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Abstracts of Presentations at the 2000 Annual Meeting
in New Orleans
Invited Speakers:
Werner J. Schmidt,
Zoologisches Institut, Neuropharmakologie, Universität Tübingen
Mohlstr. 54/1, D-72074 Tübingen, Germany.
Behavioural sensitization refers to the intensification of a behaviour
upon repeated administration of a drug. Sensitization is nearly
inextinguishable and therefore is considered to play a major role
in the formation of an "addiction memory". The finding that glutamate/NMDA
receptor (R)-antagonists block the development of sensitization
has lead to the hypothesis that repeated exposure to an addictive
drug activates glutamatergic transmission and this promotes drug
seeking and relapse. Many findings are in accordance with this view
but not all: In several experiments the development of sensitization
was not inhibited by NMDA-R-antagonists, however the expression
of sensitization (which is tested only under the sensitizing drug)
was abolished. This has been explained as a state-dependency effect,
i. e. what has been learned in the presence of an NMDA-R-antagonist
(here sensitization) can not be expressed in the absence of an NMDA-R-antagonist.
State-dependent effects may have been overlooked so far since in
many studies animals were treated in the home cages with the sensitizing
drug plus the NMDA-R-antagonist and the development of sensitization
(for example the day to day increase in locomotion) was not measured
in the experimental set up. The state-dependency interpretation
was criticised since most of the studies have been conducted with
MK-801 and this drug produces sensitization to its own locomotor
stimulant effects. To clarify this issue, we chose haloperidol-induced
catalepsy (akinesia and rigidity) of the rat that shows pronounced
sensitization when repeatedly elicited (known as the "repeated measures
effect"). Since acutely administrated NMDA-R-antagonists show clear
cut anti-cataleptic effects, a possible day to day intensification
of catalepsy can not be due to the effects of the NMDA-R-antagonist.
We showed that haloperidol-induced catalepsy was counteracted by
the NMDA-R-antagonists MK-801, CPPene, eliprodil, Ro 25-6981 as
expected, but that the development of sensitization of catalepsy
was not inhibited by these drugs. A challenge with haloperidol 14
days after sensitization revealed no sensitized catalepsy, haloperidol
plus NMDA-R-antagonist produced the sensitized response and most
interestingly, the NMDA-R-antagonist alone also elicited the sensitized
response. We concluded from these findings that sensitization of
catalepsy developed context dependently i. e. sensitization has
been associated to the drug (NMDA-R-antagonist) cue which makes
expression of sensitization dependent from the NMDA-R-antagonist
state. The paradoxical finding that an anti-cataleptic drug can
induce sensitized catalepsy shows that expression of sensitized
catalepsy has been rendered completely state-dependent. In conclusion,
two forms of sensitization exist, a context-independent (non-associative)
form, which can be inhibited by NMDA-R-antagonists, and a context-dependent
(associative) form. It may be speculated that in the latter case
NMDA-R-antagonists may disrupt the association to the environmental
context but instead represent a contextual stimulus to which sensitization
can become associated.
Paul Vezina,
Department of Psychiatry, Committee on Neurobiology, The University
of Chicago, Chicago, IL 60637.
Both drug sensitization and state-dependency are well established
phenomena that can exert powerful effects on the expression of various
behaviors. Recently, a certain degree of controversy has developed
over whether the latter phenomenon can provide an alternative account
for the apparent ability of glutamate receptor antagonists - dizocilpine,
in particular - to prevent the induction of sensitization. In a
review of the results from a number of studies, it will first be
addressed whether sensitized responding during induction is in fact
necessary and sufficient for the subsequent later expression of
sensitization. In this context, the actions of the non-competitive
NMDA receptor antagonist dizocilpine on behavioral, cellular and
biochemical responses during induction and expression of sensitization
will be compared to those of competitive antagonists of NMDA as
well as non-NMDA receptors and other manipulations impacting excitatory
amino acid transmission. While the actions of dizocilpine on acute
and sensitized drug-induced responding may be complex, the results
of the above experiments taken together strongly support a critical
need for excitatory amino acid receptor activation in the induction
of drug sensitization. Supported by US PHS grants DA-9397 and DA-9860.
Volunteered presentations:
Carol A. Paronis,
Behavioral Pharmacology Program, McLean Hospital/Harvard Medical
School, Belmont, MA 02478
Tolerance to the discriminative stimulus effects of opioids has
been well-characterized, however, less is known about the development
and expression of tolerance to the discriminative stimulus effects
of other drug classes. Moreover, most studies of tolerance to discriminative
stimulus effects have used rats as subjects and, to date, there
has been only one report that describes tolerance to discriminative
stimulus effects in monkeys (Ator and Griffiths, 1993). We investigated
the expression of tolerance to the discriminative stimulus effects
of benzodiazepines in a group of squirrel monkeys trained to discriminate
0.3 mg/kg midazolam from saline under a schedule of stimulus shock-termination.
Because tolerance to the discriminative stimulus effects of opioids
is more readily expressed when training is interrupted for the duration
of the supplemental administration of the tolerance-inducing drug,
initial studies examined the effects of interrupting daily training
sessions for six weeks, exposing the animals to intermittent test
sessions during this time. Results from these studies demonstrate
that the dose-response functions of midazolam, pentobarbital, bretazenil,
and zolpidem are not changed during the course of interrupted training
sessions. After a period of retraining, daily training sessions
were again interrupted and the animals received daily injections
of 3 mg/kg diazepam. Starting one week after the beginning of the
chronic diazepam regimen, the animals were again tested intermittently.
