National Institute on Drug Abuse
Director's Report to the National Advisory Council on Drug Abuse
Functional Neuroimaging Techniques Provide a Useful Tool in the Evaluation
of Remission Due to Peptide T AIDS Dementia Complex
AIDS Dementia Complex (ADC) is the most common presenting neurologic manifestation
of human immunodeficiency virus (HIV)-1 infection. A PET study monitored
the progress of ADC in a man who completed a 12-week treatment protocol
with intranasal peptide T, an octapeptide that blocks the binding of gp120,
the HIV envelop protein, to the cell surface antigen CD4. Data from this
patient were compared with those from a control group. From the PET images,
34 of 35 brain regions with abnormally high metabolic rates, located in
the temporal and parietal lobes, showed remission after peptide T treatment.
These preliminary observations suggest that functional neuroimaging is
a useful tool in evaluating the response to treatment in ADC patients.
Villemagne, V.L., Phillips, R.F.L., Liu, X., Gilson, S.F., Dannals, R.F.,
Wong, D.F., Harris, P.F., Ruff, M., Pert, C., Bridge, P. and London, E.D.
Peptide T and Glucose Metabolism in AIDS Dementia Complex. J. Nucl. Med.
37: pp. 1177-1180, 1996.
Role of Extracellular Dopamine in the Initiation and Long-term Expression
of Behavioral Sensitization to Cocaine
Repeated intermittent administration of cocaine sensitizes animals to the
locomotor-activating effects of this agent. The neurobiochemical basis
of sensitization was characterized by measuring extracellular dopamine levels
in the nucleus accumbens in rats after the cessation of repeated cocaine
administration. Basal dopamine levels were elevated initially following
the cessation of cocaine pretreatment and declined to reach control levels
by Day 22. In contrast, the dopaminergic response to cocaine was blunted
initially and increased thereafter. The behavioral response to cocaine
was enhanced by cocaine pretreatment and followed a different temporal pattern
than did dopaminergic activity following the cessation of repeated cocaine
treatment. These data suggest that behavioral sensitization is mediated
by different neurobiochemical events at different times following the cessation
of cocaine pretreatment. Heidbreder, C.H., Thompson, A.C., and Shippenberg,
T.C. Role of Extracellular Dopamine in the Initiation and Long-Term Expression
of Behavioral Sensitization to Cocaine. J. Pharmacol. Exp. Ther. 278: pp.
A Method for Imaging Nicotinic Acetylcholinergic Receptors in the Brain
Using Radiolabeled Pyridyl-7-Azabicyclo [2.2.1] Heptanes
Although nicotinic acetylcholine receptors are major excitatory neurotransmitter
receptors in brain, studies of these receptors, by noninvasive external
imaging, have been limited due to a need for an appropriate radiotracer.
NIDA investigators have used epibatidine, an extract from frog skin, as
the basis for design of radiotracers for noninvasive imaging of nAChRs using
positron emission tomography and single assessments of nAChRs as a function
of chronic drug administration and withdrawal, and may prove useful in diagnosis
of neurodegenerative diseases. London, E.D. Kimes, A.S., Horti, A. Dannals,
R.F., and Kassiou, M. A Method for Imaging Nicotinic Acetylcholinergic
Receptors in the Brain Using Radiolabeled pyridyl-7- azabicyclo [2.2.1]
heptanes. US Patent application Serial No. 08/642,636. Filed, May 3, 1996.
Drug Abuse Might be Better Approached as a Disorder of the Brain. In humans,
chronic cocaine abuse is associated with CNS changes, including cerebrovascular
events, EEG abnormalities, vasculitis, seizures, and decrements in neurobehavioral
performance. The acute administration of cocaine is associated with psychotic
episodes and paranoid states while withdrawal from the drug is often associated
with depressed mood. The mechanistic basis of these behavioral states is
not known. Given the structural and functional changes associated with
cocaine use, we propose that the chronic heavy use of cocaine may result
in a neuropsychiatric syndrome associated with neuropsychological changes
that are not obvious during routine clinical evaluation. This syndrome
might have deleterious effects on therapeutic interventions in drug abusers.
