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P.7.004 Nicotine influences motivational but not psychomotor inhibition
P7 Child and adolescent disorders
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Nicotine influences motivational but not psychomotor inhibition
K.B.E. B6cker 1 *, M.M. Lansbergen 2, E.H. Quik 1 , J.L. Kenemans 2. ] Utrecht University, Psychopharmacology,
Utrecht, The Netherlands; 2Utrecht University, Psychonomics and Psychopharmacology, The Netherlands Impulsivity, or lack o f inhibition, is one o f the symptom dimensions in Attention-Deficit / Hyperactivity Disorder (ADHD). Different varieties o f inhibition can be distinguished behaviourally as well as pharmacologically. Here we contrast motivational inhibition (tolerance for a larger reward after a delay) and psychomotor inhibition (interruption o f a prepotent response). We hypothesize that nicotine (cigarette smoking) increases both kinds o f inhibition. This is because A D H D and the associated impulsivity can be treated with psychostimulants, because A D H D patients are more often dependent on nicotine than control subjects (suggesting self-medication). On the other hand, the effects o f nicotine on vigilance / sustained attention and motor speed are more robust than those on psychomotor inhibition (see e.g., Levin et al., 2001). Furthermore, adult smokers show less motivational inhibition than non-smokers and adolescent smokers (Reynolds et al., 2004a), suggesting that chronic smoking decreases motivational inhibition. To our knowledge the direct effect o f nicotine on motivational inhibition has not been tested before. Nine smokers and seventeen non-smokers participated in this study with an open trial, pre / post treatment design, after overnight abstinence from smoking, alcohol and caffeine. On both pre and post test participants performed a reversed Continuous Performance Test (R-CPT) and a computerized Delay Discounting (DD) questionnaire. On the R-CPT participants had to withheld a motor response when the letter X was presented Con 24 o f 240 trials). On the DD they made hypothetical choices between an immediate reward o f 60 to 135 Euros and a delayed reward o f 150 Euro (0.5 to 24 month delay). Between pre and post-test the smokers smoked one cigarette, leading to an average dose o f about 0.8 m g nicotine, and the non-smokers had a short break. Preliminary results showed that, whereas there were no effects o f smoking on psychomotor inhibition Call F < 1), the index o f motivational inhibition increased between pre and post test for the smokers, but not for the non-smokers (F(1,24) 4.70, p < 0.05). Post-hoc tests revealed that smokers showed larger delay aversion than non-smokers on the pre-test (F(1,24) 4.41, p < 0.05) but not on the post-test (F < 1). We conclude that nicotine had an acute effect on motivational, but not on psychomotor inhibition. The pattern o f results is also compatible with the interpretation that nicotine-withdrawal increases delay aversion. The effect o f nicotine on psychomotor inhibition has been found to be variable indeed. The effect on motivational inhibition is interesting in view o f previous results showing that neither D-amphetamine, nor behavioural depressants (alcohol, diazepam) (Reynolds et al., 2004b) did affect DD. Finally, the acute affect found here is opposite to the long-term effect o f cigarette smoking.
References [1] Levin, E.D., Conners, C.K., Silva, D., Canu, W., & March, J., 2001. Effects of chronic nicotine and methylphenidate in adults with attention deficit/hyperactivity disorder. Experimental and Clinical Psychopharmacology, 9, 83 90. [2] Reynolds, B., 2004a. Do high rates of cigarette consumption increase delay discounting? A cross-sectional comparison of adolescent smokers
and young-adult smokers and nonsmokers. Behavioural Processes, 67, 545 549. [3] Reynolds, B., Richards, J.B., Dassinger, M., & de Wit, H., 2004b. Therapeutic doses of diazepam do not alter impulsive behavior in humans. Pharmacology Biochemistry and Behavior, 79, 17 24.
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of a biomarker of norepinephrine transporter (NET) inhibition to assess atomoxetine effects during clinically recommended dosing
M. Leibowitz 1 , L. Ereshefsky 1, Q. Lin 2, E. Ledent 3, R. Padich 4, A.J. Allen 5, S. Jhee 1 , D. Michelson 6, RR. Bieck 6 *, D.R. Lachno 7.
