
a major factor in determining how much drug enters hair following exposure.
Divided hair specimens (N=7) from male and female Caucasoids (black/brown
and blond colored) and Africoids (black colored) were exhaustively extracted
to remove lipid components (lipid-extracted hair). Separate portions were
bleached to denature or alter melanin content. Experiments with radiolabeled
cocaine were performed on untreated, lipid-extracted and bleached portions
of hair from different groups. Cocaine binding was significantly higher
(p<0.01) to male Africoid hair compared to other groups. The amount of
drug binding was similar among specimens from female Africoids and male
and female black/brown Caucasoids. The lowest amount of binding was observed
with blond, female Caucasoid specimens. Binding experiments also revealed
that specific cocaine binding generally did not differ significantly between
lipid-extracted hair and untreated hair, but bleaching of most hair specimens
resulted in significant (p < 0.01) decreases in specific binding compared
to untreated hair. In separate experiments with cocaine-treated hair specimens,
digested samples were evaluated to determine if removal of the insoluble
melanin fraction from soluble hair components provided a means of normalization
of drug content and elimination of color bias. Removal of the insoluble
melanin fraction was not effective in removal of significant amounts of
cocaine indicating that the digestion process released bound cocaine into
the digest solution. Overall, these experiments suggested that lipids in
hair play a minor role in drug binding, whereas melanin functions as a major
binding site for cocaine. Natural (ethnic) or artificial differences (bleaching)
in melanin content may determine the extent of cocaine entrapment in hair
after drug exposure. Further, digestion of hair samples with removal of
insoluble melanin failed to be effective in removal of hair color bias.
Phentermine Pretreatment Antagonizes the Cocaine-Induced Rise in Mesolimbic
Dopamine
Coadministration of phentermine and fenfluramine has been used to treat
cocaine dependence. Patients who relapse while receiving this treatment
report diminished subjective effects of cocaine. Due to the importance of
mesolimbic dopamine (DA) in mediating cocaine reinforcement, we hypothesized
that phentermine might attenuate the effects of cocaine on DA transmission.
We examined this proposal directly using in vivo microdialysis methods in
the nucleus accumbens of awake rats. Rats were pretreated with saline or
phentermine (1 mg/kg, iv) and then challenged with cocaine (3 mg/kg, iv).
Phentermine alone caused a modest increase in DA, and phentermine pretreatment
substantially reduced the cocaine-induced rise in extracellular DA. Alternately,
phentermine did not alter the stimulatory effect of cocaine on 5-HT. Our
findings suggest that phentermine may antagonize the subjective effects
of cocaine in humans via a DA mechanism. Rothman, R.B., Ayestas, M., and
Baumann, M.H. Neuroreport, In Press.
Sustained Decrease in Cocaine-Maintained Responding in Rhesus Monkeys
with
1-[2-[bis-(4-fluorophenyl)methoxy]ethyl]-4-[3-hydroxy-3-phenylpropyl] piper-azinyl
decanoate, a Long-Acting Ester Derivative of GBR 12909
The selective DA reuptake inhibitor GBR 12909 previously has been shown
to decrease cocaine-maintained responding without affecting similar levels
of food-maintained responding in monkeys, an effect analogous to that expected
of a medication designed to treat human cocaine abuse without adverse effect.
In the current study, we extended this type of effect by developing a decanoate
ester of a hydroxylated analog of GBR 12909 ( compound 5). Within several
days of the administration of an active dose of 5, cocaine-maintained responding
had decreased more than 80% while food-maintained responding was unaffected.
This selective effect on cocaine-maintained responding lasted almost thirty
days with a single injection, and was followed by a return to control levels
of responding. These results suggest that a similar formulation, if proven
safe for human use, should be tested as a potential medication for cocaine
abuse. Glowa, J.R., Fantegrossi, W.E., Lewis, D.B., Matecka, D.M., Rice,
K.C., and Rothman, R.B. J. Med. Chem. 39(24): pp. 4689-4691, 1996.
Serotonin-4 Receptor Antagonists Reverse Cocaine-Induced Cardiac Arrhythmia
The effect of 5-HT4 antagonists GR113808A and GR125487D were examined in
cocaine induced cardiac arrhythmia in the rat. Pre-and post i.v treatment
with the 5-HT4 receptor antagonists GR113808A and GR125487D reversed cocaine
induced arrhythmia without altering cardiovascular function. Pretreatment
with 2mg/kg of either drug increased the dose of cocaine required to induce
arrhythmia by 168 and 286 percent respectively. This effect was dose dependent.
The antagonists were ineffective when given intraperitoneally in rats. The
results of this study indicate that 5-HT4 antagonist can reverse cocaine-induced
arrhythmias.
The clinical implication of these findings is clear: 5-HT4 antagonists may
be useful in the treatment of acute cocaine induced cardiotoxicity, and
may also be useful in reversing cocaine's CNS effects. Further study is
needed to understand the exact mechanism of this phenomena. Ohuoha, D.C.,
Schindler, C.W., and Rothman, R.B. Submitted to NeuroReport.
Therapeutic Potential of Enhancing Cocaine Metabolism
Scientists from the Preclinical Pharmacology, Clinical Pharmacology, and
Treatment Branches of the Division of Intramural Research, in collaboration
with scientists at the Drug Development Program of the Gerontology Research
Center of NIA, recently completed a study providing the first experimental
demonstration that enhancing the metabolism of cocaine could significantly
reduce the acute behavioral effects of a cocaine challenge. Cocaine metabolism
in rats was increased several-fold by IV administration of exogenous butyrylcholinesterase
(extracted from horse serum), the major cocaine-metabolizing enzyme in primates.