A neurobehavioral approach, comprised of a thorough neurological and psychiatric
examination, neuropsychological testing, and imaging studies, would provide
a rational basis for cognitive and/or pharmacological therapies. Cadet,
J.L., and Bolla, K.I. Chronic Cocaine Use as a Neuropsychiatric Syndrome:
A Model for Debate. Synapse 22: pp. 28-34, 1996.
The Neurotoxic Effects of Stimulants Involves the Production of Free
Methamphetamine (METH) has long-lasting neurotoxic effects on the nigrastriatal
dopamine (DA) system of rodents. METH-induced neurotoxicity is thought
to involve release of DA in presynaptic DA terminals, which is associated
with increased formation of oxygen-based free radicals. We have recently
shown that METH-induced striatal DA depletion is attenuated in transgenic
(Tg) mice that express the human CuZn-superoxide dismutase (SOD) enzyme.
DIR investigators used receptor autoradiographic studies of DA uptake sites
to evaluate the effects of several doses of METH on striatal DA terminals
of Non-Tg as well as of heterozygous and homozygous SOD-Tg mice. In Non-Tg
mice, METH decreased striatal DA uptake sites in a dose-dependent fashion.
The loss of DA terminals caused by METH was attenuated in a gene dosage-dependent
fashion, with the homozygous mice showing the greatest protection. Female
mice were somewhat more resistant than male mice against these deleterious
effects of METH. These results provide further evidence for a role of superoxide
radicals in the long-term effects of METH. They also suggest the notion
of a gender-specific handling of oxidative stress. Hiroshi, H., Ladenheim,
B., Carlson, E., Epstein, C., and Cadet, J.L. Autoradiographic Evidence
for Methamphetamine-Induced Striatal Dopaminergic Loss in Mouse Brain:
Attenuation in CuZn-Superoxide Dismutase Transgenic Mice. Brain Research
714: pp. 95-103, 1996.
GBR12909 Decanoate Derivative Produced a Long-Acting Decrease in Cocaine-
Maintained Responding in Rhesus Monkeys
The selective DA reuptake inhibitor GBR 12909 has been shown to decrease
cocaine-maintained behavior without affecting similar levels of food-maintained
behavior in monkeys, an effect analogous to that expected of a medication
designed to treat human cocaine abuse. In the current study, we extended
this effect by developing a decanoate ester of a hydroxylated analog of
GBR 12909 (5, DBL 583). Within several days of administration, active doses
of 5 had decreased cocaine-maintained responding more than 80%, without
affecting control (food-maintained) responding. The effect lasted almost
thirty days after a single injection, and was followed by a return of responding
to control levels. 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.
Serotonin-4 Receptor Antagonists Reverse Cocaine-Induced Cardiac Arrhythmia
The effect of 5-HT 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. The results
of this study indicate that 5-HT4 antagonist can reverse cocaine-induced
arrhythmias. The clinical implication of this study 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.
Effect of Dopamine Receptor Antagonists on Cocaine Subjective Effects:
A Naturalistic Case Study
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. Ohuoha, D.C., Maxwell, J.A., Thomson, L.E.,
Cadet, J.L., and Rothman, R.B.
Cocaine Cross-Sensitization to Dopamine Uptake Inhibitors: Unique Effects
Repeated administration of cocaine will cross-sensitize the locomotor response
to a variety of psychomotor stimulants. The ability of cocaine to cross-sensitize
the locomotor effects of other psychomotor stimulants provides information
relevant to the pharmacological mechanisms underlying the sensitization
process. The purpose of the current experiment was to investigate the ability
of cocaine to cross-sensitize the locomotor effects of several dopamine
uptake blockers with unique pharmacological profiles. Cocaine (40 mg/kg,
IP) or saline was administered prior to a locomotor session on day one.
