Kappa opioid agonists as targets for pharmacotherapies in cocaine abuse

Article abstract of DOI:10.1016/S0031-6865(99)00044-8

Kappa opioid receptors derive their name from the prototype benzomorphan, ketocyclazocine (1a) which was found to produce behavioral effects that were distinct from the behavioral effects of morphine but that were antagonized by the opioid antagonist, naltrexone. Recent evidence suggests that agonists and antagonists at kappa opioid receptors may modulate the activity of dopaminergic neurons and alter the neurochemical and behavioral effects of cocaine. Kappa agonists blocked the effects of cocaine in squirrel monkeys in studies of cocaine discrimination and scheduled-controlled responding. Studies in rhesus monkeys suggested that kappa opioids may antagonize the reinforcing effects of cocaine. These studies prompted the synthesis and evaluation of a series of kappa agonists related to the morphinan, L-cyclorphan (3a) and the benzomorphan, L-cyclazocine (2). We describe the synthesis and preliminary evaluation of a series of morphinans, structural analogs of cyclorphan 3a-c, the 10-keto morphinans 4a and b, and the 8-keto benzomorphan 1b, structurally related to ketocyclazocine (1a). In binding experiments L-cyclorphan (3a), the cyclobutyl (3b), the tetrahydrofurfuryl 3c and the 10-keto 4b analogs had high affinity for mu (μ), delta (δ) and kappa (κ) opioid receptors. Both 3a and 3b were more selective for the κ receptor than the μ receptor. However, 3b was 18-fold more selective for the κ receptor in comparison to the δ receptor, while cyclorphan (3a) had only a 4-fold greater affinity for the κ receptor in comparison to the δ receptor. The cyclobutyl compound 3b was found to have significant μ agonist properties, while 3a was a μ antagonist. All compounds were also examined in the mouse tail flick and writhing assay. Compounds 3a and 3b were κ agonists. Correlating with the binding results, compound 3a had some δ agonist properties, while 3b was devoid of any activity at the δ receptor. In addition, compounds 3a and 3b had opposing properties at the μ opioid receptor. The cyclobutyl compound 3b was found to have significant μ agonist properties, while 3a was a μ antagonist. Copyright (C) 2000 Elsevier Science B.V.

Full text of DOI:10.1016/S0031-6865(99)00044-8

Ž
.
Pharmaceutica Acta Helvetiae 74 2000 337–344
www.elsevier.comrlocaterpharmactahelv
Kappa opioid agonists as targets for pharmacotherapies in cocaine abuse
a
a
b
John L. Neumeyer a,), Nancy K. Mello , S. Stevens Negus , Jean M. Bidlack
a
Department of Psychiatry, HarÕard Medical School, McLean Hospital, Alcohol and Drug Abuse Research Center, Belmont, MA 02478-9106, USA
b Department of Pharmacology and Physiology, UniÕersity of Rochester School of Medicine and Dentistry, Rochester, NY 14642-8711, USA
Abstract
Ž
.
Kappa opioid receptors derive their name from the prototype benzomorphan, ketocyclazocine 1a which was found to produce
behavioral effects that were distinct from the behavioral effects of morphine but that were antagonized by the opioid antagonist,
naltrexone. Recent evidence suggests that agonists and antagonists at kappa opioid receptors may modulate the activity of dopaminergic
neurons and alter the neurochemical and behavioral effects of cocaine. Kappa agonists blocked the effects of cocaine in squirrel monkeys
in studies of cocaine discrimination and scheduled-controlled responding. Studies in rhesus monkeys suggested that kappa opioids may
antagonize the reinforcing effects of cocaine. These studies prompted the synthesis and evaluation of a series of kappa agonists related to
Ž
.
Ž .
the morphinan, L-cyclorphan 3a and the benzomorphan, L-cyclazocine 2 . We describe the synthesis and preliminary evaluation of a
series of morphinans, structural analogs of cyclorphan 3a–c, the 10-keto morphinans 4a and b, and the 8-keto benzomorphan 1b,
Ž
.
Ž
.
Ž
.
structurally related to ketocyclazocine 1a . In binding experiments L-cyclorphan 3a , the cyclobutyl 3b , the tetrahydrofurfuryl 3c and
Ž .
Ž .
