National Institute on Drug Abuse
Director's Report to the National Advisory Council on Drug
Abuse
May, 1997
Research Findings
Intramural Research
Adrenalectomy Modifies Nicotine-Induced Dopamine Release and Locomotor
Activity in Rats
Removal of adrenal glands can significantly modify sensitivity to both
the behavioral and neurochemical effects of nicotine. The locomotor depressant
effects of high doses of nicotine show potentiation and the locomotor activating
and dopamine-releasing properties elicited by low doses of nicotine attenuate
after adrenalectomy. This suggests that these two effects of nicotine may
be mediated via similar neural substrates. In view of the modulatory role
of corticosteroids, these hormones warrant further investigation as their
manipulation may have therapeutic utility in the treatment of certain tobacco
addictions. Shoaib, M., Shippenberg, T.S., Adrenalectomy Attenuates Nicotine-Induced
Dopamine Release and Locomotor Activity in Rats. Psychopharmacology. 128,
pp. 3443-350, 1996.
The Opiate Peptide DADLE Enhances Recovery of Myocardial Function
in Preserved Hearts
To assess the clinical practicality of using DADLE, an opiate peptide,
as a potential organ preservation agent, we examined if DADLE might prolong
the survival of a single organ. Isolated rabbit hearts were monitored for
baseline functions in a Langendorff apparatus before being subjected to
18 hrs of hypothermic global ischemic storage. Standard cardioplegia (CP),
currently used in cardiac transplantation, restored myocardial function
to only 20-30% of the preischemic values. Preperfusion of the heart with
DADLE for 15 min before standard CP treatment produced a 60-80% recovery
of myocardial function compared to the preischemic values. DADLE may, thus,
be an important, useful agent for myocardial preservation and cardiac transplantation.
Bolling, S.F., Su, T-P., Childs, K.F., Ning, X-H., Horton, N., Kilgore,
K., and Oeltgen, P.R.. The Use of Hibernation Induction Triggers for Cardiac
Transplant Preservation. Transplantation, 63, pp. 326-329, 1997.
Methamphetamine Induces Apoptosis in Immortalized Neural Cells: Protection
by the Protoncogene, bcl2
Methamphetamine (METH) is an amphetamine analog that produces degeneration
of the dopaminergic systems in mammals. The neurotoxic effects of drug are
thought to be mediated by oxygen-based free radicals. In the present report,
we have used immortalized neural cells obtained from rat mesencephalon in
order to further assess the role of oxidative stress in METH-induced neurotoxicity.
These findings may be of relevance to the cause(s) of Parkinson's disease
which involves degeneration of the nigrostriatal dopaminergic pathway. Cadet,
J.L., Ordonez S.V., and Ordonez J.V. Methamphetamine Induces Apoptosis in
Immortalized Neural Cells: Protection by the Protoncogene, bcl2. Synapse,
25, 1997.
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, it was hypothesized
that phentermine might attenuate the effects of cocaine on DA transmission.
Researchers 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. Findings from this research 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. Phentermine Pretreatment Antagonizes
the Cocaine-induced Rise in Mesolimbic Dopamine. Neuroreport 9: pp. 7-9,
1997.
Decrease in Cocaine-Maintained Responding in Rhesus Monkeys with 1-[2-[bis-(4-fluorophenyl)methoxy]ethyl]-4-[3-hydroxy-3-phenylpropyl]
Piperazinyl Decanoate
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, investigators 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. Sustained Decrease in Cocaine-Maintained Responding in
Rhesus Monkeys with 1-[2-[bis-(4-fluorophenyl)methoxy] ethyl]-4-[3-hydroxy-3-phenylpropyl]
Piperazinyl Decanoate, a Long-Acting Ester Derivative of GBR 12909. Glowa,
J.R., W.E. Fantegrossi, D.B. Lewis, D.M. Matecka, K.C. Rice, and R.B. Rothman.
J. Med. Chem. 39(24), pp. 4689-4691, 1996.
Phentermine/Fenfluramine Decreases Cocaine Self-Administration in
Rhesus Monkeys
Dopamine reuptake inhibitors can decrease cocaine self-administration
at doses that do not decrease food-maintained responding. To assess whether
similar effects could be obtained with medications currently considered
for substance abuse, fenfluramine/phentermine combinations were given to
rhesus monkeys responding under multiple fixed-ratio 30 schedules of food-
and cocaine-delivery. Phentermine decreased cocaine-maintained responding
while having less of an effect on food-maintained responding. Although fenfluramine
did not selectively affect cocaine-maintained behavior, combining a low
dose of fenfluramine with phentermine slightly enhanced the selectively
of effect of phentermine on these behaviors. These results provide further
data supporting the possible efficacy of phentermine/fenfluramine as a pharmacological
treatment for cocaine addiction. Phentermine/Fenfluramine Decreases Cocaine
Self-Administration in Rhesus Monkeys. Glowa, J.R., K.C. Rice, D. Matecka,
and R.B. Rothman. NeuroReport, In press.
