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P.1.c.022 Effects of 3,4-methylenedioxymethamphetamine (MDMA or ecstasy) on prosocial feelings and oxytocin plasma levels in humans
P.1.c. Basic and clinical neuroscience − Neuropharmacology [2] Giustizieri, M., Cucchiaroni, M. L., Guatteo, E., Bernardi, G., Mercuri, N. B., and Berretta, N., 2007. Memantine inhibits ATP-dependent K+ conductances in dopamine neurons of the rat substantia nigra pars compacta. J Pharmacol Exp Ther 322, 721–729. [3] Chen, Y. H., Lin, P. L., Hsu, H. Y., Wu, Y. T., Yang, H. Y., Lu, D. Y., Huang, S. S., Hsieh, C. L., and Lin, J. G., 2010. Action potential bursts in central snail neurons elicited by paeonol: roles of ionic currents. Acta Pharmacol Sin 31, 1553–1563.
P.1.c.021 Effect of phosphodiesterase 2A inhibition on striatal dopamine in a microdialysis study and its reflection in dopamine-associated effects in animal models B. Langen1 ° , R. Dost1 , H.J. Lankau2 , T. Hage2 , N. Hoefgen2 . 1 Biocrea GmbH, Pharmacology, Radebeul, Germany; 2 Biocrea GmbH, Chemistry, Radebeul, Germany Purpose: Phosphodiesterases (PDE) are expressed in nearly all mammalian cells. They catalyze the degradation of cAMP and/or cGMP and are thus key regulators of intracellular cyclic nucleotide levels. As a consequence, they may play an important role in numerous physiological and pathophysiological processes. PDE2A hydrolyses both cAMP and cGMP and is activated upon cGMP binding to its N-terminal GAF-B domain. It is highly expressed in different brain areas, i.e. cortex, hippocampus and striatum. Only a few PDE2 inhibitors have been pharmacologically characterised so far (BAY60–7550, ND-7001) suggesting their pro-cognitive and anxiolytic potential (1, 2). However, little is known regarding the effect of PDE2A inhibitors on the different neurotransmitter systems in the brain that may underlie such efficacy. In the present study, the effect of PDE2A inhibition on striatal dopamine and its metabolite 3,4-dihydroxyphenylacetic acid (dopac) was investigated in microdialysis. Additionally, the influence of several PDE2 inhibitors on dopamine-associated pharmacological effects was investigated. Methods: The effect of PDE2A inhibition on extracellular dopamine and dopac in the striatum was evaluated by microdialysis. A microdialysis probe (CMA/12, membrane length 4 mm) was inserted via guide cannula (AP +1.0, L −3.0, V +5.5) into the striatum. Probe was perfused with aCSF at a flow rate of 1 ml/min that allowed for the collection of 20 ml samples every 20 minutes into microvials. Samples were measured by HPLC and electrochemical detection. Additionally, the effect of several PDE2A inhibitors on reserpine-induced hypothermia in mice and on haloperidol-induced catalepsy in rats has been tested. To examine whether the effect of the PDE2A inhibition is CNS mediated, the effect of intrastriatal compound administration on haloperidol-induced catalepsy was also evaluated, using BAY60– 7550 as a reference compound. Results: The PDE2A inhibitor BCR840 at 10 mg/kg po significantly reduced extracellular dopamine and dopac levels in the striatum. BAY60–7550 at 30 mg/kg po significantly decreased extracellular dopac and slightly reduced extracellular dopamine in the striatum of rats. At the same doses both compounds significantly reversed reserpine-induced hypothermia and haloperidol induced catalepsy indicating an activating effect on the dopamine neurotransmitter system. Further confidence in the underlying mechanism of action was obtained from further PDE2A inhibitors being orally and dose-dependently active in these models. BCR909 significantly reversed haloperidol induced catalepsy starting at 10 mg/kg after oral dosing. When injected intrastriatally, the administration of 1 and 10 mM (1 ml administration volume)