On day 2, a full dose-effect curve was established for the locomotor effects
of cocaine, RTI-55, mazindol, and GBR12909. Previous exposure to cocaine
significantly affected locomotor activity and stereotopy-like behavior produced
by cocaine, mazindol, RTI-55, and GBR12909. However, GBR12909 was unique
in that the maximal stimulant effect and slope of the dose-effect curve
was significantly depressed and the stereotopy-like behavior was unchanged.
Thus, despite the similarity of these compounds in their ability to inhibit
dopamine uptake, cocaine-induced sensitization did not generalize to GBR12909.
This study further demonstrates the unique pharmacology of GBR12909 and
supports the further study of this compound as a potential treatment medication
for cocaine abuse. Elmer, G.I., Brockington, A., Gorelick, D.A., Carroll,
F.I., Rice, K.C., Matecka, D., Goldberg, S.R., and Rothman, R.B.
Evidence for Alterations in Presynaptic Serotonergic Function During
Withdrawal from Chronic Cocaine in Rats
The effects of repeated cocaine administration on serotonin (5-hydroxytryptamine,
5-HT) function were investigated by comparing the corticosterone response
to 5-HT receptor agonists in cocaine-treated and vehicle-treated rats. Male
rats were fitted with indwelling jugular catheters and received cocaine
(15 mg/kg i.p., b.i.d.) or saline for 7 days. Rats were challenged with
either saline, the 5-HT releaser fenfluramine (1.2 mg/kg i.v.). the 5-HT1a
receptor agonist 8-OH-DPAT (50 mg/kg i.v.). or the 5-HT1c receptor agonist
DOI (100 mg/kg i.v.) 42 h and 8 days after the final chronic treatment.
Repeated blood samples were withdrawn immediately before and at 15, 30
and 60 min after acute challenge injections. All 5-HT receptor agonists
increased plasma corticosterone, but the fenfluramine-induced increase in
corticosterone was significantly attenuated in cocaine-treated rats withdrawn
for 42 h. This blunted response to fenfluramine exhibited only partial recovery
when examined at 8 days post-chronic treatment. Corticosterone responses
to 8-OH-DPAT and DOI were not affected by cocaine exposure. Our data suggest
that chronic cocaine produces deficits in presynaptic 5-HT function and
alterations in 5-HT neurotransmission which may underlie the dysphoria experienced
by abstinent cocaine users. Neuroendocrine challenge tests should be performed
in human addicts to evaluate potential 5-HT dysfunction associated with
cocaine abuse. Baumann, M.H., Becketts, K.M., and Rothman, R.B.
Effects of Intravenous Cocaine on Plasma Cortisol and Prolactin in Human
The aim of the present work was to examine the cortisol and prolactin responses
to acute cocaine administration in human cocaine users. Each subject served
as its own control during intravenous saline placebo and cocaine (40 mg)
infusion sessions. Cocaine significantly elevated plasma cortisol but did
not affect prolactin. The rise in cortisol coincided with an increase in
heart rate and blood pressure after cocaine. In agreement with studies in
animals our data suggest that cocaine activates the hypothalamic-pituitary-adrenal
axis in humans. However, based on the well-known importance of dopamine
as a prolactin-inhibiting factor the failure of cocaine to suppress prolactin
in the present study raises questions concerning the role of dopamine in
the mechanism of acute cocaine action in humans. Baumann, M.H., Gendron,
T.M., Becketts, K.M., Henningfield, J.E., Gorelick, D.A., and Rothman,
Development of Novel, Potent and Selective Dopamine Reuptake dors through
Alteration of the Piperazine Ring of GBR 12935 and GBR 12909.
