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2003 Annual Meeting Abstracts
Effects of the selective kappa agonist U50,488 on cocaine discrimination
and cocaine self-administration in rhesus monkeys: Do kappa agonists
increase the abuse-related effects of cocaine?
S. Stevens Negus. McLean Hospital, Harvard Medical School
Kappa agonists have been reported to attenuate some neurochemical
and behavioral effects of cocaine, and kappa agonists constitute
one class of drugs being evaluated as potential pharmacotherapies
for cocaine dependence. We have conducted an extensive series of
studies to examine the effects of kappa agonists on the discriminative
stimulus and reinforcing effects of cocaine in rhesus monkeys, and
some of these studies will be reviewed. In drug discrimination studies,
rhesus monkeys were trained to discriminate 0.4 mg/kg cocaine from
saline. Under these conditions, acute pretreatment with the selective
kappa agonist U50,488 produced highly variable but naloxone-reversible
effects across monkeys, and leftward/upward shifts in the cocaine
discrimination dose-effect curve were observed in most monkeys.
In one set of drug self-administration studies, rhesus monkeys were
trained to respond for cocaine injections or food pellets under
a second-order schedule during alternating sessions of cocaine or
food availability. The main dependent variables were the total numbers
of cocaine injections and food pellets delivered each day. Chronic
treatment with U50,488 produced a dose-dependent and nor-binaltorphimine-reversible
decrease in cocaine self-administration. However, doses of U50,488
that decreased cocaine self-administration also usually decreased
food-maintained responding and produced other effects such as emesis
and sedation. Consequently, interpretation of kappa agonist effects
on cocaine reinforcement was complicated by the non-selective effects
of U50,488. A second set of drug self-administration studies was
conducted using a schedule of concurrent choice between food and
cocaine. The main dependent measure in this procedure was the allocation
of behavior between the food and cocaine choices. This measure of
cocaine choice provides a dependent measure that can vary independently
from response rates in much the same way that drug-appropriate responding
can vary independently from response rates in drug discrimination
studies. In this choice study, increasing doses of cocaine produced
a dose-dependent and monotonic increase in cocaine choice. Under
these conditions, chronic treatment with the selective kappa agonist
U50,488 decreased response rates but produced dose-dependent and
nor-BNI-reversible leftward shifts in the cocaine choice dose-effect
curve, suggesting that kappa agonist treatment increased the relative
reinforcing effects of cocaine. Thus, results from both the cocaine
vs. saline discrimination procedure and the cocaine vs. food choice
procedure suggest that a kappa agonist may increase the abuse-related
effects of cocaine. Choice procedures may provide a useful approach
to the study of drug-induced reinforcing effects because these procedures
provide a rate-independent measure of reinforcing efficacy.
An analysis of the utility of differential outcome procedures in
drug discrimination research.
Amy K. Goodwin* and Lisa E. Baker**. *John Hopkins Univeristy School
of Medicine, **Western Michigan University
Differential outcome procedures correlate unique reinforcers with
distinct discriminative stimuli. These procedures can decrease the
amount of time needed for response acquisition and improve terminal
accuracy of responding. Because the drug discrimination assay relies
heavily upon initial response acquisition and continuing terminal
accuracy, a procedure successful at shortening acquisition time
and improving terminal accuracy would be beneficial. The present
studies examined differences in acquisition of drug stimulus control
between rats exposed to differential outcome procedures and rats
exposed to the outcomes in a non-systematic way. The first experiment
examined acquisition of control by MDMA, d-Amphetamine, and saline;
the second examined stimulus control by MDMA, LSD, and saline. Neither
initial acquisition nor terminal accuracy was influenced by differential
outcomes in either experiment. Although the differential outcome
effect has been demonstrated in many situations, it does not appear
to be useful in the drug discrimination assay.
Acute tolerance to nicotine: Individual differences evaluated
using drug discrimination and 86RB+ effux.
Randy James. Department of Pharmaceutics, Virginia Commonwealth
University
The drug discrimination paradigm utilizes a discriminative stimulus
(DS) allowing subjects to express the subjective effects of a drug.
Male Sprague-Dawley rats were trained to discriminate nicotine (freebase)
vs saline in two lever operant chambers. Two acute tolerance testing
methods were used over a period of several months; (1) cumulative
dosing using the drug discrimination training dose (0.4 mg/kg, s.c.)
at 0, 90, 180 and 270 min. (2) challenge dose at time zero (0.8
mg/kg, s.c.) then drug discrimination training dose at 60, 90, 120,
150, 180 and 270 min. Rats in both methods were tested for 2 min.
without reinforcement. Evaluation of the chronically treated rats
(60 plus doses 0.4 mg/kg nicotine) in both methods showed rats exhibited
different levels of acute tolerance in the cumulative dosing method
and the challenge dose method. Two distinct groups emerged one exhibited
acute tolerance and the other failed to exhibit acute tolerance.
