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Buspirone and related compounds as alternative anxiolytics
Neuropeptides (1991) 19, (Suppl.) 15-19 0 Longman Group UK Ltd 1991
Buspirone and Related Compounds as Alternative Anxiolytics D. P. TAYLOR and S. L. MOON CNS Biology Wallingford,
(404), Pharmaceutical Research Institute, Bristol-Myers CT 06492-7660 USA (Reprint requests to DPT)
Squibb
Company,
PO Box 5100,
Abstract-The desire of the pharmaceutical industry to obtain more selective agents for the treatment of anxiety with fewer or diminished side effects and a profile consistent with safety during long-term use resulted in a search which has identified the azapirones as a new class of anxiolytics which lack structural or biochemical homology with the benzodiazepines. This presentation reviews the efficacy of buspirone (BuSpar@), the first of this class to reach wide acceptance, and its analogs, gepirone, ipsapirone, and tandospirone, in the clinical treatment of anxiety and compares their ‘anxioselective’ profiles to those of the benzodiazepines. The azapirones appear to act as serotonin ~-HTIA partial agonists as they all share high affinity for 5-HTIn binding sites in vitro as well as in anatomical studies. Moreover, their biochemical, electro-physiological, and behavioural actions are consistent with this suggestion. That the serotonergic actions of the azapirones are relevant to their anxiolytic efficacy is suggested by their efficacy in animal models sensitive to other effective anxiolytics as well as their loss of efficacy in such testing following lesions of serotonergic neurons. Thus action upon serotonergic neurotransmission may produce a highly desirable anxioselective profile of effects.
Iutroduction
effects (sedation, impairment of psychomotor performance and memory, interactions with other CNS depressants, development of tolerance and dependence with long-term use, potential liability for abuse). The desire of the pharmaceutical industry to obtain more selective agents for the treatment of anxiety with fewer or diminished side effects and a profile consistent with safety during long-term use resulted in a search which has identified the azapirones as a new class of anxiolytics which lack structural or biochemical homology with the benzodiazepines.
Agents which influence y-aminobutyric acid (GABA) receptors, such as benzodiazepines, propanediol carbamates, and barbiturates, have long been used for the treatment of anxiety. While these agents represent a progression in safety margin compared to historical treatments such as alcohol, belladonna, bromides, and opiates, they possess ancillary properties which are unnecessary or undesirable (anticonvulsant action, muscle relaxation) as well as potentially dangerous side 15
16
NEUROPEPTIDES
R-(CH,),-N
R
NAME
R
NAME
Buupirone (BuSpar R )
c 0
N-
Gleplrone
0
N
N- Tandoapirone .
0
Fig. 1 Structures of azapirone anxiolytic agents.
Clinical studies of azapirones
The first of this new class to be identified was buspirone (BuSpar@, Fig. 1) (1). Like benzodiazepines, buspirone was clinically effective in doubleblind, placebo-controlled trials for the treatment of generalised anxiety disorder (GAD, see refs 1 and 2 for review). In contrast to the benzodiazepines, patients receiving buspirone suffered significantly less from undesirable side effects, such as feelings of sedation, drowsiness, tiredness, and fatigue. In fact, clinical trials in nearly 1000 patients receiving buspirone revealed an incidence of these side effects comparable to that seen with placebo alone (2). Buspirone did not impair daytime wakefulness, sleep structure, or memory function or produce muscle relaxation, psychomotor impairment, or any greater incidence or kinds of side effects in elderly patients compared to younger patients (2). Abrupt cessation of buspirone therapy, following treatment for periods even as long as 1 year, was not associated with the induction of ‘rebound anxiety’, a common indica-
tor of dependence phenomena seen with chronic benzodiazepine treatment (1, 2). In addition, buspirone failed to exhibit any potential for abuse in sedative/hypnotic abusers or in alcohol-dependent anxious patients (2). These and other observations led us to describe the clinical profile of buspirone as ‘anxioselective’ when compared to the benzodiazepines (3). Other azapirone agents are at various stages in their development (1, 2). Three of these, gepirone, ipsapirone, and tandospirone (Fig. l), are undergoing clinical trials for the treatment of GAD. Preliminary evidence of efficacy for these agents in early trials has been obtained with a side effect profile similar to that of buspirone (2). Although the specialised kinds of safety trials conducted with buspirone have either not yet been conducted with these newer agents or the results await publication, it may be anticipated that these drugs will share buspirone’s anxioselective profile since their pre-clinical profiles bear so much in common.
