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2002 Annual Meeting
Discriminative stimulus properties of clozapine: further
examination of the role of dopamine, serotonin and cholinergic receptor mechanisms.
1Adam J. Prus, 2Lisa E. Baker, and 3Herbert Y. Meltzer
1Virginia Commonwealth University, Richmond, VA
2Western Michigan University, Department of Psychology, Kalamazoo, MI
3Vanderbilt University, Nashville, TN
Clozapine (CLZ) is an atypical antipsychotic which produces minimal extrapyramidal
side effects (EPS) and has significant advantages for treating positive symptoms
and cognition. The pharmacological actions responsible for these and other
advantages of clozapine are believed to involve its actions on dopamine and
serotonin receptors, primarily, but there are other candidates, e.g. actions
at muscarinic receptors, which have also been implicated. Drug discrimination
(DD) studies have been utilized to identify important pharmacological features
of clozapine’s action. Both low (1.25 mg/kg) and normal (5.0 mg/kg) dose clozapine
have been used as training doses in DD studies using rats. The present
study further evaluated the pharmacological basis for the clozapine discriminative
stimulus (DS) in rats trained to discriminate either 1.25 mg/kg (N=7) or
5.0 mg/kg (N=7) clozapine from vehicle in a two choice, food reinforced drug
discrimination task. The typical antipsychotic haloperidol (0.1-0.4
mg/kg) did not substitute for either CLZ discriminative stimulus (DS), while
the atypical antipsychotic melperone (0.37-3.0 mg/kg) engendered full substitution
in both groups ( > 80% CLZ-appropriate responding). The muscarinic M1
receptor antagonist trihexyphenidyl engendered full substitution in 1.25
mg/kg CLZ-trained but not 5.0 mg/kg CLZ-trained rats. The 5-HT1A agonist
8-OH-DPAT (0.04-0.16 mg/kg) and the 5-HT2A antagonist M100907 (0.03-1.0 mg/kg)
displayed only partial substitution in both groups. 8-OH-DPAT combined with
haloperidol did not potentiate drug lever responding greater than 8-OH-DPAT
or haloperidol alone. Haloperidol (0.10 mg/kg) and M100907 combinations produced
greater CLZ-appropriate responding than either drug alone, but only 1.25 mg/kg
subjects (N=2) exhibited greater than 80% CLZ-appropriate responding following
0.1 mg/kg haloperidol + 0.12 mg/kg M100907. Greater stimulus generalization
by 5-HT2A and D2 receptor blockade provides additional evidence that both
of these actions, in combination, contribute to the clozapine DS. The
present results provide minimal support for the conclusion that a lower training
dose (1.25 mg/kg) of CLZ is more useful than a higher dose (5.0 mg/kg) to
identify the components of the CLZ DS (Porter et al., 2000).
Influence of Reinforcer Type on the Development and Maintenance
of Gamma-Hydroxybutyrate Discrimination in Rats.
Lisa E. Baker, Dori Pynnonen, and Alan D. Poling Western Michigan University,
Kalamazoo, MI
Recreational use of gamma-hydroxybutyrate (GHB) appears
to be growing in popularity, which is cause for great concern given the recent
rise in reported fatalities associated with its use. Unfortunately, relatively
little is presently known regarding the neurobehavioral consequences of GHB
use. Studies of drugs as discriminative stimuli have played an invaluable
role in psychopharmacology. The few studies that have investigated the discriminative
stimulus of GHB in nonhumans have reported inconsistent findings, which may
be due to a number of important differences in research methodology. As part
of an ongoing series of investigations on the discriminative stimulus effects
of GHB, the present study investigated possible effects of the type of reinforcer
on the development and maintenance of a GHB-vehicle discrimination in rats.
Twelve male Sprague-Dawley rats, aged 50-60 days at the beginning of the study,
were trained to discriminate GHB (200 mg/kg, IP) from vehicle in a two-choice
drug discrimination operant procedure using an FR 20 schedule of food (group
1, n=6) or water (group 2, n=6) reinforcement. Stimulus generalization was
assessed with GHB (50-400 mg/kg, IP and IG), the GHB precursor gamma-butyrolactone
(GBL, 50-200 mg/kg, IP) and ethanol (1.0-4.0 g/kg, IG). Responding maintained
by food was significantly higher than responding maintained by water throughout
the duration of the study. Although there was no significant difference between
groups with respect to the number of training sessions required to meet the
discrimination criterion, terminal accuracy of the discrimination was slightly
greater in group 1 than in group 2. GHB produced dose-dependent increases
in both groups with full generalization at the training dose following IP
administration and at 400 mg/kg when administered orally. GBL produced stimulus
generalization in group 2, but only partial generalization in group 1, and
substantially disrupted responding in both groups at the highest dose tested.
