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Interaction of tricyclic antidepressants with liposomes
S270
I?1 Affective disorders andantidepressants
References
Ip.1.1291
[l] Reynaert et al. Acta Psychiat &and. 1995, 9: 224 [2] Kovti H. et al. Proc. Royal Micr. Sot., 1995, 30 (Pt2): 123. [3] Jain N. et al., Brit. J. Pharmacol., 1995, 116: 2127.
Ip.1.1281
Verbal memory deficits associated unipolar affective disorder
with
S. Totic, D. Marinkovic, N. Marie, S. Brankovic, M. JasovicGasic *, VR. Paunovic. Institute of Psychiatry, Clinical Center of Serbia, PAsterova 2, Belgrade Although the affective symptoms are defining characteristic of depression, cognitive impairments have also been repeatedly demonstrated (1). Individuals diagnosed as depressed have often reported problems with memory and concentration and recent research has clearly established that memory functioning appears to be impaired in depression (2). Numerous researchers have found a variety of mnemonic deficits in depression in short-and long-term memory, in both verbal and visuospatial areas, and episodic and semantic, explicit and implicit memory, as well. On the other hand, there is a little evidence about performance that characterizes mnemonic functioning of depressive individuals in the phase of clinical recovery. According to this, the aim of the current study was to investigate performance on verbal memory tasks, using tasks such as free recall and recognition memory in subjects diagnosed with unipolar depression, in remission. Forty-three subjects participated in the study: 22 depressed patients with unipolar affective disorder, in remission (UP) and 20 normal controls (NC). The mini-mental state examination (MMSE) was employed as a brief global cognitive screening test, to detect the presence of significant generalized cognitive impairment. To evaluate the pattern of memory problems, the subjects were administered the Rey Auditory Verbal Learning Test (RAVLT) and the digit span subtests, verbal pairs associates and logical memory from Wechsler Memory Scale - revised (WMS-R). The two groups did not differ on level of overall cognitive functioning as assessed by MMSE. Group comparisons also indicated that the NC group recalled significantly more words and demonstrated significantly more improvement from trial to trial than did the UP. There was no significant difference between groups in the number of correctly recognized words. The data obtained on digit span subtests did not achieve statistical significance. In this investigation we found clinically recovered depressive subjects to show deficits on verbal memory tasks compared with the control group. Although depressive symptoms remitted, we observed the selective impairment on free recall (both, immediate and delayed), but almost intact recognition. Such a pattern suggests information that has been encoded, but a selective impairment in the search and scanning process required for active recall of material, that is a particular difficulty in organizing cognitive operations necessary for successful research and retrieval. The concept of cognitive effort deficits could also be invoked. References [l] Tarbuck AF, Paykel ES (1995) Effects of major depression on the cognitive function of younger and older subjects. Psycho1 Med, 25, 285-295. [Z] Ilsley JE, Moffoot AP, O’Carroll RE (1995) An analysis of memory dysfunction in major depression. J Affect Disord, 35, l-9.
Interaction of tricyclic antidepressants liposomes
with
Z. FiSar. Charles University, Department of Psychiatry, Prague, Czech Republic Study of the mechanisms of action of antidepressants is stimulated by an effort to understand the molecular basis of affective disorders. The attention given to the interactions of tricyclic antidepressants (TCA) with the lipid component of biological membranes followed from long-term experiments seeking to explain the therapeutic effects of these drugs by blocking the function of neurotransmitter transporters, and from observations of the action of antidepressants on receptors, ion channels, second messengers systems and enzymes, which are often dependent on specific lipidprotein interactions. All these reasons make it imperative to study also the interactions of TCA with liposomes as models of the lipid part of biological membranes. Our study was designed to investigate the interactions of tricyclic antidepressants (imipramine, desipramine and amitriptyline) with phosphatidylcholine-, phosphatidylserine- and phosphatidylinositol-derived multilamellar liposomes. The contribution of various types of physical forces to the binding of these drugs in charged and uncharged forms was estimated. The temperature-, Cazf- and pH-dependencies of binding, binding kinetics, saturation and competition curves were measured. Methods: Large multilamellar vesicles were prepared using Bangham method from phosphatidylcholine, phosphatidylserine and phosphatidylinositol. Radioligand binding method was employed. The following tritium-labelled ligands were used: [3H]imipramine, [3H]desipramine and [3H]amitriptyline. To separate bound from free ligand, centrifugation and rapid filtration were employed The parameters of binding isotherms were determined by non-linear regression analysis and partition coefficients were calculated. Displacement curves were analysed using the fourparametric logistic model to establish the values cold ligand concentrations displacing 50% of bound radioligand. Results: 1. Data analysis shown that the dependencies bound on tiee ligand argues for existence of two isothermal binding processes with higher (lo+ M) and lower (10m8 M) dissociation constants values. 2. Antidepressants binding to phosphatidylserine liposomes were markedly higher than to phosphatidylcholine membranes across the whole range of concentrations used. 3. The contribution of Coulomb interactions to total TCA binding was estimated based on the measurement of pH-dependent binding. Conclusion: It was concluded that 1. binding of TCA to lipid bilayers is heterogeneous, essentially, surface adsorption and incorporation of molecules into the bilayer can be seen and characterized; 2. at low ligand concentrations, they are predominantly uncharged molecules which tend to bind into phosphatidylcholine membranes; 3. binding to phosphatidylserine liposomes is determined mainly by Coulomb and ion-induced dipole interactions between drugs and serine groups. The hypothesis assuming a role of the lipid-protein interaction in the mechanism of action of tricyclic antidepressants has been supported.