BUSPIRONE
AND RELATED
COMPOUNDS
AS ALTERNATIVE
17
ANXIOLYTICS
Partial agonist activity of azapirones at the serotonin-sensitive hippocampus
Table
forskolin-stimulated
adenylate cyclase in rat
Inhibition of 5-HTI, binding in vitro,
Compound
Znhibirion of adenylate cyclase activity, EC50 (nM)”
DPAT
Z&o, (nM) Intrinsic activity”
25
Serotonin Ipsapirone
110 100 170 200b 1000
Buspirone Tandospirone Gepirone
1.0 1.0 0.9
0.5 0.6b 0.8
13H]DPAT
[3H]Tandospironeb
2.9
0.3
4.2 7.1
0.6
31 30’ 180
1.1 5.6 7.6 80
‘Data from ref. 5, except as noted bData from ref. 4 ‘Data from ref. 6
Interaction
of azapirones with serotonin
The azapirones do not share any structural similarity with the benzodiazepines, so it is not surprising that they fail to inhibit binding to the site labelled by [3H]benzodiazepines (l-4). However, all of these compounds block binding at 5-HT1* receptor sites in vitro (1, 2, 4-6; see Table). In addition, studies of the anatomical localisation of radiolabelled azapirones reveal that buspirone, gepirone, ipsapirone, and tandospirone densely label the same structures in the limbic system, such as the amygdala, lateral septum, entorhinal cortex, and the hippocampal formation, which exhibit high affinity for serotonin or specific .5-HT1* ligands such as %hydroxy-di-N-propylaminotetralin (DPAT, 7-10). A striking example of this was seen in the comparison of labelling of human brain tissue by [3H]buspirone and [3H] serotonin (Fig. 2). Both ligands label the dentate gyrus and the same structures within the parahippocampal region, portions of the limbic system enriched in 5-HT1A receptors. Furthermore, biochemical studies of subcellular physiology reveal that these compounds are partial agonists at the serotonin-sensitive, forskolin-stimulated adenylate cyclase in rat hippocampus, and their ability to attenuate the stimulation of the enzyme is correlated with their affinity for the 5-HT1* receptor (Table). Another functional measure in which azapirones are active is the attenuation of firing of serotonergic neurons in the dorsal raphe nucleus
(1,6). In CA1 hippocampal pyramidal cells, buspirone, gepirone and ipsapirone act as partial agonists at a subpopulation of serotonin receptors (11). Consistent with the suppression of serotonergic neuronal firing in raphe nuclei by azapirones is the observation that these agents decrease the hippocampal levels of the serotonin metabolite 5-HIAA (12).
Like the benzodiazepines, the azapirones are active in pre-clinical models of anxiety such as conflict paradigms or the potentiated startle response, and these activities are also seen with the specific 5-HT1* agonist DPAT (1, 2, 13). Additional evidence that the azapirones affect the serotonergic system specifically is demonstrated by their ability to generalise in animals trained to discriminate DPAT or azapirones (1, 5, 14). An elegant example of the dependence of the azapirones (as well as of the benzodiazepines) upon an intact serotonergic system for their activity in a pre-clinical model of anxiety, the conflict test, was the demonstration that selective ablation of serotonergic neurons by the use of specific neurotoxins abolished the anticonflict activity of buspirone and gepirone (15). That clinically effective anxiolytics, such as the azapirones as well as the benzodiazepines, might produce their therapeutic benefit by action upon the serotonergic systems of the brain is an old concept which is seeing renewed interest and wider support (see refs 1 and 2 and reviews cited therein).