Thirty minutes later, the rats were challenged with IP cocaine or saline
and their locomotor activity measured for 2 hours. The rats receiving enzyme
pretreatment had a significantly blunted response to cocaine (i.e., less
of an increase in distance traveled and stereotypy) compared to those receiving
saline pretreatment. Rats receiving only butyrylcholinesterase had the same
locomotor activity as those receiving saline, indicating that the enzyme
by itself did not influence this behavior. These findings, presented at
the Society for Neuroscience annual meeting in November 1996, suggest that
enhancement of cocaine metabolism by increasing metabolizing enzyme activity
may have therapeutic potential.
Chronic Cocaine Exposure Influences Mu-Opiate Receptor Function
Scientists from the Treatment Branch, Division of Intramural Research, in
collaboration with scientists at the Johns Hopkins Medical Institutions,
recently published a study showing that chronic, heavy cocaine users have
increased mu-opiate receptor binding in selected brain areas, and that this
increased binding correlates with self-reported cocaine craving. Binding
was measured by positron emission tomography (PET) scanning using 11C-carfentanil,
a potent synthetic mu-opioid agonist drug. This finding is the first confirmation
in humans of the previously reported finding in animals that chronic cocaine
exposure influences mu-opiate receptor function, and suggests a possible
mechanism for the reported therapeutic effect of buprenorphine, a partial
mu-opioid agonist, in reducing cocaine use by cocaine addicts in treatment.
Nature Medicine, 2: pp. 1225-1229, 1996.
Cocaine Use Early In Treatment Predicts Outcome In A Behavioral Treatment
Program
To evaluate baseline drug use as a predictor of treatment outcome, cocaine
use (qualitative and quantitative urinalysis and self-report) during baseline
was compared in methadone patients who had <5 weeks of abstinence (n
= 10) during a 12-week experimental voucher-based cocaine abstinence reinforcement
treatment. Baseline cocaine use was evaluated at the first and last clinic
visit and first and last week of baseline and as a mean across the 5-week
baseline; treatment response was calculated as a mean across 12-weeks of
treatment. Those who had successful outcomes (Abstainers) used significantly
less cocaine in the 5-week baseline than those with less successful outcomes
(Nonabstainers). Differences in cocaine use were not evident in the first
baseline visit or week, but Abstainers used significantly less cocaine in
the last visit and week of baseline compared to Nonabstainers. Cocaine use
during baseline provided critical predictors of response to the experimental
treatment.
Assessment of Cocaine Use With Quantitative Urinalysis
Measures of cocaine use are pivotal both in treatment and in clinical trials
of new cocaine abuse treatments. Current qualitative urinalysis methods
of monitoring cocaine use may over-detect frequency of use because of carryover
from previous cocaine administrations, masking effective treatments and
decreasing the sensitivity of clinical trials. This study assessed the value
of quantitative urinalysis and a newly developed measure of cocaine use.
Urine specimens collected in a cocaine dosing study in non-treatment-seeking
subjects (N=5) and a clinical trial of a behavioral treatment for cocaine
abuse (N=37) were analyzed for the cocaine metabolite, benzoylecgonine (BE),
with qualitative and quantitative methods. Pharmacokinetic criteria ("New
Use" rules) were developed and applied to quantitative data to identify
occasions of new cocaine use. Results were compared to known cocaine administrations
in the laboratory study and to self-reported drug use, qualitative urinalysis
and treatment response for subjects in the treatment trial. New Use criteria
correctly identified cocaine administrations in the cocaine dosing study
in all but a small number of specimens. In the clinical trial, urine BE
concentrations and estimated New Uses were more sensitive to differences
in cocaine use in statistical analyses than qualitative urinalysis. Interpretation
of quantitative urinalysis with New Use rules appears to be a useful method
for monitoring treatment outcome and may be more accurate than traditional
qualitative urinalysis in estimating frequency of cocaine use. Methamphetamine-Associated
Neurotoxicity Investigators in the Behavioral Pharmacology and Genetics
Section and the Molecular Neuropsychiatry Section of NIDA's IRP have been
conducting a series of studies on methamphetamine self-administration and
associated neurotoxicity in rats and monkeys. D-methylamphetamine (methamphetamine)
and its stereoisomer l-methylamphetamine have been shown to have amphetamine-like
abuse liability in rats and monkeys using operant drug-discrimination and
intravenous self-administration procedures. Both isomers of methylamphetamine,
and l-deprenyl (selegiline), whose major metabolite is l-methylamphetamine,
had dose-dependent, d-amphetamine-like, discriminative-stimulus properties
in rats and monkeys. Both d-and l-methylamphetamine maintained high rates
of self-administration behavior in monkeys and rats. In rats, after 97 d-methylamphetamine
self-administration sessions, with total intake of d-methylamphetamine over
the 97 sessions ranging from 68 to 116 mg/kg, there were neuroadaptive changes
in dopamine uptake sites in the caudate and a small decrease in dopamine
transporter levels with corresponding upregulation of dopamine D1 receptors
in the nucleus acumbens. There was an indication that opioid systems may
be important in the mediation of methamphetamine's reinforcing effects since
there was marked upregulation of -opioid receptors in the nucleus acumbens,
substantia nigra compacta, ventral tegmental area, prefrontal cortex, anterior
caudate and different hippocampus regions. Further studies in rats are underway
using yoked control groups of rats that passively receive injections of
either methamphetamine or saline whenever test rats self-administer injections
of methamphetamine.
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