Ž .
the 10-keto 4b analogs had high affinity for mu m , delta d and kappa k opioid receptors. Both 3a and 3b were more selective for
the k receptor than the m receptor. However, 3b was 18-fold more selective for the k receptor in comparison to the d receptor, while
Ž
.
cyclorphan 3a had only a 4-fold greater affinity for the k receptor in comparison to the d receptor. The cyclobutyl compound 3b was
found to have significant m agonist properties, while 3a was a m antagonist. All compounds were also examined in the mouse tail flick
and writhing assay. Compounds 3a and 3b were k agonists. Correlating with the binding results, compound 3a had some d agonist
properties, while 3b was devoid of any activity at the d receptor. In addition, compounds 3a and 3b had opposing properties at the m
opioid receptor. The cyclobutyl compound 3b was found to have significant m agonist properties, while 3a was a m antagonist. q 2000
Elsevier Science B.V. All rights reserved.
Keywords: Morphinans; Benzomorphans; Kappa, delta and mu receptor affinity
.
1. Introduction
1978; Reith, 1988 , and the extensive literature which
suggests that cocaine’s reinforcing effects are mediated by
increases in extracellular dopamine levels in the mesolim-
Cocaine abuse continues to be a major public health
Ž
concern in the United States National Institutes of Health,
Ž
bic dopamine system Ritz et al., 1987; Koob and Bloom,
.
1996 . A current goal of preclinical research has been to
1988; Johanson and Fischman, 1989; Kuhar et al., 1991;
characterize the neurobiological and pharmacological de-
terminants of cocaine’s high abuse potential and to de-
velop drugs that could be used in the treatment of cocaine
abuse. One approach to develop such drugs has been the
observation that cocaine blocks the reuptake of the neuro-
.
Woolverton and Johnson, 1992 . Dopamine receptor antag-
onists have been evaluated for their potential utility in
Ž
.
treating cocaine abuse Mello and Negus, 1996 but such
agents produce extrapyramidal motor effects and other
unwanted effects that complicate their use in the treatment
of cocaine dependence.
Ž
. Ž
transmitter dopamine DA Koe, 1976; Taylor and Ho,
Compounds acting on other receptors may provide an
alternative means of modifying the neurobiological and
behavioral effects of cocaine by indirectly modulating the
)
Corresponding author. Tel.: q1-617-855-3388; fax: q1-617-855-
2519; e-mail: neumeyer@mclean.harvard.edu
0031-6865r00r$ - see front matter q 2000 Elsevier Science B.V. All rights reserved.
Ž
.
PII: S0031-6865 99 00044-8

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)
338
J.L. Neumeyer et al.rPharmaceutica Acta HelÕetiae 74 2000 337–344
activity of dopaminergic systems. For example, a growing
body of evidence suggests that agonists and antagonists at
cocaine, possibly by inhibiting the release of dopamine
from dopaminergic neurons, and may provide a new ap-
proach to the continuing search for effective treatment
Ž .
kappa k opioid receptors may modulate the activity of
Ž
.
dopaminergic neurons and alter the neurochemical and
behavioral effects of cocaine. The nucleus accumbens
medications Archer et al., 1996 .
Ž
.
The kappa antagonist norbinaltorphimine nor-BNI
Portoghese et al., 1987 was found to have no effect on
Ž
Ž
.
contains high levels of both k opioid receptors Mansour
.
Ž
et al., 1987, 1988, 1994 as well as dynorphin Hokefelt et
al., 1984 , an endogenous opioid peptide with high affinity
for kappa receptors Chavkin et al., 1982 . In contrast to
cocaine, kappa agonists have been shown to decrease
cocaine self-administration but blocked the effects of the
.
Ž
kappa agonists on cocaine self-administration Glick et al.,
Ž
.
.
1995; Negus et al., 1997 . The structures of the known
receptor selective kappa agonists are shown in Fig. 1.
Ž
striatal dopamine levels in rats DiChiara and Imperato,
These agonists can be grouped into three chemical classes:
Ž .
1 the arylacetamides such as spiradoline and enadoline;
1988; Donzanti et al., 1992; Spanagel et al., 1992; Devine
et al., 1993 . Kappa agonists also attenuated cocaine-in-
duced increases in dopamine levels in the nucleus accum-
bens. Kappa agonists also produce antagonism of the
discriminating stimulus effects of cocaine in squirrel mon-
.