During the course of the daily diazepam exposure, the midazolam
dose-effect function was displaced approximately 10-fold to the
right and qualitatively similar results were obtained with diazepam,
lorazepam, and zolpidem. Following discontinuation of the daily
diazepam injections, the dose-effect function of midazolam returned
to baseline. These results demonstrate that the interruption of
daily training sessions, in and of itself, does not disrupt schedule-controlled
performance or alter the discriminative stimulus effects of benzodiazepines
in monkeys. However, when the interruption of training sessions
is accompanied by daily injections of diazepam, tolerance develops
to the discriminative stimulus effects of benzodiazepines. (Supported
by PHS grant DA-11453)
Malath M. Makhay and James M. O'Donnell.
Central Michigan University, Dept. of Psychology, Mt. Pleasant,
MI 48859.
The discriminative stimulus effects of beta-adrenergic agonists
and NE uptake inhibitors have been studied extensively to determine
if these drugs are a) centrally active and b) to what extent do
these compounds share discriminative stimulus effects. Clenbuterol,
a beta-2 adrenergic agonist, has been studied as a discriminative
stimulus (McElroy and O'Donnell, 1988; O'Donnell, 1997; Makhay and
O'Donnell, 1999) and its stimulus effects are antagonized by the
beta adrenergic antagonist, propranolol. Other beta-2 selective
agonists such as SOM 1122 and zinterol substitute for clenbuterol
as well as the beta-1 adrenergic agonist prenalterol. Dobutamine,
a beta-1 selective agonist, partially substitutes for clenbuterol,
producing about 75% drug-appropriate responding at the highest dose
of 10 mg/kg. It is thought that dobutamine is selective for beta-1
adrenergic receptors, and its selectivity is about 10-fold for beta-1
relative to beta-2 adrenergic receptors (Tuttle and Mills, 1975;
Sonnenblick et al., 1979; Platcheka, 1981; Beer et al., 1988; Hays
et al., 1985; Ruffolo et al., 1981). Two studies were carried out
to examine beta-adrenergic receptor agonist properties. First, a
dobutamine-vehicle discrimination was studied. The objectives were
1) to determine if dobutamine can be established as a discriminative
stimulus (i.e., centrally active), 2) to characterize the dobutamine
stimulus cue, 3) to determine if other direct-acting beta adrenergic
agonists, NE uptake inhibitors, and other compounds demonstrating
antidepressant-like effects would substitute for the dobutamine
stimulus cue and 4) whether down-regulation of beta-2 adrenergic
receptors would attenuate the discriminative stimulus effects of
dobutamine. Also, the NE uptake inhibitor nisoxetine was examined
to determine 1) if a nisoxetine discriminative stimulus cue can
be established, 2) if other NE uptake inhibitors substitute for
nisoxetine, 3) if it is selective for beta-1 or beta-2 receptors
and 4) if beta adrenergic receptor antagonists can block the stimulus
cue. Rats were trained to discriminate either 5.6 mg/kg dobutamine
from vehicle or 3.2 mg/kg nisoxetine from vehicle. After training,
rats were tested with a number of compounds. It was found that clenbuterol,
nisoxetine, amitriptyline, protriptyline, maprotiline, and nortriptyline
all failed to substitute for the dobutamine stimulus cue. However,
imipramine partially substitute for dobutamine at 10 mg/kg. Prenalterol,
a purported beta-1 selective adrenergic agonist, completely substituted
for dobutamine. Also, rats were given clenbuterol chronically and
after 4 days, rats were tested with dobutamine and it was shown
that down-regulation of beta-2 receptors did not attenuate dobutamine's
discriminative stimulus cue. A dose of 1 mg/kg propranolol reduced
drug-appropriate responding to less than 25%. Propranolol and betaxolol
(nonselective and beta-1 selective adrenergic antagonists, respectively)
failed to antagonize completely the nisoxetine stimulus cue. Clenbuterol
failed to substitute for the nisoxetine stimulus cue, but dobutamine
substituted completely at the highest dose (18 mg/kg) and desipramine
substituted completely for the nisoxetine stimulus cue at the highest
dose (10 mg/kg). The inability of full antagonism of the dobutamine
stimulus cue and full substitution of clenbuterol suggest that other
pharmacological effects of the drug may contribute; this is consistent
with the known pharmacology of dobutamine (Ruffolo et al., 1991).
The results obtained with the nisoxetine discrimination lead us
to conclude that there is beta-1 involvement in nisoxetine's DS
effects, but less than complete antagonism might suggest that other
actions may contribute to nisoxetine's DS effects.
Robert E. Vann, Scott D. Philibin, Laura E. Wise,
and Joseph H. Porter,
Department of Psychology, Virginia Commonwealth University, Richmond,
Virginia.
The present study examined the importance of injection route for
testing drugs in rats trained to discriminate intraperitoneal (IP)
injections of 3.0 mg/kg methadone (METH) from vehicle (VEH) in a
two-lever drug discrimination procedure. When morphine was injected
IP it produced only partial substitution (59.1 %DLR) for METH; however,
when morphine was injected subcutaneously (SC), full substitution
(89.7 %DLR) was obtained. Similar results were obtained for (+)
methadone and (-) methadone. Heroin fully substituted for METH with
both IP and SC routes of injection, although the SC route was about
50 times more potent than the IP route. In generalization tests
with the training drug METH, the SC route of injection was about
8 times more potent than the IP route was. The kappa agonist U50-488
did not produce METH-appropriate responding with either IP or SC
routes of injection. Naltrexone antagonism tests also revealed a
similar difference in potency between the IP and SC routes, as a
10-fold increase in the naltrexone dose (given IP) was needed to
suppress the discriminative cue of SC METH relative to IP METH.
These results demonstrate that the route of injection can play an
important role in the results of drug substitution tests in drug
discrimination.
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Summer 2004