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BCR909 resulted in a significant and dose dependent inhibition of haloperidol induced cataleptic behaviour. This indicates that the PDE2A inhibitory effect in the described models was CNS mediated. Conclusions: This study indicates that PDE2A inhibition has a modulating effect on the dopamine neurotransmitter system. PDE2A inhibitors significantly reduced extracellular dopamine and dopac in the striatum of rats and reversed reserpine induced hypothermia and haloperidol induced catalepsy. The data indicate that the effects of PDE2A inhibitors are centrally-evoked and may be at least partially mediated by a modulation of the dopamine neurotransmitter system. References [1] Boess, F.G., Hendrix, M., van der Staay, F.J., Erb, C., Schreiber, R., vanStaveren, W., deVente, J., Prickaerts, J., Blokland, A., Koenig, G., 2004 Inhibition of phosphodiesterase-2 increases neuronal cGMP, synaptic plasticity and memory performance. Neuropharmacology 47, 1081–1092. [2] Masood A, Nadeem A, Mustafa SJ, O’Donnell JM (2008). Reversal of oxidative stress-induced anxiety by inhibition of phosphodiesterase-2 in mice. JPET 326: 369–379. Disclosure statement: The study was supported by European Fund for Regional Development (EFRE) and by the Free State of Saxony (grant no. SAB12525)
P.1.c.022 Effects of 3,4-methylenedioxymethamphetamine (MDMA or ecstasy) on prosocial feelings and oxytocin plasma levels in humans C.M. Hysek1 ° , L.D. Simmler1 , V.G. Nicola1 , M.E. Liechti1 . 1 Clinical Pharmacology and Toxicology, Department of Biomedicine University Hospital Basel, Basel, Switzerland Background: The recreationally abused drug ±3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is reputed to produce strong psychological effects such as increased prosocial feelings and feelings of closeness to others. These effects of possibly elevated empathy also led to the suggested classification of MDMA and related compounds into a drug class called “entactogens”. Animal studies have shown a key role for the neuropeptide oxytocin in the regulation of social cognition and prosocial behavior. MDMA increases prosocial behavior in rodents, an effect which is attenuated by an oxytocin receptor antagonist. A recent human study showed that oxytocin improved the ability to infer affective mental states of others from facial cues in a ‘mind reading’ task possibly facilitating social approach behavior. We hypothesized that MDMA would increase oxytocin plasma levels and thereby also improve performance in the ‘mind reading’ task in humans. Objective: The aim of this study was to investigate effects of MDMA on oxytocin plasma levels, prosocial feelings, and ‘mind reading’ in healthy volunteers. Methods: We assessed the effects of MDMA on oxytocin plasma levels, subjective effects, and on a ‘mind reading’ task in 16 drug-na¨ıve healthy subjects using a double-blind, placebocontrolled, within-subject design. Oxytocin plasma levels were assessed at baseline and 120 min after placebo or MDMA. Subjective effects were repeatedly measured by Visual Analogue Scales (VAS) and an Adjective Mood Rating Scale. A computerized version of the Reading the Mind in the Eyes-Revised test (RMET) was applied to assess the subjects ability to identify complex emotions from 36 pictures of the eye regions of different men and
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women. The RMET is known to be sensitive to a nasal administration of oxytocin. To exclude cognitive impairment subjects also underwent a Choice Reaction Time Task (CRTT). In the CRTT subjects had to respond during a 3 min period to the presentation of colored lights (five colors) appearing in random sequence by pressing the button with the corresponding color as quickly and accurately as possible. Results: MDMA significantly increased oxytocin plasma levels (22.23±9.11 pg/mL; mean±SEM) compared to placebo (1.38±7.09 pg/mL). MDMA increased self-rated prosocial effects including “closeness to others”, “openness”, “talkative”, and “extraversion” compared to placebo. The increase in oxytocin plasma levels following MDMA administration correlated with the VAS score increase in “closeness to others” (spearman rank coefficient: Rs =0.427, P < 0.001). MDMA did not improve ‘mind reading’ in the RMET and did not affect cognitive performance in the CRTT. Conclusion: We found that MDMA increased oxytocin plasma levels and subjective prosocial-like effects of MDMA compared to placebo. In addition, MDMA-induced oxytocin plasma levels correlated with “closeness to others”. However, MDMA did not improve ‘mind reading’ performance as previously shown for a nasal oxytocin administration using the same task. The role of oxytocin in the potential prosocial and emotional effects of MDMA needs further investigation.