NEUROPEFTIDES
Summary
The side effects and unwanted or unnecessary ancillary pharmacologic properties of benzodiazepine anxiolytic drugs resulted in a continuing search for new agents with improved profiles of activity. Buspirone was the first novel drug, identified as safe and effective in the treatment of GAD, to emerge from this search in almost 30 years. The structurally related azapirones, gepirone, ipsapirone, and tandospirone, appear to share the anxioselective profile of buspirone. Investigations into the mechanism of action of the azapirones indicate that these agents have no direct effects upon the benzodiazepine receptor/GABA receptor/chloride ionophore complex. Rather, these agents act upon serotonergic neurotransmission, and this action is evidenced by the pharmacology of receptor binding interactions, the anatomic localisation of radioligand binding, the neurochemical actions evoked by these agents, the neurophysiologic effects which result, and the behavioural patterns which are observed. These findings support a key role for serotonin as one of the neurobiological substrates of anxiety and its treatment. As new drugs, these agents constitute a significant alternative to previous pharmacotherapies for this disorder. Acknowledgments
Fig. 2 In vitro autoradiography of human brain through the dentate gyrus and parahippocampal region. Tissues were obtained from a 70-year-old male who died of cardiac arrest. No gross neuropathology was observed at autopsy. A. Labelling with [3H]buspirone: Tissues were pre-treated for 15min at 4°C in 50mM HepesKOH, pH 7.4, with 1% bovine serum albumin (BSA). Subsequently, tissues were incubated with 12nM [3H]buspirone (71.5 Ci/mmol, New England Nuclear, Boston) in 50mM HepesKOH, pH 7.4, with 1% BSA and 2mM Cat& for 35min at 22°C. Non-specific binding was defined by the presence of 1OOuM unlabelled buspirone; specific binding was 70%. B. Labelling with [3H]serotonin: Tissues were pre-treated for 30min at 4°C in 170mM TrisHCl, pH 7.4, with 4mM Cat& followed by incubation for 1 h at 22°C with 2nM [3H]serotonin (27.3 Wmmol, New England Nuclear) in 170mM Tris.HCI, pH 7.4, with 4mM CaCla, 10t~M pargyline, 0.001% ascorbic acid, and 1 uM fluoxetine. Non-specific binding was defined by the presence of lt.~M unlabelled serotonin; specific binding was 75%.
We are grateful to our colleagues and friends, Drs Arlene Eison, Michael Eison, Cam VanderMaelen, and Frank Yocca, for their insight, assistance, criticism, and support. We are indebted to Jeanne Stockla and Marj Haas for artwork and manuscript preparation. We regret that space did not permit citation of all original contributors to the studies reviewed here. References Taylor, D. P. (1988) Buspirone, a new approach to the treatment of anxiety. FASEB Journal 2: 2445-2452. Taylor, D. P. (1990) Serotonin agents in anxiety. Annals of the New York Academy of Sciences, in press. Taylor, D. P., Hyslop, D. K. and Riblet, L. A. (1980) Buspirone: model for anxioselective drug action. Society for Neuroscience Abstracts 6: 791. Hamik, A., Oksenburg, D., Fischette, C. and Peroutka, S. J. (1990) Analysis of tandospirone (SM-3997) interactions
BUSPIRONE AND RELATED COMPOUNDS AS ALTERNATIVE
5.
6.
7.
8.
9.
10.