] California Clinical Trials, Glendale CA, USA," 2Eli Lilly & Company, Statistics, USA," 3Eli Lilly & Company, Mont-SaintGuibert, Belgium," 4Eli Lilly & Company, Global Scientific Information and Communication, USA," 5Eli Lilly & Company, Medical, USA," 6Eli Lilly & Company, Neuroscience Therapeutic Area, Indianapolis, USA," 7Eli Lilly & Company, Erlwood, United Kingdom Background/Purpose: The degree o f NET blockade can be assessed in the periphery using the plasma or urine dihydroxyphenylglycol (DHPG)/NE ratio as a biomarker (Vincent et al., 2004). Atomoxetine is a highly specific NET inhibitor approved for the treatment o f attention deficit disorder (ADHD). This study was designed to evaluate if the NET inhibiting effect can be demonstrated at steady state in the cerebrospinal fluid (CSF), and to assess the duration o f drug action centrally during once daily dosing. Methods: 12 healthy subjects took atomoxetine 4 0 m g QD for 3 days followed by 8 0 m g QD for 15 days in this open label, multiple-dose study. Samples were obtained before treatment (Rx), on day 17 (plasma/urine) and 2 4 h after the final atomoxetine dose on day 18 (CSF). NE and D H P G were analyzed by HPLCEC. Safety assessments included adverse events, heart rate, blood pressure and orthostatic tests. Additional measures (PK, ex vivo effect on NET binding) will be reported separately. Results: see Table. Marx
Day I no treatment(1Lx) Day 1Lx Day 17/18 atomoxetine1Lx P-value DHPG DHPG vs. Day l Mean, geometric(N) Mean, geometric(N)
CSF 2450.4pg/ml(ll) 18 Plasma 1237.1pg/ml (ll) 17 Urine 35.1 ug/g creatinine(ll) 17 (24 hour)
1735.9pg/ml(8) 901.5pg/ml(8) 24.6 ug/g creatinine(10)
<0.001 <0.001 <0.01
Conclusions: CSF D H P G is a potentially sensitive biomarker o f NET inhibition. Atomoxetine treatment for 17 18 days was associated with a highly significant 30% decrease o f D H P G in the central and peripheral compartments that was observable 24 h after the previous atomoxetine dose. The two-fold higher CSF concentrations o f D H P G suggest that the drug effects originate in the brain. These data suggest that once daily atomoxetine is associated with central effects that persist in the CNS for at least 24 h. D H P G changes in 24-h urine mirror the central effect in magnitude and appear to be useful as a non-invasive biomarker o f NET inhibition.
References [1] Vincent, S., Bieck P.R., Garland, E.M., Loghin C., Bymaster F.P., Black, B.K., Gonzales, C., Potter, W.Z., Robertson, D. 2004. Clinical
$594
•
Nicotine influences motivational but not psychomotor inhibition
K.B.E. B6cker 1 *, M.M. Lansbergen 2, E.H. Quik 1 , J.L. Kenemans 2. ] Utrecht University, Psychopharmacology,
Utrecht, The Netherlands; 2Utrecht University, Psychonomics and Psychopharmacology, The Netherlands Impulsivity, or lack o f inhibition, is one o f the symptom dimensions in Attention-Deficit / Hyperactivity Disorder (ADHD). Different varieties o f inhibition can be distinguished behaviourally as well as pharmacologically. Here we contrast motivational inhibition (tolerance for a larger reward after a delay) and psychomotor inhibition (interruption o f a prepotent response). We hypothesize that nicotine (cigarette smoking) increases both kinds o f inhibition. This is because A D H D and the associated impulsivity can be treated with psychostimulants, because A D H D patients are more often dependent on nicotine than control subjects (suggesting self-medication). On the other hand, the effects o f nicotine on vigilance / sustained attention and motor speed are more robust than those on psychomotor inhibition (see e.g., Levin et al., 2001). Furthermore, adult smokers show less motivational inhibition than non-smokers and adolescent smokers (Reynolds et al., 2004a), suggesting that chronic smoking decreases motivational inhibition. To our knowledge the direct effect o f nicotine on motivational inhibition has not been tested before. Nine smokers and seventeen non-smokers participated in this study with an open trial, pre / post treatment design, after overnight abstinence from smoking, alcohol and caffeine. On both pre and post test participants performed a reversed Continuous Performance Test (R-CPT) and a computerized Delay Discounting (DD) questionnaire. On the R-CPT participants had to withheld a motor response when the letter X was presented Con 24 o f 240 trials). On the DD they made hypothetical choices between an immediate reward o f 60 to 135 Euros and a delayed reward o f 150 Euro (0.5 to 24 month delay). Between pre and post-test the smokers smoked one cigarette, leading to an average dose o f about 0.8 m g nicotine, and the non-smokers had a short break. Preliminary results showed that, whereas there were no effects o f smoking on psychomotor inhibition Call F < 1), the index o f motivational inhibition increased between pre and post test for the smokers, but not for the non-smokers (F(1,24) 4.70, p < 0.05). Post-hoc tests revealed that smokers showed larger delay aversion than non-smokers on the pre-test (F(1,24) 4.41, p < 0.05) but not on the post-test (F < 1). We conclude that nicotine had an acute effect on motivational, but not on psychomotor inhibition. The pattern o f results is also compatible with the interpretation that nicotine-withdrawal increases delay aversion. The effect o f nicotine on psychomotor inhibition has been found to be variable indeed. The effect on motivational inhibition is interesting in view o f previous results showing that neither D-amphetamine, nor behavioural depressants (alcohol, diazepam) (Reynolds et al., 2004b) did affect DD. Finally, the acute affect found here is opposite to the long-term effect o f cigarette smoking.