Ž . Ž .
zomorphans such as cyclazocine 2 and ethylketocycla-
Ž .
2
the morphinan, L-cyclorphan 3a and
3
the ben-
Ž .
Ž
.
zocine 1b . Although kappa opioid agonists have been
found to attenuate some neurochemical and behavioral
effects of cocaine, they also produce unwanted side-effects
such as dysphoria and sedation that may compromise their
clinical utility as medications for the treatment of cocaine
dependence. We wish to describe here the synthesis and
Ž
keys Spealman and Bergman, 1992; Spealman and
.
Bergman, 1994 .
These findings suggest that activation of kappa opioid
receptors may functionally antagonize some effects of
Fig. 1. Structures of kappa agonists.

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)
J.L. Neumeyer et al.rPharmaceutica Acta HelÕetiae 74 2000 337–344
339
Fig. 2. Structures of synthesized morphinans and benzomorphans.
Ž
.
preliminary evaluation of a series of morphinans 3a–c ,
structural analogs of cyclorphan 3a, the 10-keto morphi-
nans 4a and b, and the 8-keto benzomorphan 1b, an analog
The 8-keto benzomorphan derivative 1b was prepared
X
Ž
.
from y 5,9-a-dimethyl-2 -hydroxy-6,7-benzomorphan
Ž
. wŽ
.
x Ž
.
14 y -nor-metazocine Tullar et al., 1967 as outlined
in Scheme 2. Protection of the amine with ditertiarybutyl
Ž
.
of ketocyclazocine 1a Fig. 2 .
Ž
.
dicarbonate boc and O-methylation with dimethylsulfate
led to 16. Acid hydrolysis followed by oxidation of 17
Ž
.
2. Experimental procedures
with CrO3rH2 SO4 Michne and Albertson, 1972 led to
18. O-demethylation and alkylation with 5-tetrahydrofur-
Ž
.
Ž .
The synthesis of the morphinans 3a–c and the 10-keto
derivatives 4a–b are shown in Scheme 1. The experimen-
tal details of the syntheses of these compounds will be
furyl 1R -camphor-10-sulfonate 10 gave 1b which was
isolated as the HCl salt.
Ž
.
reported elsewhere Neumeyer et al., 1999 . The com-
pounds were all prepared from commercially available
levorphanol 3d which was converted to the O-methyl ether
6 and N-dealkylated to norlevorphanol methyl ether 7.
2.1. Determination of K1 Õalues at m, d and k opioid
receptors
Frozen guinea pig brains were thawed and homogenized
in 10 times the wet weight of tissue in cold 50 mM
Tris–HCl, pH 7.5, followed by centrifugation at 39,000=g
for 20 min at 48C. The membranes were resuspended in
the original volume of buffer and incubated at 378C for 30
min, followed by centrifugation at 39,000=g for 20 min
at 48C. The membranes were resuspended at a protein
concentration of 8–12 mgrml in 50 mM Tris–HCl, pH
7.5, and stored at y808C until use. The protein concentra-
tion of membranes was determined by the method of
Ž
.
Alternatively, levorphanol 3d was directly N-dealkylated
Ž .
to norlevorphanol 8 .
The intermediate 8 was N-and-Odiacylated with cyclo-
propane carbonyl chloride in triethylamine. The crude
diacyl compound 9a was further reduced with lithium
aluminum hydride to yield known cyclorphan 3a previ-
ously prepared Gates and Montzka, 1964 from y -3-hy-
Ž
.
Ž
.
Ž .
droxymorphinan.
The free base 3a was further converted to the mandelate
salt, a white crystalline product. The cyclobutyl analog 3b
was similarly prepared from 8 and converted to the crys-
talline mandelate salt. The S N-tetrahydrofurfuryl deriva-
tive 3c was prepared from
camphor-10-sulfonate 10 as previously reported Mertz
et al., 1997 . The 10-keto morphinans were prepared by
the oxidation Michne and Albertson, 1972 of the morphi-
nan 7 with CrO3rH2 SO4 followed by alkylation with
cyclopropyl methyl bromide and O-demethylation to yield
Ž
.
Bradford 1976 , using bovine serum albumin as standard.
Guinea pig brain membranes, 500 mg of membrane
protein, were incubated with 12 different concentrations of
the compound in the presence of either 0.25 nM
Ž .
Ž .
