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Psychological functions of forebrain serotonin: evidence from animal studies
177
Symposia S-1
Dimensional Psychopharmacology: A Serotonin Link
Monday, 19 October 1992
Psychological functions of forebrain serotonin: evidence from animal studies
E v e r i t t , B.J. Department of Anatomy, University of Cambridge, Downing Street, Cambridge, CB2 3DY, U.K.
Key words: Serotonin; Raphe; Leaming; Memory; Anxiety; Fear There is now considerable evidence that certain forms of depression and anxiety are associated with alterations in central serotoninergic function. However, it is unclear whether these changes in central serotonin (5-HT) activity contribute to the somatic, behavioural or cognitive components of these conditions. In experimental studies, considerable evidence now indicates that 5-HT is involved especially in somatic and behavioural functions, such as the control of sleep, feeding, sexual behaviour, aggression, nociception and flight. Some of these behavioural effects can be unified by the hypothesis that serotonin is implicated in behavioural inhibition and it has been suggested that the main effect of antidepressant and anxiolytic drugs with predominantly serotoninergic modes of action is on this process. However, such a singular view is hard to sustain in the face of growing evidence that 5-HT systems may directly modulate cognitive processes such as learning, memory and the control of selective attention. Much of the early experimental analysis of the role of 5-HT systems in learning and memory has focused on aversive processes, but has produced inconsistent results. For example, various lesions of the 5-HT-containing neurons of the raphe have been shown to improve, to impair or nor to affect learning of an active avoidance task, where changes in behaviour could in any case reflect more general effects on sensory reactivity or behavioural inhibition. However, there is now considerable evidence linking 5-HT function to the formation of aversive memories that cannot readily be explained in these terms. For example, post-training administration of 5-HT receptor antagonists has been reported to improve memory of a previously learned aversive response and to attenuate deficits in passive avoidance retention normally seen in aged rats. A preponderance of evidence is consistent with the view that pharmacological manipulations that increase 5-HT activity in the brain interfere with aversive learning and memory. However, this leaves open the question of functional effects and the role of fluctuations in central 5-HT in the untreated animal. Whereas behavioural inhibition has obvious adaptive consequences in a variety contexts, it is more difficult to discern the adaptive value of a system, the activity of which appears to inhibit cognitive function in highly stressful situations. Furthermore, the recent reports of profound alterations in such cognitive functions in appetitive tasks argue that a unitary role restricted to aversive situations is no longer tenable Thus, central 5-HT depletion, or more focal depletion of hippocampal 5-HT, produced large improvements in the acquisition of the Stone maze, a reference memory task which requires learning a specific route to food. These effects appear difficult to explain in terms of altered sensory reactivity or behavioural inhibition. However, there have also been some discrepant findings: chronic treatment with the 5-HT 2 receptor antagonist ketanserin immediately following each daily training session on the Stone maze task have been reported to impair learning, whereas systemic administration of the 5-HTIA receptor agonist, 8-OH-DPAT, impaired acquisition of the Morris water maze and radial 8 arm maze. The basis for these discrepancies is not uniformly clear, but probably depends in large part upon assumptions about how and where the drug used actually affect 5-HT mechanisms (e.g. 5-HTIA agonists may interact with both postsynaptic and raphe somatodendritic receptors which have opposing regulatory roles in 5-HT function), differences in the precise cognitive demands of the tasks used (e.g. spatial versus non spatial) and their controlling neural substrates (e.g. neocortex, hippocampus, amygdala and striatum) which may receive distinct 5-HT inputs from dorsal or median raphe nuclei.