with neurotransmitter receptor binding sites. Biological Psychiatry 28: 99-109. Yocca, F. D., Smith, D. W., Hyslop, D. K. and Maayani, S. (1986) Dissociation of efficacy from affinity at the 5-HTiA receptor in rat hippocampal preparation. Society for Neuroscience Abstracts 12: 422. Seymour, P. A., Mena, E. E., McLean, S. and Heym, J. (1989) Pharmacology of the serotonergic anxiolytic tandospirone (SM-3997). In: Current and Future Trends in Anticonvulsant, Stroke and Anxiety Therapy. Abstracts of the First Princeton Drug Research Symposium, p.33. Moon, S. L. andTaylor, D. P. (1985) Invivo autoradiography of 3H-buspirone and 3H-2-deoxyglucose after buspirone administration. Society for Neuroscience Abstracts 11: 114. Bennett, J. E. and Matheson, G. K. (1990) Autoradiographic localisation of [3H] gepirone in the rat brain. FASEB Journal 4: A617. Traber, J. and Glaser, T. (1987) 5-HTiA receptor-related anxiolytics. Trends in Pharmacological Sciences 8: 432437. Shimizu, H., Tatsuno, T., Hirose, A., Tanaka, H., Kumasuka, Y. and Nakamura, M. (1988) Characterization of the
ANXIOLYTICS
19
putative anxiolytic SM-3997 recognition sites in rat brain. Life Sciences 2: 2419-2427. 11. Andrade, R. and Nicoll, R. A. (1987) Novel anxiolytics discriminate between postsynaptic serotonin receptors mediating different physiological responses on single neurons of rat hippocampus. Naunyn-Schmiedeberg’s Archives of Pharmacology 336: 5-10. 12. Tatsuno, T., Shim&H., Hirose, A., Tanaka, H., Kumasaka, T. and Nakamura, M. (1989) Effects of the putative anxiolytic SM-3997 on central monoaminergic systems. Pharmacology Biochemistry and Behavior 32: 1049-1055. 13. Mansbach, R. S. and Geyer, M. A. (1988) Blockade of potentiated startle responding in rats by %hydroxytryptaminei* receptor ligands. European Journal of Pharmacology 156: 375-383. 14. Glennon. R. A. and Lucki, I. (1988) Behavioural models of serotonin receptor activation. In: Sanders-Bush, E. (ed) The Serotonin Receptors. Humana Press, Clifton, New Jersey, p. 253-293. 1.5. Eison, A. S., Eison, M. S., Stanley, M. and Riblet, L. A. (1986) Serotonergic mechanisms in the behavioural effects of buspirone and gepirone. Pharmacology Biochemistry and Behavior 24: 701-707.
Buspirone and Related Compounds as Alternative Anxiolytics D. P. TAYLOR and S. L. MOON CNS Biology Wallingford,
(404), Pharmaceutical Research Institute, Bristol-Myers CT 06492-7660 USA (Reprint requests to DPT)
Squibb
Company,
PO Box 5100,
Abstract-The desire of the pharmaceutical industry to obtain more selective agents for the treatment of anxiety with fewer or diminished side effects and a profile consistent with safety during long-term use resulted in a search which has identified the azapirones as a new class of anxiolytics which lack structural or biochemical homology with the benzodiazepines. This presentation reviews the efficacy of buspirone (BuSpar@), the first of this class to reach wide acceptance, and its analogs, gepirone, ipsapirone, and tandospirone, in the clinical treatment of anxiety and compares their ‘anxioselective’ profiles to those of the benzodiazepines. The azapirones appear to act as serotonin ~-HTIA partial agonists as they all share high affinity for 5-HTIn binding sites in vitro as well as in anatomical studies. Moreover, their biochemical, electro-physiological, and behavioural actions are consistent with this suggestion. That the serotonergic actions of the azapirones are relevant to their anxiolytic efficacy is suggested by their efficacy in animal models sensitive to other effective anxiolytics as well as their loss of efficacy in such testing following lesions of serotonergic neurons. Thus action upon serotonergic neurotransmission may produce a highly desirable anxioselective profile of effects.
Iutroduction
effects (sedation, impairment of psychomotor performance and memory, interactions with other CNS depressants, development of tolerance and dependence with long-term use, potential liability for abuse). The desire of the pharmaceutical industry to obtain more selective agents for the treatment of anxiety with fewer or diminished side effects and a profile consistent with safety during long-term use resulted in a search which has identified the azapirones as a new class of anxiolytics which lack structural or biochemical homology with the benzodiazepines.
