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Effects of Psychomotor Stimulants: A Closer Look at Methylphenidate Reward and Sensitization Amy Gancarz PSY 890 26 April 2007

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Presentation on theme: "Effects of Psychomotor Stimulants: A Closer Look at Methylphenidate Reward and Sensitization Amy Gancarz PSY 890 26 April 2007"— Presentation transcript:

1 Effects of Psychomotor Stimulants: A Closer Look at Methylphenidate Reward and Sensitization Amy Gancarz PSY April 2007

2 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.

3 Overview of Prototypic Drugs Cocaine –Botany –History –Current Usage Amphetamine –Origin/ –Clinical Uses

4 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

5 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

6 Repeated Administration Tolerance –Most autonomic effects –Anorectic effects Sensitization –Rewarding effects –Enhances psychosis (AMPH)

7 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)

8 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

9 Methylphenidate

10 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

11 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

12 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

13 CPP: IP MPH Meririnne et al. 2001

14 Sensitization to MPH Reward Meririnne et al. 2001

15 CPP: MPH, SCH & RAC Meririnne et al. 2001

16 Effects of D1- and D2-Receptor Blockade on Sensitization to the Rewarding Properties of MPH Meririnne et al. 2001

17 Other Controls Meririnne et al. 2001

18 CPP: IV MPH Sellings et al. 2006

19 CPP: MPH and DA Depletions and DA ANT Sellings et al. 2006

20 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

21 Clinical and illegal abuse Dose Pharmacokinetics Individual differences Context

22 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

23 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): Caine, S.B. and Koob, G.F. (1993). Modulation of cocaine self-administration in the rat through D-3 dopamine receptors. Science 260 (5115): 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): 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): Johanson, C.E., Schuster, C.R. Psychopharmacology: The Fourth Generation of Progress. (2000). Cocaine and Chronic Amphetamine Use and Abuse. 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): Meririnne, E. (2002). Rewarding properties of psychomotor stimulants and morphine: Pharmacological modulation of their conditioning or sensitization in rats. Academic Dissertation: 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): Schenk, S. and Davidson, E.S. Stimulant Preexposure sensitizes rats and humans to the rewarding effects of cocaine 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: Swanson, J.D. & Volkow, N.D. (2003). Serum and brain concentrations of methylphenidate: Implications for use and abuse. Neuroscience and Biobehavioral Reviews 27(7): Wise, R.A. and Bozarth, M.A. (1987). A psychomotor stimulant theory of addiction. Psychological Review. 94(4): Websites

24 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

25 Volkow 2003

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