178 In our own recent work, intracerebroventricular 5,7-DHT leading to profound forebrain 5-HT depletion has also been found to enhance the acquisition of a conditional visual discrimination (CVD), the neural substrates of which we have also elucidated. Thus, medial prefrontal, cingulate and striatal, but not hippocampal or amygdala lesions retard the acquisition of the CVD, suggesting the existence of a neural system mediating the learning of this typical procedural (i.e. stimulus-response) task. Post-acquisition, the rats with 5-HT depletion were actually worse than controls when a 3 second delay was introduced between the presentation of the stimulus and the opportunity to respond, suggesting impairments of working memory that we also observe following hippocampal lesions in this task. Thus, in the same experiment we have shown apparently opposite effects of global forebrain 5-HT depletion on learning and short-term memory that are difficult to explain in the unitary terms of, for example, a theory of behavioural inhibition. The functions of the forebrain 5-HT systems must also be considered in comparison with those of other chemically-defined, "non-specific' afferents to telencephalic structures e.g., acetylcholine (ACh), noradrenaline (NA) and dopamine (DA), in order to discern the distinct contributions of each to cognitive processing. For example, acquisition of the CVD is impaired by cortical (primarily cingulate) noradrenergic depletion, striatal dopamine depletion and reductions in cholinergic activity in the cingulate cortex. A particularly apt comparison is with the noradrenergic projections arising from the locus coeruleus which also project diffusely over the neuraxis through widely branching axons that can simultaneously affect information processing in diverse terminal domains, including the neocortex, hippocampus, amygdala and diencephalon. There is also increasing evidence that the functions of serotoninergic systems have to be studied in the context of their interactions with these other systems; for example, there appears to be a mutual antagonism of the noradrenergic and serotoninergic systems, through the presence of inhibitory 5-HT 2 receptors on locus coeruleus cell bodies and the inhibitory effects of 0t2 adrenoceptors on activity in the dorsal raphe nucleus. This would suggest in some instances that the effects of forebrain NA and 5-HT depletion would be in opposing directions, as we have seen with the opposite effects of forebrain NA and 5-HT depletion on the acquisition of the CVD described above. Some evidence also supports the hypothesis that there is a special interaction between 5-HT and ACh in tests of learning and memory. Studies of the functions of forebrain 5-HT systems are at a crucial stage and have yet to result in encompassing functional hypotheses. The requirements of such hypotheses will be discussed in this presentation.
Functional investigation in psychiatry using single photon emission tomography with 99mTc-exametazime
Goodwin, G.M. MRC Brain Metabolism Unit, Royal Edinburgh Hospital, Morningside Park, Edinburgh, EHIO 5HF, U.K. Key words: Affective disorders; 5-Hydroxytryptamine; Single photon emission tomography (SPET or SPECT)
The demand for metabolic substrate of different brain regions is usually yoked tightly to regional cerebral blood flow. A tomographic estimate of regional cerebral blood flow in man can be made by single photon emission tomography (SPET or SPECT) with 99mTc-cxametazime, an intravenous ligand taken into brain in proportion to local tissue perfusion. Accordingly, the method provides a measure of regional brain function. Together with selective SPET ligands for receptor binding sites, the approach comprises a two-pronged technique for pharmacological investigation in man. It allows the identification of the regional topography characteristic of particular psychiatric syndromes and promises to shed light on how treatments serve to modify function in these and other brain areas. In principle, it promises to allow a much more rigorous examination of theories that propose the involvement of an individual neurotransmitter such as 5-hydroxytryptamine (5-HT) in the expression or treatment of particular diseases or their component symptoms. For example, 40 patients with a major depressive episode were investigated at rest using SPET. All patients ere unipolar and were rated on the Newcastle scale and with the 17-item Hamilton scale. They also completed a range of neuro-
Symposia S-1
Dimensional Psychopharmacology: A Serotonin Link
Monday, 19 October 1992
Psychological functions of forebrain serotonin: evidence from animal studies
E v e r i t t , B.J. Department of Anatomy, University of Cambridge, Downing Street, Cambridge, CB2 3DY, U.K.