Agents which influence y-aminobutyric acid (GABA) receptors, such as benzodiazepines, propanediol carbamates, and barbiturates, have long been used for the treatment of anxiety. While these agents represent a progression in safety margin compared to historical treatments such as alcohol, belladonna, bromides, and opiates, they possess ancillary properties which are unnecessary or undesirable (anticonvulsant action, muscle relaxation) as well as potentially dangerous side 15
16
NEUROPEPTIDES
R-(CH,),-N
R
NAME
R
NAME
Buupirone (BuSpar R )
c 0
N-
Gleplrone
0
N
N- Tandoapirone .
0
Fig. 1 Structures of azapirone anxiolytic agents.
Clinical studies of azapirones
The first of this new class to be identified was buspirone (BuSpar@, Fig. 1) (1). Like benzodiazepines, buspirone was clinically effective in doubleblind, placebo-controlled trials for the treatment of generalised anxiety disorder (GAD, see refs 1 and 2 for review). In contrast to the benzodiazepines, patients receiving buspirone suffered significantly less from undesirable side effects, such as feelings of sedation, drowsiness, tiredness, and fatigue. In fact, clinical trials in nearly 1000 patients receiving buspirone revealed an incidence of these side effects comparable to that seen with placebo alone (2). Buspirone did not impair daytime wakefulness, sleep structure, or memory function or produce muscle relaxation, psychomotor impairment, or any greater incidence or kinds of side effects in elderly patients compared to younger patients (2). Abrupt cessation of buspirone therapy, following treatment for periods even as long as 1 year, was not associated with the induction of ‘rebound anxiety’, a common indica-
tor of dependence phenomena seen with chronic benzodiazepine treatment (1, 2). In addition, buspirone failed to exhibit any potential for abuse in sedative/hypnotic abusers or in alcohol-dependent anxious patients (2). These and other observations led us to describe the clinical profile of buspirone as ‘anxioselective’ when compared to the benzodiazepines (3). Other azapirone agents are at various stages in their development (1, 2). Three of these, gepirone, ipsapirone, and tandospirone (Fig. l), are undergoing clinical trials for the treatment of GAD. Preliminary evidence of efficacy for these agents in early trials has been obtained with a side effect profile similar to that of buspirone (2). Although the specialised kinds of safety trials conducted with buspirone have either not yet been conducted with these newer agents or the results await publication, it may be anticipated that these drugs will share buspirone’s anxioselective profile since their pre-clinical profiles bear so much in common.
BUSPIRONE
AND RELATED
COMPOUNDS
AS ALTERNATIVE
17
ANXIOLYTICS
Partial agonist activity of azapirones at the serotonin-sensitive hippocampus
Table
forskolin-stimulated
adenylate cyclase in rat
Inhibition of 5-HTI, binding in vitro,
Compound
Znhibirion of adenylate cyclase activity, EC50 (nM)”
DPAT
Z&o, (nM) Intrinsic activity”
25
Serotonin Ipsapirone
110 100 170 200b 1000
Buspirone Tandospirone Gepirone
1.0 1.0 0.9
0.5 0.6b 0.8
13H]DPAT
[3H]Tandospironeb
2.9
0.3
4.2 7.1
0.6
31 30’ 180
1.1 5.6 7.6 80
‘Data from ref. 5, except as noted bData from ref. 4 ‘Data from ref. 6
Interaction
of azapirones with serotonin
The azapirones do not share any structural similarity with the benzodiazepines, so it is not surprising that they fail to inhibit binding to the site labelled by [3H]benzodiazepines (l-4). However, all of these compounds block binding at 5-HT1* receptor sites in vitro (1, 2, 4-6; see Table). In addition, studies of the anatomical localisation of radiolabelled azapirones reveal that buspirone, gepirone, ipsapirone, and tandospirone densely label the same structures in the limbic system, such as the amygdala, lateral septum, entorhinal cortex, and the hippocampal formation, which exhibit high affinity for serotonin or specific .5-HT1* ligands such as %hydroxy-di-N-propylaminotetralin (DPAT, 7-10). A striking example of this was seen in the comparison of labelling of human brain tissue by [3H]buspirone and [3H] serotonin (Fig. 2). Both ligands label the dentate gyrus and the same structures within the parahippocampal region, portions of the limbic system enriched in 5-HT1A receptors. Furthermore, biochemical studies of subcellular physiology reveal that these compounds are partial agonists at the serotonin-sensitive, forskolin-stimulated adenylate cyclase in rat hippocampus, and their ability to attenuate the stimulation of the enzyme is correlated with their affinity for the 5-HT1* receptor (Table). Another functional measure in which azapirones are active is the attenuation of firing of serotonergic neurons in the dorsal raphe nucleus
(1,6). In CA1 hippocampal pyramidal cells, buspirone, gepirone and ipsapirone act as partial agonists at a subpopulation of serotonin receptors (11). Consistent with the suppression of serotonergic neuronal firing in raphe nuclei by azapirones is the observation that these agents decrease the hippocampal levels of the serotonin metabolite 5-HIAA (12).