P.1.c.023 Effects of the forced swim test and fluoxetine pretreatment on brain expression of genes related to neuronal plasticity
midbrain, brain stem and hippocampus, but increased in the frontal cortex, an effect that was abolished by fluoxetine pretreatment for 8, but not 2, weeks, at the period when this treatment decreased immobility time in the forced swim test [2]. The finding that the forced swim stress increased the expression of cortical Bax and that long-term antidepressant pretreatment prevented this increase suggests that regulators of apoptosis might be involved in this brain region in both the pathogenesis of depression and in the mechanism of antidepressant drug action. This suggestion is supported by the signifucant negative correlations between cortical Bcl-xl as well as Bcl-xl/Bax ratio and immobility in the forced swim test (r = −0.42, p < 0.05 and r = −0.46, p < 0.05; n = 23, accordingly). In conclusion, our data demonstrate increase in both of pro- and anti-apoptotic gene expression after forced swim stress. Expression of pro-apoptotic Bax and anti-apoptotic Bcl-xl gene expressions may be modified by fluoxetine in a regiondependent manner. This work was supported by RFBR grant N 09−04–00284. References [1] Shishkina, G.T., Kalinina, T.S., Berezova, I.V., Bulygina, V.V., Dygalo, N.N., 2010 Resistance to the development of stress-induced behavioral despair in the forced swim test associated with elevated hippocampal Bcl-xl expression. Behavioural Brain Research 213, 218– 224. [2] Shishkina, G.T., Kalinina, T.S., Dygalo, N.N., 2007 Up-regulation of tryptophan hydroxylase-2 mRNA in the rat brain by chronic fluoxetine treatment correlates with its antidepressant effect. Neuroscience 150, 404–412.
G.T. Shishkina1 ° , T.S. Kalinina1 , I.V. Berezova1 , N.N. Dygalo1 . 1 Institute of Cytology and Genetics SD RAS, Siberian Division, Novosibirsk, Russia
P.1.c.024 The effect of the brain noradrenergic system on liver cytochrome P450: the role of neuroendocrine regulation
Stressful life events have been implicated in the pathophysiology of depression. However, stressors induce numerous adaptive changes, some of which can diminish vulnerability to stress in relation to psychopathology. For example, we recently suggested that the ability to increase the expression of anti-apoptotic protein, Bcl-xl, in the hippocampus in response to stress may be an important factor for determining the resistance to the development of stress-induced depression [1]. In order to further characterize the neurobiological mechanisms by which stress precipitates depression, we exploited the forced swim test model to investigate the effects of swim stress and pretreatment with antidepressant fluoxetine (7.5 mg/kg/day with drinking water for 2, 4 or 8 weeks) on expression of genes for brain-derived neurotrophic factor (BDNF), anti-apoptotic Bcl-xl and pro-apoptotic Bax, proteins that were associated with cell survival and proliferation, in the rat brain regions. Real time RT-PCR analyses showed slightly increased basal BDNF mRNA levels in the hippocampus after 2 weeks of fluoxetine treatment. No marked changes were observed in the neurotrophin gene expression in the frontal cortex, midbrain and brain stem after fluoxetine for 2, 4 or 8 weeks. BDNF gene expression was not altered in any brain region investigated at 24 h after the forced swim test. In contrast to BDNF, forced swim pretest and test sessions significantly increased hippocampal levels of antiapoptotic protein, Bcl-xl, mRNA at 24 h. This increase was weakened by fluoxetine pretreatment. In the midbrain, fluoxetine pretreatment for 2 weeks, as well as in the brain stem, fluoxetine pretreatment for 4 or 8 weeks significantly augmented Bcl-xl mRNA levels after the forced swim test. After forced swim, the levels of the proapoptotic protein, Bax, were unchanged in the
A. Haduch1 ° , A. Sadakierska-Chudy1 , K. Golembiowska2 , W.A. Daniel1 . 1 Institute of Pharmacology of Polish Academy of Sciences, Department of Pharmacokinetics and Drug Metabolism, Krakow, Poland; 2 Institute of Pharmacology of Polish Academy of Sciences, Department of Pharmacology, Krakow, Poland Introduction: Genes coding for cytochrome P450 (CYP) are regulated by many factors, including endogenous hormones (growth hormone, glucocorticoids, thyroid hormones) which are under control of the central nervous system (CNS). Our previous study using lesion and stimulation of brain dopaminergic pathways demonstrated the role of CNS in the regulation of liver cytochrome P450 [1]. Since the hypothalamus receives noradrenergic inputs, it is likely that the brain noradrenergic system can also affect the expression of liver cytochrome P450. Our preliminary study carried out after intraperitoneal administration of DSP-4, a specific noradrenergic neurotoxin, suggested a role of the noradrenergic system in the regulation of cytochrome P450 expression [2]. The aim of the present study was to investigate the role of the brain noradrenergic system (i.e. the effect of intracerebral administration of DSP-4) on the expression of liver cytochrome P450. Materials and Methods: Male Wistar rats were injected intracerebroventricularly with DSP-4, a selective neurotoxin to noradrenergic terminals. The neurotoxin was administered in a dose of 200 mg/ventricle (bilaterally). One week after neurotoxin injection, selected brain structures (the hypothalamus, cortex, hippocampus, striatum, nucleus accumbens, brain stem, cerebellum) and liver tissue were isolated. The levels of neurotransmitters (noradrenaline, dopamine, serotonin) in those brain structures were determined by
