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The effects of repeated pentylenetetrazol administration on rat emotional behavior
l?3. Anxiety disorders and anviolytics
The effects of repeated pentylenetetrazol administration on rat emotlonal behavior J. Szyndler’, I? Maciejak2, H. Sienkiewicz-Jarosz3, A. Czlonkowska’ , M. Siemiatkowski2, A. Plazr~ik’*~*. ‘Department of Pharmacology, Medical University, Warsaw; 2Department of Pharmacology; ‘Department of Neurology; 4Department of Biochemistry, Institute of Psychiatry and Neurology, Poland Interictal behavioural disorder belongs to the specific syndromes observed in epilepsy and involves, among others, anxiety and depression. In the present study we investigated the influence of repeated administration of a proconvulsive agent, pentylenetetrazol (PTZ), at the subtreshold dose (30 mg/kg i.p.) gradually leading to seizures, on rat emotional behaviour. The animals were considered to be kindled after reaching at least the stage 4 or 5 (maximum) of seizures, on two consecutive test days. Rats were tested in several tests of anxiety-like behaviour: the open field test of neophobia, the Vogel test of conflict behaviour, step-down avoidance test of learning and memory, conditioned fear test (treezing reaction of rats in a context conditioned to the aversive stimulation), and ultra-vocalization test (USV) (reaction of animals to the acute or conditioned aversive stimuli). In the Vogel, open field, and step-down avoidance tests there were no significant differences in behaviour between the kindled and control rats. However, in the conditioned fear test, kindled rats expressed the reduced number of freezing episodes. In the USV test kindled animals exhibited also decreased basal, and enhanced shock-induced conditioned vocalization. The kindled rats did not differ from controls in their reactivity to the painful stimuli (flinchjump test), and motor activity. A challenge dose of yohimbine (a fear-evoking drug, given at the dose of 2.5 mg/kg, i.p.) produced a clear tendency to enhance thigmotaxis in the kindled rats only. These data suggest that pentylenetetrazol kindling is associated with behavioural changes in rats, indicative of increased emotionality and disturbances in the processes of selective attention. The pentylenetetrazol kindled rats may be a useful model to study the mechanisms contributing to the interictal disorders in emotional behaviour, similar to those observed in epileptic patients.
IP.3.012)
1231Beta-CIT SPECT of dopamine and serotonine transporters in obsessive compulsive disorder
N. Van der Wee, H. Stevens, M. Harmelink, H.G.M. Van Megen, P. Van Rijk, H.G.M. Westenberg. University Medical Center Utrecht, Department of Psychiatry, Utrecht, The Netherlands Background: Although the serotonergic (5HT) system may play a pivotal role in the pathophysiology of obsessive compulsive disorder (OCD), the involvement of the serotonergic system in OCD has never been directly anatomically investigated in vivo. The SPECT ligand 1231Beta-CIT binds to serotonine (5HT) and dopamine transporters in the living human brain (Tiihonen et al., 1997). Due to the different phannacokinetics and the different sites of binding both 5-HT and dopamine transporters can be visualised separately in the same subject. Aim of the present study was to examine the differences between the binding patterns of ‘231 P-CIT in drug naive OCD patients and healthy controls. Methods: Fifteen drug naive patients with OCD according to DSM-IV criteria and a Y-BOCS > 16, without other Axis
s303
I and major Axis II disorders and 15 gender and age matched healthy controls participated. All subjects were in good physical condition and without a history of medical problems potentially having central nervous system se uelae, drug addiction or abuses. Subjects received 150 MBq of I23 I Beta-CIT. SPECT scans were performed 4 and 22-24 hours after administration of the ligand. Directly after the first SPECT scan subjects received paroxetine 20 mg in order to displace the radioactive ligand to the dopamine transporters. For a preliminary analysis data from 11 patients and 8 controls were available. Volumes of interest (VOI’s) were semiautomatically drawn on the SPECT scans around the forebrain, basal ganglia, midbrain and cerebellum (reference region). Uptake ratio’s were calculated as VOI-reference region/reference region and compared with a t-test, Bonferroni corrected. Results: There was a significant lower uptake in the forebrain (5-HT transporter) and a significant higher uptake in the basal ganglia (dopamine transporter) of the patients with OCD. Conclusion: These preliminary direct anatomical data suggest abnormalities at the 5-HT and dopamine transporter level in the brains of drug naive patients with OCD. References [l] Tiihonen, J., Kuildcs, J.T., Bergstrom, K. A., Karhu, J., Viinamaki, H., Lehtonen, J., Hallikainen, T., Yang, J., and Hakola, P (1997). Singlephoton emission tomography imaging of monoamine transporters in impulsive violent behaviour. Eur. J. Nucl. Med. 24: 1253-1260.