S
Ž
.
tetrahydrofurfuryl 1R
w3
x
Ž . Ž .
H U69,593 k in a final volume of 1 ml of 50 mM
w3
x
Ž
.
Ž
H DAMGO m , 0.2 nM H naltrindole d or 1 nM
w3
x
Ž .
.
Ž
.
Tris–HCl, pH 7.5 at 258C. Naloxone at a final concentra-
tion of 1 mM was used to measure nonspecific binding.
w3
x
w3
x
Samples incubated with either H DAMGO or H U69,
593 were incubated at 258C for 60 min. To measure
binding to d receptors, 5 ml MgCl2 and 1 mM PMSF were
Ž
.
4b Scheme 1 . O-Demethylation of 11 to form 13 fol-
Ž .
Ž
.
lowed by alkylation with S tetrahydrofurfuryl 1R cam-
w3
x
Ž
.
phor-10 sulfonate 10 , led to 4a. The assignment of the
stereochemistry of 4a was based on the work of Merz and
included with H naltrindole and the test compound. These
samples were incubated at 258C for 3 h. Binding was
terminated by filtering samples through Schleicher &
Ž
.
Stockhaus 1979 .

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)
340
J.L. Neumeyer et al.rPharmaceutica Acta HelÕetiae 74 2000 337–344
Scheme 1.
w3
x
H U69,593 binding to guinea pig membranes were 0.45
Scheull No. 32 glass fiber filters. The filters were subse-
quently washed three times with 3 ml of cold 50 mM
Tris–HCl, pH 7.5, and were counted in 2 ml of Ecoscint A
Ž
.
nM, 0.086 nM, and 0.46 nM, respectively Table 1 .
w3
x
w3
x
scintillation fluid. For H naltrindole and H U69,593
binding, the filters were soaked in 0.25% polyethylenimine
for at least 60 min before use.
2.2. Mouse antinociceptiÕe assays
All antinociceptive experiments used male, ICR mice
Ž
.
IC50 values were determined using the least squares fit
20–24 g, Harlan Sprague Dawley . Mice were kept in
Ž
.
to a logarithm–probit analysis Cheng and Prusoff, 1973 .
groups of eight in a temperature controlled room with a
12-h light–dark cycle. Food and water were available ad
w3 w3
x
x
The Kd values for H DAMGO, H naltrindole, and

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)
J.L. Neumeyer et al.rPharmaceutica Acta HelÕetiae 74 2000 337–344
341
Scheme 2.
.
1979 . After determining control latencies, the mice re-
libitum until the time of the experiment. Intracerebroven-
tricular injections were made directly into the lateral ven-
Ž
.
ceived graded i.c.v. doses of either y cyclorphan or
Ž
.
Ž .
tricle Haley and McCormick, 1957 . The volume of all
i.c.v. injections was 5 ml, using a 10-ml Hamilton micro-
liter syringe. The mouse was lightly anesthetized with
ether, an incision was made in the scalp, and the injection
was made 2 mm lateral and 2 mm caudal to bregma at a
depth of 3 mm.
MCL-101. Morphine sulfate, DPDPE, U50, 488, y cy-
clorphan, and MCL-101 were given as single i.c.v. injec-
tions with antinociceptive effect measured 20 min after
injection. In the antagonist study, various doses of
Ž
.
y cyclorphan and MCL-101 were co-administered with
3-nmol morphine by i.c.v. injection, 20 min before testing.
In the receptor selectivity studies, either the k-selective
antagonist, nor-BNI, or the d-selective antagonist, ICI
174,864 were each given with the agonist in the same
injection. b-FNA, the m-selective antagonist, was injected
24 h before agonist injection. A cut-off time of 15 s was
used; if the mouse failed to display a tail flick in that time,
the tail was removed from the water and the animal
2.3. Tail-flick assay
The tail flick assay was performed as previously de-
Ž
.
scribed McLaughlin et al., 1999 . The thermal nociceptive
stimulus was 558C water, with the latency to tail flick or
Ž
withdrawal taken as the endpoint Vaught and Takemori,
Table 1
Ki inhibition values m, d and k opioid binding to guinea pig brain membranes by kappa opioids
Guinea pig brain membranes, 0.5 mg of proteinrsample, were incubated with 12 different concentrations of the compounds in the presence of
receptor-specific radioligands at 258C, in a final volume of 1 ml of 50 mM Tris–HCl, pH 7.5. Nonspecific binding was determined using 1 M naloxone.