P.1.c.021 Effect of phosphodiesterase 2A inhibition on striatal dopamine in a microdialysis study and its reflection in dopamine-associated effects in animal models B. Langen1 ° , R. Dost1 , H.J. Lankau2 , T. Hage2 , N. Hoefgen2 . 1 Biocrea GmbH, Pharmacology, Radebeul, Germany; 2 Biocrea GmbH, Chemistry, Radebeul, Germany Purpose: Phosphodiesterases (PDE) are expressed in nearly all mammalian cells. They catalyze the degradation of cAMP and/or cGMP and are thus key regulators of intracellular cyclic nucleotide levels. As a consequence, they may play an important role in numerous physiological and pathophysiological processes. PDE2A hydrolyses both cAMP and cGMP and is activated upon cGMP binding to its N-terminal GAF-B domain. It is highly expressed in different brain areas, i.e. cortex, hippocampus and striatum. Only a few PDE2 inhibitors have been pharmacologically characterised so far (BAY60–7550, ND-7001) suggesting their pro-cognitive and anxiolytic potential (1, 2). However, little is known regarding the effect of PDE2A inhibitors on the different neurotransmitter systems in the brain that may underlie such efficacy. In the present study, the effect of PDE2A inhibition on striatal dopamine and its metabolite 3,4-dihydroxyphenylacetic acid (dopac) was investigated in microdialysis. Additionally, the influence of several PDE2 inhibitors on dopamine-associated pharmacological effects was investigated. Methods: The effect of PDE2A inhibition on extracellular dopamine and dopac in the striatum was evaluated by microdialysis. A microdialysis probe (CMA/12, membrane length 4 mm) was inserted via guide cannula (AP +1.0, L −3.0, V +5.5) into the striatum. Probe was perfused with aCSF at a flow rate of 1 ml/min that allowed for the collection of 20 ml samples every 20 minutes into microvials. Samples were measured by HPLC and electrochemical detection. Additionally, the effect of several PDE2A inhibitors on reserpine-induced hypothermia in mice and on haloperidol-induced catalepsy in rats has been tested. To examine whether the effect of the PDE2A inhibition is CNS mediated, the effect of intrastriatal compound administration on haloperidol-induced catalepsy was also evaluated, using BAY60– 7550 as a reference compound. Results: The PDE2A inhibitor BCR840 at 10 mg/kg po significantly reduced extracellular dopamine and dopac levels in the striatum. BAY60–7550 at 30 mg/kg po significantly decreased extracellular dopac and slightly reduced extracellular dopamine in the striatum of rats. At the same doses both compounds significantly reversed reserpine-induced hypothermia and haloperidol induced catalepsy indicating an activating effect on the dopamine neurotransmitter system. Further confidence in the underlying mechanism of action was obtained from further PDE2A inhibitors being orally and dose-dependently active in these models. BCR909 significantly reversed haloperidol induced catalepsy starting at 10 mg/kg after oral dosing. When injected intrastriatally, the administration of 1 and 10 mM (1 ml administration volume)
S265
BCR909 resulted in a significant and dose dependent inhibition of haloperidol induced cataleptic behaviour. This indicates that the PDE2A inhibitory effect in the described models was CNS mediated. Conclusions: This study indicates that PDE2A inhibition has a modulating effect on the dopamine neurotransmitter system. PDE2A inhibitors significantly reduced extracellular dopamine and dopac in the striatum of rats and reversed reserpine induced hypothermia and haloperidol induced catalepsy. The data indicate that the effects of PDE2A inhibitors are centrally-evoked and may be at least partially mediated by a modulation of the dopamine neurotransmitter system. References [1] Boess, F.G., Hendrix, M., van der Staay, F.J., Erb, C., Schreiber, R., vanStaveren, W., deVente, J., Prickaerts, J., Blokland, A., Koenig, G., 2004 Inhibition of phosphodiesterase-2 increases neuronal cGMP, synaptic plasticity and memory performance. Neuropharmacology 47, 1081–1092. [2] Masood A, Nadeem A, Mustafa SJ, O’Donnell JM (2008). Reversal of oxidative stress-induced anxiety by inhibition of phosphodiesterase-2 in mice. JPET 326: 369–379. Disclosure statement: The study was supported by European Fund for Regional Development (EFRE) and by the Free State of Saxony (grant no. SAB12525)
