Transcript Methylphenidate - Addiction Science Network

Effects of Psychomotor Stimulants:
A Closer Look at Methylphenidate
Reward and Sensitization
Amy Gancarz
PSY 890
26 April 2007
www.psychoactive.org
www.intervention.net
Overview of drug class
• Psychomotor stimulants are compounds that
can produce increases in psychological and
physical functioning.
• Two primary groups in this drug class:
– Naturally occurring cocaine
• Various forms
– synthetically produced amphetamine
• Other analogues.
Overview of Prototypic Drugs
• Cocaine
– Botany
– History
– Current Usage
• Amphetamine
– Origin/
– Clinical Uses
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Behavioral Affects
• Low to moderate doses
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Induce wakefulness
Increase activity
Decrease appetite
Stimulate the sympathetic
nervous system
– Feelings of euphoria,
well-being and selfconfidence
• Higher doses
– Produce stereotypic behaviors
• Brief and highly patterned behavior
produced in repetitive manner.
– Psychosis
• Vivid hallucinations
• Paranoid ideation
Major Effects of Psychomotor
Stimulants
• Sympathomimetrics
– Broad range of autonomic NS activation in sympathetic
division
– Increases in cardiovascular function
– Increased blood pressure
– Increased body temperature
– “side effect” of drug
• Effects of CNS
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Decreased fatigue, increased alertness
Arousal
Elevated mood
euphoria
Repeated Administration
• Tolerance
– Most autonomic effects
– Anorectic effects
• Sensitization
– Rewarding effects
– Enhances psychosis (AMPH)
Mechanism of Action
• Psychomotor stimulants do not have
true receptors in CNS
– Cocaine
• binds to site on dopamine transporter
(DAT)
• Blocks monoamine reuptake into
presynaptic terminals
– AMPH and METH also bind to DAT
• Block reuptake
• Release monoamines from presynaptic
terminal
• Inhibit action of monoamine oxidase
(MAO)
• May directly activate catecholamine
receptor
• Produce effects by increasing synaptic
activity of DA, NE and 5-HT
(Carroll et al. 1992)
Psychomotor Stimulant
Reinforcement
• Robust positive reinforcer
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– Effects mediated by mesolimbic/mesocortical DA neuronal
systems
• 6-OHDA lesions in mesolimbic/mesocortical pathway
attenuate cocaine self-administration
Methylphenidate
Methylphenidate Overview
• First synthesized in 1940s
– Marketed as Ritalin in
1960s
• Schedule II since 1971
• Used for treatment of
ADHD
• Exact mechanism of
action unknown
• Metabolism occurs
extracellularly
– Ritalinic acid
• Excreted in the urine
http://www.methylphenidate.net/
Methylphenidate Abuse
• Human self-administration intranasally
– grinding tablets and sniffing the powder
• Rare cases:
– Powder mixed in liquid and administered IV
• Risk of cardiac problems associated with
contamination by non-active ingredients of oral
tablets injected along with MPH
Mechanism of MPH:
• Increases both DA and NE by blocking
DAT and NE transporters
• Results in rapid increase in DA levels in
cortical and subcortical brain regions
(NAC)
Swanson & Volkow 2003
CPP: IP MPH
Meririnne et al. 2001
Sensitization to MPH Reward
Meririnne et al. 2001
CPP:
MPH,
SCH & RAC
Meririnne et al. 2001
Effects of D1- and D2-Receptor Blockade on
Sensitization to the Rewarding Properties of
MPH
Meririnne et al. 2001
Other Controls
Meririnne et al. 2001
CPP: IV MPH
Sellings et al. 2006
CPP: MPH and DA Depletions
and DA ANT
Sellings et al. 2006
MPH Time course
• Highest uptake of MPH occurred in basal ganglia
• Temporal patterns of MPH different from Cocaine
– Entered brain rapidly
• 8-10 minutes
– Slow rate of clearance
• Approximately 90 minutes
• “High” induced does not correlate with time course of drug
Clinical and illegal abuse
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Dose
Pharmacokinetics
Individual differences
Context
Bottom Line
• Psychomotor stimulants reinforcing affects appear to be
mediated by Mesolimbic dopamine pathway via D1/D2
receptors
• Methylphenidate can produce conditioned place preference
at higher doses, indicating it produces reinforcing affects
similar to other prototypic psychomotor stimulants
– D1 antagonists attenuate conditioned place preference
– amOT DA depletion lesions attenuate conditioned place preference
• Blockade of >50% DAT necessary in order to produce
feeling of being ‘high’
• Although Methylphenidate saturates receptors quicker than
cocaine, the clearance from receptors is much slower
making it more difficult to administer in short interval
– Less likely to abuse
References
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Anderson, S.L., Arvanitogiannis, A., Pliakas, A.M., LeBlanc, C. and Carlexon, W.A. (2002). Altered responsiveness to
cocaine in rats exposed to methylphenidate during development. Nature Neuroscience. 5(1): 13-14.