Ip.3.013)
Assessment of potential interaction between naloxone and diazepam in anxious subjects
A. Prosperi, J. Micallef, D. Dubreuil, B. Bruguerolle, 0. Blin’. Cenhe de Pharmacologic Unique et d’Eualuations Thkrapeutiques H6pital de la Timone, 13385 Marseille cedex 5, France Previous studies have shown that the opiate antagonist naloxone blocks the anxiolytic-like effects of benzodiazepines in several animals models of anxiety (Belzung et al, 1997; Belzung et al, 1998). The aim of the present study was to assess this potential interaction between opioid and GABaergic system using naloxone (1.6 mg SC) and diazepam (oral dose of 2 mg) in anxious subjects. A randomised double blind, placebo controlled parallel group study was performed in 27 healthy subjects of both sex. On the basis of interview by the same psychiatrist (AP), the score on Anxiety rating scale AMDP-AT, associated with the clinical diagnosis of anxiety (generalized anxiety disorder or adjustment disorder of anxiety; DSM IV, 1994) the subjects were judged as anxious (minimum score of 20 on AMDP-AT scale). Subjects were randomly assigned to one of the three groups (9 subjects per group) as follow: a group received a single oral dose of diazepam and naloxone; a group received placebo of diazepam and naloxone; and a group received placebo of diazepam and placebo of naloxone. The subcutaneous administration of naloxone (or placebo) was performed lh15 after oral administration of diazepam (or placebo) They were evaluated for efficacy (anxiety rating scale AMDPAT), memory tests (immediate and delayed free recall of a word list; digit span) and vigilance (visual analog scale). On basis of the pharmacokinetics parameters of the two drugs, the time of assessments for AMDP-AT, memory tests and VAS was the following: before drug administration, 30 minutes after oral dose of diazepam (or placebo) and 15 minutes after subcutaneous dose of naloxone (or placebo) An anxiolytic effect was found in the group diazepam
The effects of repeated pentylenetetrazol administration on rat emotlonal behavior J. Szyndler’, I? Maciejak2, H. Sienkiewicz-Jarosz3, A. Czlonkowska’ , M. Siemiatkowski2, A. Plazr~ik’*~*. ‘Department of Pharmacology, Medical University, Warsaw; 2Department of Pharmacology; ‘Department of Neurology; 4Department of Biochemistry, Institute of Psychiatry and Neurology, Poland Interictal behavioural disorder belongs to the specific syndromes observed in epilepsy and involves, among others, anxiety and depression. In the present study we investigated the influence of repeated administration of a proconvulsive agent, pentylenetetrazol (PTZ), at the subtreshold dose (30 mg/kg i.p.) gradually leading to seizures, on rat emotional behaviour. The animals were considered to be kindled after reaching at least the stage 4 or 5 (maximum) of seizures, on two consecutive test days. Rats were tested in several tests of anxiety-like behaviour: the open field test of neophobia, the Vogel test of conflict behaviour, step-down avoidance test of learning and memory, conditioned fear test (treezing reaction of rats in a context conditioned to the aversive stimulation), and ultra-vocalization test (USV) (reaction of animals to the acute or conditioned aversive stimuli). In the Vogel, open field, and step-down avoidance tests there were no significant differences in behaviour between the kindled and control rats. However, in the conditioned fear test, kindled rats expressed the reduced number of freezing episodes. In the USV test kindled animals exhibited also decreased basal, and enhanced shock-induced conditioned vocalization. The kindled rats did not differ from controls in their reactivity to the painful stimuli (flinchjump test), and motor activity. A challenge dose of yohimbine (a fear-evoking drug, given at the dose of 2.5 mg/kg, i.p.) produced a clear tendency to enhance thigmotaxis in the kindled rats only. These data suggest that pentylenetetrazol kindling is associated with behavioural changes in rats, indicative of increased emotionality and disturbances in the processes of selective attention. The pentylenetetrazol kindled rats may be a useful model to study the mechanisms contributing to the interictal disorders in emotional behaviour, similar to those observed in epileptic patients.