P.1.c.022 Effects of 3,4-methylenedioxymethamphetamine (MDMA or ecstasy) on prosocial feelings and oxytocin plasma levels in humans C.M. Hysek1 ° , L.D. Simmler1 , V.G. Nicola1 , M.E. Liechti1 . 1 Clinical Pharmacology and Toxicology, Department of Biomedicine University Hospital Basel, Basel, Switzerland Background: The recreationally abused drug ±3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is reputed to produce strong psychological effects such as increased prosocial feelings and feelings of closeness to others. These effects of possibly elevated empathy also led to the suggested classification of MDMA and related compounds into a drug class called “entactogens”. Animal studies have shown a key role for the neuropeptide oxytocin in the regulation of social cognition and prosocial behavior. MDMA increases prosocial behavior in rodents, an effect which is attenuated by an oxytocin receptor antagonist. A recent human study showed that oxytocin improved the ability to infer affective mental states of others from facial cues in a ‘mind reading’ task possibly facilitating social approach behavior. We hypothesized that MDMA would increase oxytocin plasma levels and thereby also improve performance in the ‘mind reading’ task in humans. Objective: The aim of this study was to investigate effects of MDMA on oxytocin plasma levels, prosocial feelings, and ‘mind reading’ in healthy volunteers. Methods: We assessed the effects of MDMA on oxytocin plasma levels, subjective effects, and on a ‘mind reading’ task in 16 drug-na¨ıve healthy subjects using a double-blind, placebocontrolled, within-subject design. Oxytocin plasma levels were assessed at baseline and 120 min after placebo or MDMA. Subjective effects were repeatedly measured by Visual Analogue Scales (VAS) and an Adjective Mood Rating Scale. A computerized version of the Reading the Mind in the Eyes-Revised test (RMET) was applied to assess the subjects ability to identify complex emotions from 36 pictures of the eye regions of different men and
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women. The RMET is known to be sensitive to a nasal administration of oxytocin. To exclude cognitive impairment subjects also underwent a Choice Reaction Time Task (CRTT). In the CRTT subjects had to respond during a 3 min period to the presentation of colored lights (five colors) appearing in random sequence by pressing the button with the corresponding color as quickly and accurately as possible. Results: MDMA significantly increased oxytocin plasma levels (22.23±9.11 pg/mL; mean±SEM) compared to placebo (1.38±7.09 pg/mL). MDMA increased self-rated prosocial effects including “closeness to others”, “openness”, “talkative”, and “extraversion” compared to placebo. The increase in oxytocin plasma levels following MDMA administration correlated with the VAS score increase in “closeness to others” (spearman rank coefficient: Rs =0.427, P < 0.001). MDMA did not improve ‘mind reading’ in the RMET and did not affect cognitive performance in the CRTT. Conclusion: We found that MDMA increased oxytocin plasma levels and subjective prosocial-like effects of MDMA compared to placebo. In addition, MDMA-induced oxytocin plasma levels correlated with “closeness to others”. However, MDMA did not improve ‘mind reading’ performance as previously shown for a nasal oxytocin administration using the same task. The role of oxytocin in the potential prosocial and emotional effects of MDMA needs further investigation.
P.1.c.023 Effects of the forced swim test and fluoxetine pretreatment on brain expression of genes related to neuronal plasticity
midbrain, brain stem and hippocampus, but increased in the frontal cortex, an effect that was abolished by fluoxetine pretreatment for 8, but not 2, weeks, at the period when this treatment decreased immobility time in the forced swim test [2]. The finding that the forced swim stress increased the expression of cortical Bax and that long-term antidepressant pretreatment prevented this increase suggests that regulators of apoptosis might be involved in this brain region in both the pathogenesis of depression and in the mechanism of antidepressant drug action. This suggestion is supported by the signifucant negative correlations between cortical Bcl-xl as well as Bcl-xl/Bax ratio and immobility in the forced swim test (r = −0.42, p < 0.05 and r = −0.46, p < 0.05; n = 23, accordingly). In conclusion, our data demonstrate increase in both of pro- and anti-apoptotic gene expression after forced swim stress. Expression of pro-apoptotic Bax and anti-apoptotic Bcl-xl gene expressions may be modified by fluoxetine in a regiondependent manner. This work was supported by RFBR grant N 09−04–00284. References [1] Shishkina, G.T., Kalinina, T.S., Berezova, I.V., Bulygina, V.V., Dygalo, N.N., 2010 Resistance to the development of stress-induced behavioral despair in the forced swim test associated with elevated hippocampal Bcl-xl expression. Behavioural Brain Research 213, 218– 224. [2] Shishkina, G.T., Kalinina, T.S., Dygalo, N.N., 2007 Up-regulation of tryptophan hydroxylase-2 mRNA in the rat brain by chronic fluoxetine treatment correlates with its antidepressant effect. Neuroscience 150, 404–412.