Effect of Dopamine Receptor Antagonists on Cocaine Subjective Effects
Schizophrenic patients on neuroleptic medications abuse cocaine and report
cocaine-induced euphoria. This study was undertaken to provide better clinical
characterization of these phenomena by administering the POMS and a custom
designed questionnaire. A group of heavy cocaine users who were not mentally
ill served as the control group. The results clearly suggest that schizophrenic
patients report cocaine-induced euphoria and post-use craving despite being
treated with therapeutic doses of haloperidol or fluphenazine. The responses
of the control group were similar to that of the schizophrenic group except
that the latter subjects reported a greater degree of anxiety. These results
suggest that blockade of D2 receptors is not sufficient to block cocaine-induced
subjective effects in humans. Effect of Dopamine Receptor Antagonists on
Cocaine Subjective Effects: A Naturalistic Case Study. Ohuoha, D.C., J.A.
Maxwell, L.E. Thomson, J.L. Cadet, and R.B. Rothman. J. Subst. Abuse Treat.,
In press.
Opioid Peptide Receptor Studies
Mutational analysis of opioid receptors indicates that dissimilar receptor
domains contribute to the binding affinity and pharmacological effects of
different ligands. The availability of four stereoisomers of (±)-cis-N-[1-(2-hydroxy-2-phenylethyl)
3-methyl-4-piperidyl]-N- phenylpropanamide (RTI-4614-4) allowed us to determine
if enantiomeric ligands can distinguish among the four parameters of the
ligand-receptor interaction: potency (ED50), efficacy (maximal stimulation),
intrinsic efficacy (effect as a function of receptor occupation) and binding
affinity, since the use of ligand stereoisomers focuses the analysis on
asymmetric structural factors while avoiding confounding changes in physiochemical
characteristics. The data, obtained with cloned rat receptors, demonstrate
that the four isomers of RTI-4614-4 differ in binding affinity, potency,
efficacy and intrinsic efficacy. We speculate that this results from binding
to different domains of the opioid receptor. Opioid Peptide Receptor Studies.
6. The 3-methylfentanyl Congeners RTI-4614-4 and its Enantiomers Differ
in Efficacy, Potency and Intrinsic Efficacy as Measured by Stimulation of
[35S]GTP-g-S Binding by Cloned Mu Opioid Receptors. Xu, H., Y.F. Lu, J.S.
Partilla, G.A. Brine, F.I. Carroll, K.C. Rice, J. Lai, F. Porrca, and R.B.
Rothman. Analgesia, In press.
Doses of GBR12909 Which Suppress Cocaine Self-Administration in Nonhuman
Primates Substantially Occupy Dopamine Transporters
GBR12909 (GBR) is a high affinity, selective and long-acting inhibitor
of DA uptake which has been proposed as a potential treatment agent. GBR
produces a persistent and noncompetitive blockade of DA transporters and
substantially reduces cocaine-induced increases in extracellular DA. Slow
iv infusion of GBR to Rhesus monkeys selectively reduced (1 mg/kg) and eliminated
(3 mg/kg) cocaine self-administration. This study tested the hypothesis
that doses of GBR which reduce cocaine self-administration in nonhuman primates
produce significant occupation of DA transporters. DA transporters were
quantitated in two baboons using [11C]WIN35,428 and PET. The baboons underwent
four PET scans (performed on two separate study days, 3-4 weeks apart).
Blood pressure, temperature, heart rate and oxygen saturation were monitored
throughout each study. On the first scan of the first study day the baboon
received saline (3 ml/kg) 90 min before the injection of the radiotracer.
GBR (1 mg/kg i.v.) was infused 90 min before the second [11C]WIN 35,428
study. The second study (3-4 weeks from the first study day) was conducted
identically to the first study, except that the dose of GBR was 3 mg/kg.