Like the benzodiazepines, the azapirones are active in pre-clinical models of anxiety such as conflict paradigms or the potentiated startle response, and these activities are also seen with the specific 5-HT1* agonist DPAT (1, 2, 13). Additional evidence that the azapirones affect the serotonergic system specifically is demonstrated by their ability to generalise in animals trained to discriminate DPAT or azapirones (1, 5, 14). An elegant example of the dependence of the azapirones (as well as of the benzodiazepines) upon an intact serotonergic system for their activity in a pre-clinical model of anxiety, the conflict test, was the demonstration that selective ablation of serotonergic neurons by the use of specific neurotoxins abolished the anticonflict activity of buspirone and gepirone (15). That clinically effective anxiolytics, such as the azapirones as well as the benzodiazepines, might produce their therapeutic benefit by action upon the serotonergic systems of the brain is an old concept which is seeing renewed interest and wider support (see refs 1 and 2 and reviews cited therein).
NEUROPEFTIDES
Summary
The side effects and unwanted or unnecessary ancillary pharmacologic properties of benzodiazepine anxiolytic drugs resulted in a continuing search for new agents with improved profiles of activity. Buspirone was the first novel drug, identified as safe and effective in the treatment of GAD, to emerge from this search in almost 30 years. The structurally related azapirones, gepirone, ipsapirone, and tandospirone, appear to share the anxioselective profile of buspirone. Investigations into the mechanism of action of the azapirones indicate that these agents have no direct effects upon the benzodiazepine receptor/GABA receptor/chloride ionophore complex. Rather, these agents act upon serotonergic neurotransmission, and this action is evidenced by the pharmacology of receptor binding interactions, the anatomic localisation of radioligand binding, the neurochemical actions evoked by these agents, the neurophysiologic effects which result, and the behavioural patterns which are observed. These findings support a key role for serotonin as one of the neurobiological substrates of anxiety and its treatment. As new drugs, these agents constitute a significant alternative to previous pharmacotherapies for this disorder. Acknowledgments
Fig. 2 In vitro autoradiography of human brain through the dentate gyrus and parahippocampal region. Tissues were obtained from a 70-year-old male who died of cardiac arrest. No gross neuropathology was observed at autopsy. A. Labelling with [3H]buspirone: Tissues were pre-treated for 15min at 4°C in 50mM HepesKOH, pH 7.4, with 1% bovine serum albumin (BSA). Subsequently, tissues were incubated with 12nM [3H]buspirone (71.5 Ci/mmol, New England Nuclear, Boston) in 50mM HepesKOH, pH 7.4, with 1% BSA and 2mM Cat& for 35min at 22°C. Non-specific binding was defined by the presence of 1OOuM unlabelled buspirone; specific binding was 70%. B. Labelling with [3H]serotonin: Tissues were pre-treated for 30min at 4°C in 170mM TrisHCl, pH 7.4, with 4mM Cat& followed by incubation for 1 h at 22°C with 2nM [3H]serotonin (27.3 Wmmol, New England Nuclear) in 170mM Tris.HCI, pH 7.4, with 4mM CaCla, 10t~M pargyline, 0.001% ascorbic acid, and 1 uM fluoxetine. Non-specific binding was defined by the presence of lt.~M unlabelled serotonin; specific binding was 75%.