G.T. Shishkina1 ° , T.S. Kalinina1 , I.V. Berezova1 , N.N. Dygalo1 . 1 Institute of Cytology and Genetics SD RAS, Siberian Division, Novosibirsk, Russia
P.1.c.024 The effect of the brain noradrenergic system on liver cytochrome P450: the role of neuroendocrine regulation
Stressful life events have been implicated in the pathophysiology of depression. However, stressors induce numerous adaptive changes, some of which can diminish vulnerability to stress in relation to psychopathology. For example, we recently suggested that the ability to increase the expression of anti-apoptotic protein, Bcl-xl, in the hippocampus in response to stress may be an important factor for determining the resistance to the development of stress-induced depression [1]. In order to further characterize the neurobiological mechanisms by which stress precipitates depression, we exploited the forced swim test model to investigate the effects of swim stress and pretreatment with antidepressant fluoxetine (7.5 mg/kg/day with drinking water for 2, 4 or 8 weeks) on expression of genes for brain-derived neurotrophic factor (BDNF), anti-apoptotic Bcl-xl and pro-apoptotic Bax, proteins that were associated with cell survival and proliferation, in the rat brain regions. Real time RT-PCR analyses showed slightly increased basal BDNF mRNA levels in the hippocampus after 2 weeks of fluoxetine treatment. No marked changes were observed in the neurotrophin gene expression in the frontal cortex, midbrain and brain stem after fluoxetine for 2, 4 or 8 weeks. BDNF gene expression was not altered in any brain region investigated at 24 h after the forced swim test. In contrast to BDNF, forced swim pretest and test sessions significantly increased hippocampal levels of antiapoptotic protein, Bcl-xl, mRNA at 24 h. This increase was weakened by fluoxetine pretreatment. In the midbrain, fluoxetine pretreatment for 2 weeks, as well as in the brain stem, fluoxetine pretreatment for 4 or 8 weeks significantly augmented Bcl-xl mRNA levels after the forced swim test. After forced swim, the levels of the proapoptotic protein, Bax, were unchanged in the
A. Haduch1 ° , A. Sadakierska-Chudy1 , K. Golembiowska2 , W.A. Daniel1 . 1 Institute of Pharmacology of Polish Academy of Sciences, Department of Pharmacokinetics and Drug Metabolism, Krakow, Poland; 2 Institute of Pharmacology of Polish Academy of Sciences, Department of Pharmacology, Krakow, Poland Introduction: Genes coding for cytochrome P450 (CYP) are regulated by many factors, including endogenous hormones (growth hormone, glucocorticoids, thyroid hormones) which are under control of the central nervous system (CNS). Our previous study using lesion and stimulation of brain dopaminergic pathways demonstrated the role of CNS in the regulation of liver cytochrome P450 [1]. Since the hypothalamus receives noradrenergic inputs, it is likely that the brain noradrenergic system can also affect the expression of liver cytochrome P450. Our preliminary study carried out after intraperitoneal administration of DSP-4, a specific noradrenergic neurotoxin, suggested a role of the noradrenergic system in the regulation of cytochrome P450 expression [2]. The aim of the present study was to investigate the role of the brain noradrenergic system (i.e. the effect of intracerebral administration of DSP-4) on the expression of liver cytochrome P450. Materials and Methods: Male Wistar rats were injected intracerebroventricularly with DSP-4, a selective neurotoxin to noradrenergic terminals. The neurotoxin was administered in a dose of 200 mg/ventricle (bilaterally). One week after neurotoxin injection, selected brain structures (the hypothalamus, cortex, hippocampus, striatum, nucleus accumbens, brain stem, cerebellum) and liver tissue were isolated. The levels of neurotransmitters (noradrenaline, dopamine, serotonin) in those brain structures were determined by