Effects of Psychomotor Stimulants: A Closer Look at Methylphenidate

Reward and Sensitization

Amy Gancarz

PSY 890

26 April 2007www.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

www.dea.gov/demand/speakout/03so.htm

www.lawbuzz.com/movies/blow/blow_story_ch4.htm www.umsl.edu

Behavioral Affects

• Low to moderate doses– Induce wakefulness

– Increase activity

– Decrease appetite

– Stimulate the sympathetic nervous system

– Feelings of euphoria, well-being and self-confidence

• 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– 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– Effects mediated by mesolimbic/mesocortical DA neuronal

systems

• 6-OHDA lesions in mesolimbic/mesocortical pathway attenuate cocaine self-administration

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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

• 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• 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 structure-activity

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• 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?

• 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)

• 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