The design, synthesis and biological evaluation of compounds related to
the dopamine (DA) uptake inhibitors GBR 12395 (1) and GBR 12909 (2), directed
towards the development and identification of new ligands interacting with
high potency and selectivity at the dopamine transporter (DAT) is reported.
The substitution of the piperazine ring in the GBR structure with other
diamine moieties resulted in the retention of the high affinity of new ligands
for the DAT. Some of the modified GBR analogs (e.g. 8, 10, (-)-49 or (-)-50)
displayed substantially higher selectivity (4732-to 694-fold) for the DA
versus the serotonin (5-HT) reuptake site than the parent compounds. The
bis(p-fluoro) substitution in the diphenylmethoxyethyl fragment slightly
increased the affinity of the ligands at the DA reuptake site but reduced
their selectivity at this site (e.g. 9 and 8, 11 and 10 or 17 and 16, respectively).
Congeners, such as the series of mono-and symmetrically disubstituted piperazine
and trans-2,5-dimethylpiperazine, which lack the diphenylmethoxyethyl substituent
("left" fragment of GBR molecule), lost the affinity for the DAT,
yet exhibited very high potency for binding to the sigma receptors (e.g.
28). The chiral pyrrolidine derivatives of GBR 12935, (-)-49 and (+)-49,
exhibited an enantioselectivity ratio of 181 and 146 for the inhibition
of DA reuptake and binding to the DAT, respectively. Matecka, D., Rothman,
R.B., Radesca, L., de Costa, B.R., Dersch, C.M., Partilla, J.S., Pert,
A., Glowa, J.R., Wojnicki, F.H.E., and Rice, K.C.
A Continuum Model of Central Dopamine-Serotonin Interactions: Studies
Dopamine (DA) neuronal activity is modulated by serotonin (5-HT) in a complex
manner. In the present work, investigators examined the relationship between
DA and 5-HT function by testing a series of amphetamine analogs in neurochemical
and behavioral assays. In vivo microdialysis was performed in the nucleus
accumbens of awake rats. Phentermine, chlorphentermine, fenfluramine, or
a mixture of phentermine plus fenfluramine (PHEN/FEN), was administered
locally through the probe and by ip injection. Phentermine preferentially
elevated extracellular DA whereas fenfluramine elevated 5-HT. Chlorphentermine
and PHEN/FEN produced concurrent increases in DA and 5-HT. These agents
were tested for their ability to release preloaded [3H]DA and [3H]5-HT from
rat brain synaptosomes; the relative potencies and DA/5-HT selectivity ratios
determined in vitro were similar to in vivo findings. Phentermine produced
robust locomotor activation in mice, but fenfluramine and chlorphentermine
did not. Interestingly, coadministration of fenfluramine antagonized the
stimulant effects of phentermine. Our data support historical literature
that suggests DA and 5-HT neuronal systems can be viewed as opposing forces
along a continuum, with the net behavioral state being defined by the sum
total of these forces. Shifting the balance in favor of DA is expressed
as behavioral activation whereas shifting the balance in favor of 5-HT results
in behavioral inhibition. Baumann, M.H., Ayestas, M.A., Dersch, C.M., and
Characterization of a Novel Cocaine Binding Site Identified with [125I]RTI-55
in Membranes Prepared from Human, Monkey and Guinea Pig Caudate
[125I]RTI-55 is a cocaine analog with high affinity for dopamine (DA) and
serotonin (5-HT) transporters. Quantitative ligand binding studies revealed
a novel high affinity [125I]RTI-55 binding site assayed under 5-HT transporter
(SERT) conditions which has low affinity for almost all classic biogenic
amine transporter ligands, including high affinity 5-HT transporter inhibitors
such as paroxetine, but which retains high affinity for cocaine analogs.
This site, termed SERTsite2 for its detection under 5-HT transporter conditions
(not for an association with the SERT) occurs in monkey caudate, human
caudate and guinea pig caudate membranes, but not in rat caudate membranes.