Caine, S.B. and Koob, G.F. (1993). Modulation of cocaine self-administration in the rat through D-3 dopamine receptors.
Science 260 (5115): 1814-1816.
Carroll, F.I., Lewin, A.H., Boja, J.W., Kuhar, M.J. (1992). Cocaine receptor: Biochemical characterization and structureactivity relationships of cocaine analogues and the dopamine transporter. 35(6): 969-981.
Cornish, J.L. and Kalivas, P.W. (2001): Cocaine Sensitization and craving: Differing roles for dopamine and glutamate in the
nucleus accumbens. Journal of Addictive Diseases 20(3): 43- 54.
Johanson, C.E., Schuster, C.R. Psychopharmacology: The Fourth Generation of Progress. (2000). Cocaine and Chronic
Amphetamine Use and Abuse. www.acnp.org
Johanson, C.E. and Fischman, M.W. (1989). The Pharmacology of Cocaine related to its abuse. The American Society for
Pharmacology and Experimental Therapeutics. 41(1): 3-52.
Meririnne, E. (2002). Rewarding properties of psychomotor stimulants and morphine: Pharmacological modulation of their
conditioning or sensitization in rats. Academic Dissertation: 2-80.
Meririnne, E., Kankaanpaa, A., Seppala, T.(2001). Rewarding properties of methylphenidate: sensitization by prior exposure
to the drug and effects of dopamine D1- and D2 – receptor antagonists. Journal of Pharmacology and Experimental
Therapeutics: 298(2): 539-550.
Schenk, S. and Davidson, E.S. Stimulant Preexposure sensitizes rats and humans to the rewarding effects of cocaine. 56-82.
Sellings, L.H., McQuade, L.E., Clarke, P.B. (2006). Characterization of dopamine dependent rewarding and locomotor
stimulant effects of intravenously-administered methylphenidate in rats. Neuroscience 141: 1457-1468.
Swanson, J.D. & Volkow, N.D. (2003). Serum and brain concentrations of methylphenidate: Implications for use and abuse.
Neuroscience and Biobehavioral Reviews 27(7): 615-621.
Wise, R.A. and Bozarth, M.A. (1987). A psychomotor stimulant theory of addiction. Psychological Review. 94(4): 469-492.
Websites
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www.nida.org
www.intervention.net
www.umsl.edu
www.druginfo.adf.org
www.psychoactive.org
www.addictionca.com
www.drugscope.ca.org
www.mla-hhss.org/gifs
www.ucimc.org/media/all
www.dea.gov/demand/speakout/03so.htm
http://health.howstuffworks.com/crack2.htm
www.historyhouse,com
www.stopaddiction.com
www.lawbuzz.com
www.methylphenidate.net
Is MPH a weak stimulant compared
to cocaine?
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Dose of IV MPH (0.075 mg/kg) required to block 50% of the DAT was about
half the dose required for IV dose of cocaine (0.13 mg/kg)
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An iv dose of MPH (0.1mg/kg) that exceeded 60% DAT blockade reliably
produced a reinforcing effect (‘high’)
Volkow et al. 2002
Volkow 2003