A third group of rats had their DS ability attenuated. Correlations
between the two methods are presented. This study was performed
in an attempt to attribute the varying effects of chronic nicotine
administration on rats as observed in a DS behavioural paradigm,
to nAChRıs in specific brain areas using 86Rb+ efflux techniques.
A 86Rb+ efflux assay was used to evaluate nicotinic receptor function
using synaptosomes from the same rats used in the drug discrimination
and acute tolerance testing. Two assays were performed for each
brain area using 2 different nicotine concentrations (1uM; 30uM).
Significant differences in nicotine-stimulated 86Rb+ efflux were
seen between rats exhibiting desensitization (DZ) and non-desensitization
(NDZ). Significant differences are reported for the following brain
areas and concentrations; (1) cortex 30uM, (2) hippocampus 30uM,
(3) striatum 1uM, 30uM, (4) thalamus 30uM. Previous work by the
author has shown differences in alpha 7 nicotinic receptor populations
in these brain areas. Rats exhibiting acute tolerance have more
alpha-bungarotoxin binding sites than rats not exhibiting acute
tolerance.
Supported by: Philip Morris External Research Program, NIDA, Karolinska
Institute and German Council For Smoking
Conflict of Interest: Research funded by a corporation that may
benefit financially
Drug discrimination with the atypical antipsychotic clozapine
in C57BL/6 mice.
Scott D. Philibin, Laura E. Wise, Adam J. Prus, Alan L. Pehrson,
and Joseph H. Porter. Department of Psychology Virginia Commonwealth
University
Clozapine (CLZ) is the prototypical atypical antipsychotic drug
(APD) and is superior to typical APDs for the treatment of schizophrenia.
Understanding the pharmacological properties important for the unique
effects of CLZ can help lead to the development of other APDs with
greater therapeutic efficacy and less side effect liability. One
approach for studying the genetic basis for drug effects on behavior
is the use of knockout or transgenic animals. An advantage of these
new molecular techniques is the manipulation of neurotransmitter
receptors for which pharmacological ligands do not exist. A limitation
of this approach is that most knockout animals are currently available
only in mice not rats. One important preclinical assay used in
drug development to help identify neurotransmitter receptor targets
for putative APDs is drug discrimination. CLZ has previously been
studied in the drug discrimination paradigm with rats, pigeons,
and non-human primates. The purpose of the present study was to
establish CLZ in a two-lever drug discrimination procedure in wild-type
C57BL/6 mice and to compare CLZ to other atypical and typical APDs.
C57BL/6 mice (N=17) were trained to discriminate 2.5 mg/kg CLZ (s.c.)
from Vehicle using a fixed ratio 10 reinforcement schedule for sweetened-condensed
milk. The mice learned the discrimination in an average number of
36.5 training sessions (SEM = 3.47). A dose effect curve for CLZ
yielded an ED50 = 1.14 mg/kg (95% C.I. = 0.95 1.37 mg/kg) with
full generalization at the training dose and at 5.0 mg/kg; however,
there were strong rate suppressant effects at the 5.0 dose. The
typical APD haloperidol (0.05 0.4 mg/kg) did not substitute for
CLZ. Other APDs are currently being tested, but these preliminary
results demonstrate that CLZ two-lever discrimination can be established
in mice and that the results appear to be similar to that seen in
other species.
Serotonin2C agonists produce aversive stimulus properties in
Swiss-Webster mice
Ellen A. Walker, Department of Pharmaceutical Sciences, Temple
University School of Pharmacy
The purpose of the present study was to investigate the aversive
stimulus effects of two serotonin agonists MK212 and m-chlorophenylpiperazine
(mCPP) using a conditioned taste aversion procedure. Swiss Webster
male mice weighing 20-35 g were used. For two conditioning days,
30-min access to a novel flavored solution (conditioned stimulus)
was paired with injections of different doses of MK212 or mCPP (unconditioned
stimulus). On two alternate conditioning days, a different flavored
solution was paired with injections of saline in both training groups.
The flavor of the conditioned stimulus was either almond-saccharin
solution (almond-scented, 0.15% sodium saccharin) or banana-saline
solution (banana-scented, 0.09% sodium chloride) and was counterbalanced
within the training groups. The unconditioned stimuli in the different
groups of mice were injections of 1.0, 3.2, 10, or 32 mg/kg MK212,
i.p., or 1.0, 3.2, 10, 32 mg/kg mCPP, i.p. Under test conditions,
the mice were not injected and had access to both flavored solutions.
During the choice tests, mice choose the flavor associated with
saline and avoided the solution associated with MK212 or mCPP. Furthermore,
these conditioned taste aversions were dose-dependent. Nonselective
5-HT2C antagonists, methysergide, 2-bromo-LSD, mianserin, and cyproheptadine
blocked the acquisition of conditioned taste aversions produced
by either 10 mg/kg MK212 or 10 mg/kg mCPP. These data indicate that
the serotonin agonists MK212 and mCPP possess aversive stimulus
effects and that these effects are mediated through actions at serotonin
receptors. (Supported by USPHS grant DA14673)
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Summer 2004