I?1 Affective disorders andantidepressants
References
Ip.1.1291
[l] Reynaert et al. Acta Psychiat &and. 1995, 9: 224 [2] Kovti H. et al. Proc. Royal Micr. Sot., 1995, 30 (Pt2): 123. [3] Jain N. et al., Brit. J. Pharmacol., 1995, 116: 2127.
Ip.1.1281
Verbal memory deficits associated unipolar affective disorder
with
S. Totic, D. Marinkovic, N. Marie, S. Brankovic, M. JasovicGasic *, VR. Paunovic. Institute of Psychiatry, Clinical Center of Serbia, PAsterova 2, Belgrade Although the affective symptoms are defining characteristic of depression, cognitive impairments have also been repeatedly demonstrated (1). Individuals diagnosed as depressed have often reported problems with memory and concentration and recent research has clearly established that memory functioning appears to be impaired in depression (2). Numerous researchers have found a variety of mnemonic deficits in depression in short-and long-term memory, in both verbal and visuospatial areas, and episodic and semantic, explicit and implicit memory, as well. On the other hand, there is a little evidence about performance that characterizes mnemonic functioning of depressive individuals in the phase of clinical recovery. According to this, the aim of the current study was to investigate performance on verbal memory tasks, using tasks such as free recall and recognition memory in subjects diagnosed with unipolar depression, in remission. Forty-three subjects participated in the study: 22 depressed patients with unipolar affective disorder, in remission (UP) and 20 normal controls (NC). The mini-mental state examination (MMSE) was employed as a brief global cognitive screening test, to detect the presence of significant generalized cognitive impairment. To evaluate the pattern of memory problems, the subjects were administered the Rey Auditory Verbal Learning Test (RAVLT) and the digit span subtests, verbal pairs associates and logical memory from Wechsler Memory Scale - revised (WMS-R). The two groups did not differ on level of overall cognitive functioning as assessed by MMSE. Group comparisons also indicated that the NC group recalled significantly more words and demonstrated significantly more improvement from trial to trial than did the UP. There was no significant difference between groups in the number of correctly recognized words. The data obtained on digit span subtests did not achieve statistical significance. In this investigation we found clinically recovered depressive subjects to show deficits on verbal memory tasks compared with the control group. Although depressive symptoms remitted, we observed the selective impairment on free recall (both, immediate and delayed), but almost intact recognition. Such a pattern suggests information that has been encoded, but a selective impairment in the search and scanning process required for active recall of material, that is a particular difficulty in organizing cognitive operations necessary for successful research and retrieval. The concept of cognitive effort deficits could also be invoked. References [l] Tarbuck AF, Paykel ES (1995) Effects of major depression on the cognitive function of younger and older subjects. Psycho1 Med, 25, 285-295. [Z] Ilsley JE, Moffoot AP, O’Carroll RE (1995) An analysis of memory dysfunction in major depression. J Affect Disord, 35, l-9.
Interaction of tricyclic antidepressants liposomes
with
Z. FiSar. Charles University, Department of Psychiatry, Prague, Czech Republic Study of the mechanisms of action of antidepressants is stimulated by an effort to understand the molecular basis of affective disorders. The attention given to the interactions of tricyclic antidepressants (TCA) with the lipid component of biological membranes followed from long-term experiments seeking to explain the therapeutic effects of these drugs by blocking the function of neurotransmitter transporters, and from observations of the action of antidepressants on receptors, ion channels, second messengers systems and enzymes, which are often dependent on specific lipidprotein interactions. All these reasons make it imperative to study also the interactions of TCA with liposomes as models of the lipid part of biological membranes. Our study was designed to investigate the interactions of tricyclic antidepressants (imipramine, desipramine and amitriptyline) with phosphatidylcholine-, phosphatidylserine- and phosphatidylinositol-derived multilamellar liposomes. The contribution of various types of physical forces to the binding of these drugs in charged and uncharged forms was estimated. The temperature-, Cazf- and pH-dependencies of binding, binding kinetics, saturation and competition curves were measured. Methods: Large multilamellar vesicles were prepared using Bangham method from phosphatidylcholine, phosphatidylserine and phosphatidylinositol. Radioligand binding method was employed. The following tritium-labelled ligands were used: [3H]imipramine, [3H]desipramine and [3H]amitriptyline. To separate bound from free ligand, centrifugation and rapid filtration were employed The parameters of binding isotherms were determined by non-linear regression analysis and partition coefficients were calculated. Displacement curves were analysed using the fourparametric logistic model to establish the values cold ligand concentrations displacing 50% of bound radioligand. Results: 1. Data analysis shown that the dependencies bound on tiee ligand argues for existence of two isothermal binding processes with higher (lo+ M) and lower (10m8 M) dissociation constants values. 2. Antidepressants binding to phosphatidylserine liposomes were markedly higher than to phosphatidylcholine membranes across the whole range of concentrations used. 3. The contribution of Coulomb interactions to total TCA binding was estimated based on the measurement of pH-dependent binding. Conclusion: It was concluded that 1. binding of TCA to lipid bilayers is heterogeneous, essentially, surface adsorption and incorporation of molecules into the bilayer can be seen and characterized; 2. at low ligand concentrations, they are predominantly uncharged molecules which tend to bind into phosphatidylcholine membranes; 3. binding to phosphatidylserine liposomes is determined mainly by Coulomb and ion-induced dipole interactions between drugs and serine groups. The hypothesis assuming a role of the lipid-protein interaction in the mechanism of action of tricyclic antidepressants has been supported.