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Bill Fantegrossi, Ph.D. |
Self-administration:
Behaviorism proposes that the actions of an organism are governed by their consequences according to principles
of operant conditioning (Skinner 1938; Ferster and Skinner 1957). One critical factor in establishing and maintaining behavior under
a given set of contingencies is immediacy of reinforcer delivery, but when studying drugs as reinforcers, this can sometimes pose
problems. Essentially, experimenters ask laboratory animals to associate their behavior (typically the depression of a response lever)
with some reinforcing change in interoceptive state induced by drug administration. Ideally, this change in interoceptive state should
occur as rapidly after drug administration as possible in order to facilitate such an association. To the extent that different routes
of drug administration can influence onset of drug action, a majority of researchers using drug self-administration procedures have
chosen to use intravenous preparations in order to maximize the speed with which drug effects are induced. In laboratory primates,
these preparations involve the surgical insertion of an indwelling venous catheter (typically into a femoral or jugular vein) that is
then routed subcutaneously to the mid-scapular region. From here, the catheter either exits the animal and passes through a “tether”
system (e.g. Yanagita et al 1963; Schuster and Thompson 1963) or connects to a subcutaneously implanted vascular access port (e.g.
Carroll 1994; Wojnicki et al. 1994). In either case, the catheter can then be attached to a drug supply via an electronic infusion
pump, the operation of which is controlled by the behavior of the animal according to experimenter-determined schedule contingencies.
Intravenous self-administration procedures allow us to study the positive reinforcing effects of drugs of abuse, and have been used
fairly extensively to investigate various factors associated with the abuse of psychostimulants (such as cocaine and amphetamine) and
opioids (such as morphine and heroin). Interestingly, the traditional hallucinogens of phenylisopropylamine and indolealkylamine
structures have long been distinguished as drugs that are abused by humans but fail to engender reliable self-administration behavior
in laboratory animals (Poling and Bryceland 1979; Fantegrossi et al. 2004). And yet, hallucinogen-like methylenedioxy amphetamine
congeners -- such as MDMA and its analogues -- are readily self-administered by non-human primates (Fantegrossi, in press).
I am particularly interested in this distinction between the reinforcing effects of MDMA (and its analogues) and those of the
traditional psychostimulants and hallucinogens. We have found, for example, that the selective 5-HT2A antagonist
(+)-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol (M100907, formerly MDL100907) completely suppresses
self-administration of R(-)-MDMA at a dose that does not alter cocaine-maintained behavior, implying that the reinforcing effects
of MDMA may be mediated via novel serotonergic mechanisms (see the figure below, re-drawn from data previously published in
Fantegrossi et al. 2002).
Studies of MDMA analogues have also been extrmemely interesting. For example, N-methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine (MBDB) is the alpha-ethyl homologue of MDMA. This compound is similar to MDMA in
terms of inhibition of 5-HT uptake and stimulation of 5-HT release, but has greatly reduced dopaminergic effects (Nichols 1986; Johnson
et al 1986). Furthermore, MBDB generalizes to the interoceptice cue induced by MDMA, but does not occasion LSD- or DOM-appropriate
responding in drug discrimination tests (Oberlender and Nichols 1988). Although MBDB has previously been shown to elicit conditioned
place preference in the rat (Marona-Lewicka et al 1996), the reinforcing effects of this compound have not previously been studied in
any species using intravenous self-administration procedures. It was therefore of interest to assess the reinforcing effects of racemic
MBDB in monkeys with extensive histories of intravenous drug self-administration. As seen in the figure below (data collected from a
single monkey), MBDB dose-dependently engendered significant self-administration behavior, but was less potent and less effective in
its reinforcing effects than MDMA. These results thus recapitulate the previous place preference experiments where the conditioned
effects of MBDB were at least 2.5-fold weaker than those of MDMA (Marona-Lewicka et al 1996). Despite the reduced conditioned and
reinforcing effects of the alpha-ethyl homologue as compared to the parent compound, moderate MBDB self-administration and conditioned
place preference are nevertheless remarkable considering the almost complete lack of dopaminergic effects induced by this compound
(Nichols 1986; Johnson et al 1986; Johnson et al 1991; Nash and Nichols 1991; Marona-Lewicka et al 1996). As seems to be the case with
MDMA, particularly the R(-) enantiomer (Fantegrossi et al 2002), the reinforcing effects of MBDB may be mediated through serotonergic
mechanisms. Further study of MBDB (and other 5-HT-selective analogues of MDMA) using self-administration techniques may uncover novel
pharmacological mediators of the reinforcing effects of the methylenedioxy amphetamine congeners. Such studies are currently underway
here in the lab.
Referencecs: Carroll ME (1994) Pharmacological and behavioral treatment of cocaine addiction: animal models. NIDA Res Monogr 145:113-130
Fantegrossi W, Ullrich T, Rice K, Woods J, and Winger G (2002) 3,4-Methylenedioxymethamphetamine (MDMA,’Ecstasy’) and its stereoisomers as reinforcers in rhesus monkeys: serotonergic involvement. Psychopharmacology161:356-364
Fantegrossi WE, Woods JH and Winger G (2004) Transient reinforcing effects of phenylisopropylamine and indolealkylamine hallucinogens in rhesus monkeys. Behav Pharmacol 15(2):149-57
Fantegrossi WE (in press) The monkey is always right: drug self-administration as an alternative to interspecies dose scaling, and relevance to MDMA neurotoxicity. Psychopharmacology
Ferster CB and Skinner BF (1957) Schedules of Reinforcement. Appleton-Century-Crofts, New York
Johnson MP, Hoffman AJ and Nichols DE (1986) Effects of the enantiomers of MDA, MDMA and related analogues on [3H]serotonin and [3H]dopamine release from superfused rat brain slices. Eur J Pharmacol 132(2-3):269-76
Johnson MP, Conarty PF and Nichols DE (1991) [3H]monoamine releasing and uptake inhibition properties of 3,4-methylenedioxymethamphetamine and p-chloroamphetamine analogues. Eur J Pharmacol 200(1):9-16
Marona-Lewicka D, Rhee GS, Sprague JE and Nichols DE (1996) Reinforcing effects of certain serotonin-releasing amphetamine derivatives. Pharmacol Biochem Behav 53(1):99-105
Nash JF and Nichols DE (1991) Microdialysis studies on 3,4-methylenedioxyamphetamine and structurally related analogues. Eur J Pharmacol 200(1):53-8
Nichols DE (1986) Differences between the mechanism of action of MDMA, MBDB, and the classic hallucinogens. Identification of a new therapeutic class: entactogens. J Psychoactive Drugs 18(4):305-13
Oberlender R and Nichols DE (1988) Drug discrimination studies with MDMA and amphetamine. Psychopharmacology 95(1):71-76
Poling A and Bryceland J (1979) Voluntary drug self-administration by nonhumans: a review. J Psychedelic Drugs 11:185-190
Schuster CR and Thompson T (1963) A technique for studying self-administration of opiates in Rhesus monkeys. Committee on Drug Addiction and Narcotics, NRCNAS, Ann Arbor, MI
Skinner BF (1938) The Behavior of Organisms. Appleton-Century-Crofts, New York
Wojnicki FH, Bacher JD and Glowa JR (1994) Use of subcutaneous vascular access ports in rhesus monkeys. Lab Anim Sci 44(5):491-494
Yanagita T, Deneau GA and Seevers, MH (1963) Methods for studying psychogenic dependence to opiates in the monkey. Committee on Drug Addiction and Narcotics, NRCNAS, Ann Arbor, MI