SERTsite2 is distinguished from the DA transporter (DAT) and SERT by several
criteria, including a distinct ligand-selectivity profile, the inability
to detect SERTsite2 in cells stably expressing the cloned human DAT, insensitivity
to irreversible ligands which inhibit [125I]RTI-55 binding to the DAT and
SERT, and an anatomical distribution distinct from the SERT. Perhaps the
most striking finding about SERTsite2 is that a wide range of representative
antidepressant agents have very low affinity for SERTsite2. The affinity
of cocaine for this site is not very different from the concentration cocaine
achieves in the brain at pharmacological doses. Viewed collectively with
the observation that ligands with high affinity for SERTsite2 are mostly
cocaine analogs, these data lead us to speculate that actions of cocaine
which differ from those of classic biogenic amine uptake inhibitors may
be mediated in part via SERTsite2. Rothman, R.B., Silverthorn, M.L.,
Glowa, J.R., Matecka, D., Rice, K.C., Carroll, F.I., Partilla, J.S., Uhl,
G.R., Vandenbergh, D.J., and Dersch, C.M.
Changes in Cocaine Metabolism Alter the Acute Behavioral Effects of
Scientists in the Pharmacotherapy Section, Treatment Branch, in collaboration
with colleagues in the Behavioral Pharmacology & Genetics Section, Preclinical
Pharmacology Laboratory, and the National Institute on Aging Gerontology
Research Center, recently completed a study showing that changes in cocaine
metabolism could significantly alter the acute behavioral effects of cocaine.
Rats were injected IV with a cocaine dose that substantially increased
their motor activity over a 2-hour period. Separate groups of rats were
pretreated with either butyrylcholinesterase (BChE), a major cocaine-metabolizing
enzyme, or cymserine, a specific inhibitor of BChE. Rats pretreated with
BChE had significantly less of an increase in motor activity than those
pretreated with saline, while those pretreated with cymserine had more of
an increase. These findings suggest that speeding up cocaine metabolism
can reduce acute behavioral effects of cocaine, and could have potential
therapeutic benefits. Gorelick, D.A., and Schindler, C.W.
Distinctive Pharmacological Mechanisms of Cocaine Tolerance and Sensitization
Sari Izenwasser of the DIR's Psychobiology Section has found evidence that
tolerance and sensitization to cocaine are mediated by distinctive pharmacological
mechanisms. When cocaine is injected on a daily basis, sensitization occurs,
whereas continuously infused cocaine leads to tolerance in laboratory animals.
Rats treated with cocaine pumps showed large increases in locomotor activity,
compared to saline controls, after the pumps were implanted and partial
tolerance to this effect developed over the course of five days. Activity
levels dropped to saline levels shortly after the pumps were removed. Rats
receiving a challenge injection of cocaine showed significant elevations
in locomotor activity which were greater in rats that were not exposed to
cocaine. The cocaine dose-effect curve was shifted to the right compared
to saline controls in these subjects. When the rats were injected again
on the next day their activity levels were increased even further showing
sensitization. Despite this sensitization the cocaine-exposed rats were
still tolerant compared to the saline controls. These findings indicate
that tolerance and sensitization can exist simultaneously, implying a mediation
by distinctive neuronal mechanisms.
Central Role of mu Receptor in Morphine Effects
At the International Narcotics Research Committee (INRC) Dr. George Uhl
of the NIDA-IRP presented data on "knockout" transgenic mice deficient
in the morphine-preferring mu opiate receptor. These mice, developed and
tested in his laboratory by Drs. Sora and Miner, display increased sensitivity
to painful stimuli without morphine. They also show no morphine analgesia.
These results provide, for the first time, dramatic demonstration of the
central role that the mu receptor, whose cDNA and gene was cloned by Dr.
Uhl's laboratory (as well as others) in 1993 plays in morphine effects and
even on day-to-day nociception.
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