IP.3.012)
1231Beta-CIT SPECT of dopamine and serotonine transporters in obsessive compulsive disorder
N. Van der Wee, H. Stevens, M. Harmelink, H.G.M. Van Megen, P. Van Rijk, H.G.M. Westenberg. University Medical Center Utrecht, Department of Psychiatry, Utrecht, The Netherlands Background: Although the serotonergic (5HT) system may play a pivotal role in the pathophysiology of obsessive compulsive disorder (OCD), the involvement of the serotonergic system in OCD has never been directly anatomically investigated in vivo. The SPECT ligand 1231Beta-CIT binds to serotonine (5HT) and dopamine transporters in the living human brain (Tiihonen et al., 1997). Due to the different phannacokinetics and the different sites of binding both 5-HT and dopamine transporters can be visualised separately in the same subject. Aim of the present study was to examine the differences between the binding patterns of ‘231 P-CIT in drug naive OCD patients and healthy controls. Methods: Fifteen drug naive patients with OCD according to DSM-IV criteria and a Y-BOCS > 16, without other Axis
s303
I and major Axis II disorders and 15 gender and age matched healthy controls participated. All subjects were in good physical condition and without a history of medical problems potentially having central nervous system se uelae, drug addiction or abuses. Subjects received 150 MBq of I23 I Beta-CIT. SPECT scans were performed 4 and 22-24 hours after administration of the ligand. Directly after the first SPECT scan subjects received paroxetine 20 mg in order to displace the radioactive ligand to the dopamine transporters. For a preliminary analysis data from 11 patients and 8 controls were available. Volumes of interest (VOI’s) were semiautomatically drawn on the SPECT scans around the forebrain, basal ganglia, midbrain and cerebellum (reference region). Uptake ratio’s were calculated as VOI-reference region/reference region and compared with a t-test, Bonferroni corrected. Results: There was a significant lower uptake in the forebrain (5-HT transporter) and a significant higher uptake in the basal ganglia (dopamine transporter) of the patients with OCD. Conclusion: These preliminary direct anatomical data suggest abnormalities at the 5-HT and dopamine transporter level in the brains of drug naive patients with OCD. References [l] Tiihonen, J., Kuildcs, J.T., Bergstrom, K. A., Karhu, J., Viinamaki, H., Lehtonen, J., Hallikainen, T., Yang, J., and Hakola, P (1997). Singlephoton emission tomography imaging of monoamine transporters in impulsive violent behaviour. Eur. J. Nucl. Med. 24: 1253-1260.
Ip.3.013)
Assessment of potential interaction between naloxone and diazepam in anxious subjects
A. Prosperi, J. Micallef, D. Dubreuil, B. Bruguerolle, 0. Blin’. Cenhe de Pharmacologic Unique et d’Eualuations Thkrapeutiques H6pital de la Timone, 13385 Marseille cedex 5, France Previous studies have shown that the opiate antagonist naloxone blocks the anxiolytic-like effects of benzodiazepines in several animals models of anxiety (Belzung et al, 1997; Belzung et al, 1998). The aim of the present study was to assess this potential interaction between opioid and GABaergic system using naloxone (1.6 mg SC) and diazepam (oral dose of 2 mg) in anxious subjects. A randomised double blind, placebo controlled parallel group study was performed in 27 healthy subjects of both sex. On the basis of interview by the same psychiatrist (AP), the score on Anxiety rating scale AMDP-AT, associated with the clinical diagnosis of anxiety (generalized anxiety disorder or adjustment disorder of anxiety; DSM IV, 1994) the subjects were judged as anxious (minimum score of 20 on AMDP-AT scale). Subjects were randomly assigned to one of the three groups (9 subjects per group) as follow: a group received a single oral dose of diazepam and naloxone; a group received placebo of diazepam and naloxone; and a group received placebo of diazepam and placebo of naloxone. The subcutaneous administration of naloxone (or placebo) was performed lh15 after oral administration of diazepam (or placebo) They were evaluated for efficacy (anxiety rating scale AMDPAT), memory tests (immediate and delayed free recall of a word list; digit span) and vigilance (visual analog scale). On basis of the pharmacokinetics parameters of the two drugs, the time of assessments for AMDP-AT, memory tests and VAS was the following: before drug administration, 30 minutes after oral dose of diazepam (or placebo) and 15 minutes after subcutaneous dose of naloxone (or placebo) An anxiolytic effect was found in the group diazepam