Ethanol (1.0 – 4.0 g/kg) produced only partial generalization in both groups
and appeared to disrupt responding to a greater degree in group 2. Results
are discussed with respect to potential influences of reinforcer type on response
rate and how this might affect GHB-maintained stimulus control.
The discriminative stimulus effects of 5-HT2C compounds in
mice.
Ellen Ann Walker, Ph.D.
Department of Psychology, La Salle University, Philadelphia, PA,
Office of Research and Technology Development, Albert Einstein Healthcare
Network, Philadelphia, PA
The objectives of this series of experiments were to establish methods for
training 5-HT2C compounds as discriminative stimuli in mice. Swiss-Webster
and C57Bl/6 mice were trained to discriminate 5-HT2C agonist mCPP using a
discriminated conditioned taste aversion (CTA) procedure. On mCPP training
days, 4.0 mg/kg mCPP, i.p., was administered 15 min prior to 30-min access
to saccharin solution. Mice were then injected with 2.4 mEq/kg LiCl, i.p.
On saline training days, saline was injected before and after saccharin access.
Swiss-Webster mice learned the discrimination in 6 pairing days. C57Bl/6
mice failed to acquire mCPP as a stimulus. To determine if C57Bl/6 mice are
insensitive to the effects of 5-HT2C agonists, mCPP was used to induce CTA.
One group of mice received 30-min access to saccharin solution and then 4.0
mg/kg mCPP, i.p. A second group of mice received 30-min access to saccharin
solution but then received 32 mg/kg mCPP, i.p. A dose of 32 mg/kg mCPP
produced stable CTA whereas 4.0 mg/kg mCPP produced unstable CTA. Another
procedure was used to more rapidly establish 5-HT2C compounds as discriminative
stimulus in Swiss-Webster mice. A multielement CTA procedure was used to
train mice to discriminate between mCPP and saline or mianserin and saline.
On the LiCl pairing days, mice were injected with 4.0 mg/kg mCPP or 1.0 mg/kg
mianserin i.p. 15 min prior to 30-min access to an almond-scented saccharin
solution. Mice then received 2.4 mEq/kg LiCl i.p. On saline pairing
days, mice were injected with saline i.p. 15 min prior to 30-min access to
a banana-scented NaCl solution. Mice then received saline i.p. Mice rapidly
learned the discriminations. To establish the contribution of the training
drug, almond scent, and saccharin flavoring to the discrimination, individual
elements as well as additional mCPP and mianserin doses were tested alone
and in combination. These data indicate that 1) Swiss-Webster mice
can learn to discriminate mCPP or mianserin from saline in a pharmacologically
relevant manner and 2) C57Bl/6 mice are less sensitive to the effects of mCPP
than Swiss-Webster mice. (Supported by USPHS Grant DA 014673).
EFFECTS OF INFUSION RATE ON THE DISCRIMINATIVE EFFECTS OF INTRAVENOUSLY
ADMINISTERED MORPHINE IN THE RAT.
M. D. B. Swedberg*, M. Ståhlberg and C. Velasquez.
AstraZeneca R&D Södertälje, Dept. General Pharmacology &
Animal Care, S-151 85 Södertälje, Sweden.
The “rush” is an important factor to maintain i.v. drug abuse. It has been
assumed that the rush is related to the speed at which a drug is infused intravenously.
Indeed, the rate of infusion has been demonstrated to be important to cocaine’s
ability to maintain self-administration behavior in monkeys (Balster and
Schuster, 1973). It was recently shown that the infusion rate might
influence the subjective effects of morphine in human volunteers (Marsch
et. al., 2001). The drug discrimination procedure is commonly used to make
assumptions about abuse liability in several species. To our knowledge no
studies have investigated whether the discriminative effects as the self-administration
effects may also depend on the speed at which a drug is administered when
given intravenously.
The present study was designed to assess the influence of rate of infusion
on the discriminative effects of morphine in rats. Infusions of morphine were
administered at two different infusion rates: 2 min or 15 min, respectively,
in rats trained to discriminate 10 µmol/kg of subcutaneously administered
morphine from no drug.
Rats received i.v. infusions via the tail-vein and were then immediately
put into the operant test chambers. Doses of 1, 3 or 10 µmol/kg were
tested in 8 or 10 rats per dose and infusion condition. The dose response
curves did not differ between the two infusion conditions. These data show
that the discriminative effects of morphine are not changed between the two
infusion rates studied. It is hypothesized that the infusion rates were not
sufficiently dissimilar to produce difference in the discriminative effects
in the rat.
Balster, R.L. and Shuster, C.R. J. Exp. Anal. Behav. 20:119-120, 1973.
Marsch, L. A., Bickel, W. K., Badger, G. J., Rathmell, J., Swedberg, M.
D. B., Jonzon, B and Norsten-Höög, C. J. Pharmacol. Exp.
Ther. 299: 1056-1065, 2001.
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Summer 2004