References [1] Levin, E.D., Conners, C.K., Silva, D., Canu, W., & March, J., 2001. Effects of chronic nicotine and methylphenidate in adults with attention deficit/hyperactivity disorder. Experimental and Clinical Psychopharmacology, 9, 83 90. [2] Reynolds, B., 2004a. Do high rates of cigarette consumption increase delay discounting? A cross-sectional comparison of adolescent smokers
and young-adult smokers and nonsmokers. Behavioural Processes, 67, 545 549. [3] Reynolds, B., Richards, J.B., Dassinger, M., & de Wit, H., 2004b. Therapeutic doses of diazepam do not alter impulsive behavior in humans. Pharmacology Biochemistry and Behavior, 79, 17 24.
~ U s e
of a biomarker of norepinephrine transporter (NET) inhibition to assess atomoxetine effects during clinically recommended dosing
M. Leibowitz 1 , L. Ereshefsky 1, Q. Lin 2, E. Ledent 3, R. Padich 4, A.J. Allen 5, S. Jhee 1 , D. Michelson 6, RR. Bieck 6 *, D.R. Lachno 7.
] California Clinical Trials, Glendale CA, USA," 2Eli Lilly & Company, Statistics, USA," 3Eli Lilly & Company, Mont-SaintGuibert, Belgium," 4Eli Lilly & Company, Global Scientific Information and Communication, USA," 5Eli Lilly & Company, Medical, USA," 6Eli Lilly & Company, Neuroscience Therapeutic Area, Indianapolis, USA," 7Eli Lilly & Company, Erlwood, United Kingdom Background/Purpose: The degree o f NET blockade can be assessed in the periphery using the plasma or urine dihydroxyphenylglycol (DHPG)/NE ratio as a biomarker (Vincent et al., 2004). Atomoxetine is a highly specific NET inhibitor approved for the treatment o f attention deficit disorder (ADHD). This study was designed to evaluate if the NET inhibiting effect can be demonstrated at steady state in the cerebrospinal fluid (CSF), and to assess the duration o f drug action centrally during once daily dosing. Methods: 12 healthy subjects took atomoxetine 4 0 m g QD for 3 days followed by 8 0 m g QD for 15 days in this open label, multiple-dose study. Samples were obtained before treatment (Rx), on day 17 (plasma/urine) and 2 4 h after the final atomoxetine dose on day 18 (CSF). NE and D H P G were analyzed by HPLCEC. Safety assessments included adverse events, heart rate, blood pressure and orthostatic tests. Additional measures (PK, ex vivo effect on NET binding) will be reported separately. Results: see Table. Marx
Day I no treatment(1Lx) Day 1Lx Day 17/18 atomoxetine1Lx P-value DHPG DHPG vs. Day l Mean, geometric(N) Mean, geometric(N)
CSF 2450.4pg/ml(ll) 18 Plasma 1237.1pg/ml (ll) 17 Urine 35.1 ug/g creatinine(ll) 17 (24 hour)
1735.9pg/ml(8) 901.5pg/ml(8) 24.6 ug/g creatinine(10)
<0.001 <0.001 <0.01
Conclusions: CSF D H P G is a potentially sensitive biomarker o f NET inhibition. Atomoxetine treatment for 17 18 days was associated with a highly significant 30% decrease o f D H P G in the central and peripheral compartments that was observable 24 h after the previous atomoxetine dose. The two-fold higher CSF concentrations o f D H P G suggest that the drug effects originate in the brain. These data suggest that once daily atomoxetine is associated with central effects that persist in the CNS for at least 24 h. D H P G changes in 24-h urine mirror the central effect in magnitude and appear to be useful as a non-invasive biomarker o f NET inhibition.
References [1] Vincent, S., Bieck P.R., Garland, E.M., Loghin C., Bymaster F.P., Black, B.K., Gonzales, C., Potter, W.Z., Robertson, D. 2004. Clinical