Data are the mean values S.E.M. from three experiments, performed in triplicate.
3
3
3
w
x
Ž
.
w
x
Ž .
w
x
Ž .
Compound
H DAMGO m
H Naltrindole d
H U69,593 k
Selectivity k:m
Selectivity k:d
Ž
.
Ki nM"S.E.
220"5.6
U50,488
2500"170
0.58"0.06
0.22"0.01
1.3"0.06
0.27"0.02
4.2"0.45
1.0"0.18
150"71
0.36"0.056
610
2
2
2
0.066
0.09
2
1
4
6900
11
4
18
2
Ž
.
.
Ž .
Ž .
. Ž
y Cyclazocine 2
0.10"0.03
0.092"0.005
0.12"0.012
0.010"0.002
0.21"0.017
0.38"0.004
240"89
0.052"0.0009
0.053"0.003
0.073"0.012
0.15"0.01
2.3"0.26
0.18"0.019
24"1.6
720"57
Ž
y Cyclorphan 3a
Ž
Ž
.
Morphinan 3b MCL-101
.
Morphinan 3c
Levorphanol 3d
Morphinan 4a
Morphinan 4be
Ž
.
2
6
6
Ž
Ž
.
.
Ž
.
Benzomorphan 1b
2900"58
)100,000

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)
342
J.L. Neumeyer et al.rPharmaceutica Acta HelÕetiae 74 2000 337–344
assigned a maximal antinociceptive score of 100%. Mice
who showed no response within 5 s in the initial control
test were eliminated from the experiment. At each time
point, antinociception was calculated according to the fol-
The receptor selectivity for antinociception produced by
Ž
.
y cyclorphan and MCL-101 in the writhing test was also
Ž
.
determined. y Cyclorphan produced antinociception that
was mediated by k and d opioid receptors. In contrast,
MCL-101 produced antinociception that was mediated by
k and m receptors, which is in agreement with the results
from the tail flick assay. The receptor selectivity results in
the writhing assay correlated with the binding results in
Ž
lowing formula: %antinociceptions100= test latencyy
. Ž
.
control latency r 15ycontrol latency .
Ž
.
2.4. Mouse writhing assay
Table 1, which showed that y cyclorphan had a higher
affinity than MCL-101 for the d receptor.
Ž
.
Because y cyclorphan did not produce a full dose
–response curve in the 558C warm-water tail flick test,
experiments were performed to determine if it would anta-
gonize morphine-induced antinociception. Mice were co-
injected with 3-nmol of morphine and varying doses of
Since antinociception of k opioid agonists has been
Ž
difficult to evaluate in the tail-flick test Porreca et al.,
.
Ž .
1987 , we also investigated the action of y cyclorphan
and MCL-101 in the mouse acetic acid writhing test Xu et
al., 1996 . After receiving graded i.c.v. doses of opioid
Ž
.
Ž
.
y cyclorphan. Antinociception was determined 20 min
agonists and antagonists at various times, an i.p. injection
Ž
.
later. y Cyclorphan at a dose of 1 nmol, completely
Ž
.
of 0.6% acetic acid 10 mlrkg was administered to each
mouse. Five min after administration, the number of
writhing signs displayed by each mouse was counted for
an additional 5 min. Antinociception for each tested mouse
were calculated by comparing the test group to a control
group in which mice were treated with i.c.v. vehicle
solution.
antagonized morphine-induced antinociception, indicating
Ž
.
that y cyclorphan was a potent m antagonist. In contrast,
MCL-101 was a weak m agonist, with only partial antago-
nism of morphine-induced antinociception, at a dose that
did not produce antinociception by itself.
To determine the receptor selectivity of the antagonism
Ž
.
induced by y cyclorphan, mice were co-injected with
either the m agonist, morphine, the k-selective agonist,
U50,488, or the d-selective peptide DPDPE along with
Ž
.
Ž .
1-nmol y cyclorphan. y Cyclorphan did not antagonize
antinociception mediated by either the d or the k recep-
tors, but did antagonize morphine-induced antinociception,
3. Results and discussion
Ž
.
All compounds were examined for their affinity and
demonstrating that y cyclorphan was a m-selective an-
selectivity at m, d and k opioid receptors in Guinea
tagonist.
w3
x
Ž .