We are grateful to our colleagues and friends, Drs Arlene Eison, Michael Eison, Cam VanderMaelen, and Frank Yocca, for their insight, assistance, criticism, and support. We are indebted to Jeanne Stockla and Marj Haas for artwork and manuscript preparation. We regret that space did not permit citation of all original contributors to the studies reviewed here. References Taylor, D. P. (1988) Buspirone, a new approach to the treatment of anxiety. FASEB Journal 2: 2445-2452. Taylor, D. P. (1990) Serotonin agents in anxiety. Annals of the New York Academy of Sciences, in press. Taylor, D. P., Hyslop, D. K. and Riblet, L. A. (1980) Buspirone: model for anxioselective drug action. Society for Neuroscience Abstracts 6: 791. Hamik, A., Oksenburg, D., Fischette, C. and Peroutka, S. J. (1990) Analysis of tandospirone (SM-3997) interactions
BUSPIRONE AND RELATED COMPOUNDS AS ALTERNATIVE
5.
6.
7.
8.
9.
10.
with neurotransmitter receptor binding sites. Biological Psychiatry 28: 99-109. Yocca, F. D., Smith, D. W., Hyslop, D. K. and Maayani, S. (1986) Dissociation of efficacy from affinity at the 5-HTiA receptor in rat hippocampal preparation. Society for Neuroscience Abstracts 12: 422. Seymour, P. A., Mena, E. E., McLean, S. and Heym, J. (1989) Pharmacology of the serotonergic anxiolytic tandospirone (SM-3997). In: Current and Future Trends in Anticonvulsant, Stroke and Anxiety Therapy. Abstracts of the First Princeton Drug Research Symposium, p.33. Moon, S. L. andTaylor, D. P. (1985) Invivo autoradiography of 3H-buspirone and 3H-2-deoxyglucose after buspirone administration. Society for Neuroscience Abstracts 11: 114. Bennett, J. E. and Matheson, G. K. (1990) Autoradiographic localisation of [3H] gepirone in the rat brain. FASEB Journal 4: A617. Traber, J. and Glaser, T. (1987) 5-HTiA receptor-related anxiolytics. Trends in Pharmacological Sciences 8: 432437. Shimizu, H., Tatsuno, T., Hirose, A., Tanaka, H., Kumasuka, Y. and Nakamura, M. (1988) Characterization of the
ANXIOLYTICS
19
putative anxiolytic SM-3997 recognition sites in rat brain. Life Sciences 2: 2419-2427. 11. Andrade, R. and Nicoll, R. A. (1987) Novel anxiolytics discriminate between postsynaptic serotonin receptors mediating different physiological responses on single neurons of rat hippocampus. Naunyn-Schmiedeberg’s Archives of Pharmacology 336: 5-10. 12. Tatsuno, T., Shim&H., Hirose, A., Tanaka, H., Kumasaka, T. and Nakamura, M. (1989) Effects of the putative anxiolytic SM-3997 on central monoaminergic systems. Pharmacology Biochemistry and Behavior 32: 1049-1055. 13. Mansbach, R. S. and Geyer, M. A. (1988) Blockade of potentiated startle responding in rats by %hydroxytryptaminei* receptor ligands. European Journal of Pharmacology 156: 375-383. 14. Glennon. R. A. and Lucki, I. (1988) Behavioural models of serotonin receptor activation. In: Sanders-Bush, E. (ed) The Serotonin Receptors. Humana Press, Clifton, New Jersey, p. 253-293. 1.5. Eison, A. S., Eison, M. S., Stanley, M. and Riblet, L. A. (1986) Serotonergic mechanisms in the behavioural effects of buspirone and gepirone. Pharmacology Biochemistry and Behavior 24: 701-707.