Doses of 1 (n=1) and 3 mg/kg (n=2) produced % reductions of binding potential
of 18 and 53%, respectively. GBR was well tolerated in all baboons. One
baboon showed transient bradycardia (that lasted less than 5 min) immediately
after the injection of 1 mg of GBR. No changes in blood pressure or oxygen
saturation were observed in any of the baboons. These results demonstrate
that doses of GBR which suppress cocaine self-administration in nonhuman
primates also produce high occupancy of the DA transporter. Viewed collectively
with other work, these data strongly suggest that occupancy for the DA transporter
by GBR explains its ability to attenuate cocaine-induced increases in extracellular
DA and to suppress cocaine self-administration. Moreover, these data suggest
that clinical trials (planned) of orally administered GBR should use doses
which produce at least 50% occupancy of the DA transporter. Doses of GBR12909
Which Suppress Cocaine Self-Administration in Nonhuman Primates Substantially
Occupy Dopamine Transporters. Villemagne, V., Wong, D.F., Yokoi, F., Rice,
K.C., Matecka, D. and Rothman, R.B.
An Open-Label Study of a Functional Opioid Kappa Antagonist in the
Treatment of Opioid Dependence
Several lines of evidence, including the well-established observation
that kappa opiate agonists produce dysphoria and psychotomimetic effects
in humans, suggest that dysfunction of the endogenous kappa opioid system
may contribute to opioid and cocaine addiction. The objective of this open-label
study was to determine the effectiveness of a functional kappa antagonist
as a treatment for opioid dependence. Fifteen treatment-seeking heroin dependent
(DSM-IV) men (41±7 yrs old; 19±8 years heroin use) who were
eligible for methadone maintenance but did not want it enrolled in the study.
After inpatient detoxification at the VA and a naloxone-challenge test to
verify that they were not physically dependent on opioids, subjects received
naltrexone (50 mg po per day) to block mu opioid receptors. On the fourth
day patients received liquid buprenorphine (4 mg sl), a partial mu agonist
and a kappa antagonist, in addition to naltrexone. All patients received
medication at the clinic six days per week and a full program of psychosocial
treatment. Outcome variables included pupillary diameter, urine toxicology,
self-reported drug use, the SCL-90, ASI and the Beck Depression Inventory.
Five patients (33%) completed the three-month study. Four were abstinent
from opioids and cocaine for the entire study, and one was abstinent from
opioids and cocaine for the last nine weeks. Six subjects dropped out due
to either minor side effects or disliking the sensation of sublingual buprenorphine.
Initial analysis of the data shows no changes in pupillary diameter. The
positive response to treatment exceeds that ordinarily expected from naltrexone
alone (90% drop-out). These promising results suggest that controlled studies
of this medication combination should be conducted. An Open-Label Study
of a Functional Opioid Kappa Antagonist in the Treatment of Opioid Dependence.
Rothman, R.B., Gorelick, D.A., Eichmiller, P.R., Hill, B.H., Norbeck, J.,
and Liberto, J.G.
Anatomical Distribution of a Novel Kappa2 Opioid Receptor in Guinea
Pig Brain
Visualized with [125I]IOXY. Previous studies demonstrated unique opioid
receptor distributions in guinea pig brain sections at the level of the
caudate putamen. Mu, delta, and kappa1 receptors were depleted by the irreversible
ligands BIT, FIT, and UPHIT, and opioid receptors were labeled with the
opioid antagonist [125I]IOXY and subjected to autoradiographic analysis.
The objective of this study was to characterize further these unique binding
sites (designated kappa2). Kappa2 binding was quantitated by autoradiography
in specific regions of four different levels of guinea pig brain (olfactory
bulb, caudate putamen, hippocampus, and substantia nigra) for a total of
37 determinations across all levels. The kappa2 distribution was then compared
with the binding sites labeled by [125I]DAMGO (mu), [125I]deltorphin II
(delta), and [125I]IOXY under kappa1 conditions to identical regions in
adjacent guinea pig brain sections. The results are: (1) kappa2 binding
greatly exceeded mu and delta binding in all regions; (2) kappa2 binding
exceeded kappa1 binding in all regions except the deep cortex at the level
of the hippocampus; (3) the kappa2 distribution was different than that
of mu, delta or kappa1 receptors. These results provide further evidence
for the existence of a novel opioid binding site in guinea pig brain. Anatomical
Distribution of a Novel Kappa2 Opioid Receptor in Guinea Pig Brain Visualized
with [125I]IOXY. Partilla, J.S., Ni, Q., Rice, K.C., Matecka, D., and Rothman,
R.B.
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