Pig brain membranes labeled with H DAMGO m ,
w3 w3
Ž . Ž . Ž
x
x
.
H Naltrindole d and H U69,593 k Table 1 . The
antinociceptive activity of the two morphinans with the
highest affinity and selectivity were examined further in
the tail flick and acetic-acid writhing tests in mice.
4. Conclusions
Ž
.
Ž .
In the warm-water tail flick test, y cyclorphan 3a
The binding results demonstrate that MCL-101, like
Ž
.
produced 37"10% antinociception after an i.c.v. dose of
y cyclorphan, had high affinity for m, d and k opioid
Ž
.
100 nmol. In contrast, MCL-101 3b produced a full
dose–response curve. In the 558C warm-water tail flick
test an ED50 value and 95% confidence limits of 7.3
receptors. Both compounds were approximately 2-fold
more selective for the k receptor than the m receptor.
However, MCL-101 was 18-fold more selective for the k
Ž
.
5.7–9.4 nmol were obtained for MCL-101, with testing
taking place 20 min after an i.c.v. injection.
receptor in comparison to the
d receptor, while
Ž
.
y cyclorphan had only a 4-fold greater affinity for the k
Ž
.
Because MCL-101 3b generated a full dose–response
curve in the tail flick test, the receptor selectivity of the
agonist effect was determined by using selective antago-
nists. In the tail flick test, antinociception induced by
MCL-101 3b was mediated by both k and m opioid
receptors.
receptor in comparison to the d receptor. This finding was
confirmed in the antinociceptive tests, which demonstrated
Ž
.
that y cyclorphan produced some antinociception that
was mediated by the d receptor, while MCL-101 did not
produce agonist or antagonist effects at the d receptor.
MCL-101 had significant m agonist properties, while
Ž
.
Ž
.
Ž
.
Ž
.
Ž
.
The effect of y cyclorphan 3a and MCL-101 3b
y cyclorphan was a m antagonist. So, while their affinity
were also characterized in the writhing test. Both
y cyclorphan and MCL-101 produced full dose–re-
sponse curves in the writhing test, with ED50 values and
for the m receptor is comparable, they produce different
effects at the m opioid receptor. However, the two com-
pounds had comparable k agonist properties. In summary,
Ž
.
Ž
.
Ž
.
Ž
.
95% C.L. of 0.65 0.35–1.2 nmol and 0.79 0.48–1.3
both MCL-101 and y cyclorphan were k agonists.
Ž
.
nmol, respectively, demonstrating that in this assay, the
two compounds were equipotent.
y Cyclorphan produced some antinociception mediated
by the d opioid receptor; this property was not shared with

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)
J.L. Neumeyer et al.rPharmaceutica Acta HelÕetiae 74 2000 337–344
343
Ž
.
Eds. , Central and Peripheral Endorphins: Basic and Clinical As-
MCL-101. While having similar affinity for the m opioid
pects. Raven Press, New York, pp. 1–16.
Ž
.
receptor, y cyclorphan and MCL-101 had opposing ef-
Johanson, C.E., Fischman, M.W., 1989. The pharmacology of cocaine
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fects at the m receptor. MCL-101 was a m agonist, while
Ž
.
y cyclorphan was a m antagonist. Recent findings from
Ž
our laboratories Mello and Negus, 1996; Negus et al.,
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.
Koob, G.F., Bloom, F.E., 1988. Cellular and molecular mechanisms of
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mal effects on food self-administration, supports our on-
going studies with these novel kappa agonists to carry out
a comprehensive behavioral analysis of the interactions of
these potential medications with cocaine. Such studies will
help to define the clinical approach and suggest the rela-
tive effectiveness of these compounds as anti-cocaine med-
ications.
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Acknowledgements
McLaughlin, J.P., Hill, K.P., Jiang, Q., Sebastian, A., Archer, S., Bidlack,
J.M., 1999. Nitrocinnamoyl and chlorocinnamoyl derivatives of dihy-
drocodeinone: in vivo and in vitro characterization of m-selective
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Supported by NIDA grants DA00360, U-19-DA11007
and K05-DA00101.
Mello, N.K., Negus, S.S., 1996. Preclinical evaluation of pharmacothera-
pies for treatment of cocaine and opioid abuse using drug self-admin-
istration procedures. Neuropsychopharmacology 14, 375–424.
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