Key words: Serotonin; Raphe; Leaming; Memory; Anxiety; Fear There is now considerable evidence that certain forms of depression and anxiety are associated with alterations in central serotoninergic function. However, it is unclear whether these changes in central serotonin (5-HT) activity contribute to the somatic, behavioural or cognitive components of these conditions. In experimental studies, considerable evidence now indicates that 5-HT is involved especially in somatic and behavioural functions, such as the control of sleep, feeding, sexual behaviour, aggression, nociception and flight. Some of these behavioural effects can be unified by the hypothesis that serotonin is implicated in behavioural inhibition and it has been suggested that the main effect of antidepressant and anxiolytic drugs with predominantly serotoninergic modes of action is on this process. However, such a singular view is hard to sustain in the face of growing evidence that 5-HT systems may directly modulate cognitive processes such as learning, memory and the control of selective attention. Much of the early experimental analysis of the role of 5-HT systems in learning and memory has focused on aversive processes, but has produced inconsistent results. For example, various lesions of the 5-HT-containing neurons of the raphe have been shown to improve, to impair or nor to affect learning of an active avoidance task, where changes in behaviour could in any case reflect more general effects on sensory reactivity or behavioural inhibition. However, there is now considerable evidence linking 5-HT function to the formation of aversive memories that cannot readily be explained in these terms. For example, post-training administration of 5-HT receptor antagonists has been reported to improve memory of a previously learned aversive response and to attenuate deficits in passive avoidance retention normally seen in aged rats. A preponderance of evidence is consistent with the view that pharmacological manipulations that increase 5-HT activity in the brain interfere with aversive learning and memory. However, this leaves open the question of functional effects and the role of fluctuations in central 5-HT in the untreated animal. Whereas behavioural inhibition has obvious adaptive consequences in a variety contexts, it is more difficult to discern the adaptive value of a system, the activity of which appears to inhibit cognitive function in highly stressful situations. Furthermore, the recent reports of profound alterations in such cognitive functions in appetitive tasks argue that a unitary role restricted to aversive situations is no longer tenable Thus, central 5-HT depletion, or more focal depletion of hippocampal 5-HT, produced large improvements in the acquisition of the Stone maze, a reference memory task which requires learning a specific route to food. These effects appear difficult to explain in terms of altered sensory reactivity or behavioural inhibition. However, there have also been some discrepant findings: chronic treatment with the 5-HT 2 receptor antagonist ketanserin immediately following each daily training session on the Stone maze task have been reported to impair learning, whereas systemic administration of the 5-HTIA receptor agonist, 8-OH-DPAT, impaired acquisition of the Morris water maze and radial 8 arm maze. The basis for these discrepancies is not uniformly clear, but probably depends in large part upon assumptions about how and where the drug used actually affect 5-HT mechanisms (e.g. 5-HTIA agonists may interact with both postsynaptic and raphe somatodendritic receptors which have opposing regulatory roles in 5-HT function), differences in the precise cognitive demands of the tasks used (e.g. spatial versus non spatial) and their controlling neural substrates (e.g. neocortex, hippocampus, amygdala and striatum) which may receive distinct 5-HT inputs from dorsal or median raphe nuclei.
178 In our own recent work, intracerebroventricular 5,7-DHT leading to profound forebrain 5-HT depletion has also been found to enhance the acquisition of a conditional visual discrimination (CVD), the neural substrates of which we have also elucidated. Thus, medial prefrontal, cingulate and striatal, but not hippocampal or amygdala lesions retard the acquisition of the CVD, suggesting the existence of a neural system mediating the learning of this typical procedural (i.e. stimulus-response) task. Post-acquisition, the rats with 5-HT depletion were actually worse than controls when a 3 second delay was introduced between the presentation of the stimulus and the opportunity to respond, suggesting impairments of working memory that we also observe following hippocampal lesions in this task. Thus, in the same experiment we have shown apparently opposite effects of global forebrain 5-HT depletion on learning and short-term memory that are difficult to explain in the unitary terms of, for example, a theory of behavioural inhibition. The functions of the forebrain 5-HT systems must also be considered in comparison with those of other chemically-defined, "non-specific' afferents to telencephalic structures e.g., acetylcholine (ACh), noradrenaline (NA) and dopamine (DA), in order to discern the distinct contributions of each to cognitive processing. For example, acquisition of the CVD is impaired by cortical (primarily cingulate) noradrenergic depletion, striatal dopamine depletion and reductions in cholinergic activity in the cingulate cortex. A particularly apt comparison is with the noradrenergic projections arising from the locus coeruleus which also project diffusely over the neuraxis through widely branching axons that can simultaneously affect information processing in diverse terminal domains, including the neocortex, hippocampus, amygdala and diencephalon. There is also increasing evidence that the functions of serotoninergic systems have to be studied in the context of their interactions with these other systems; for example, there appears to be a mutual antagonism of the noradrenergic and serotoninergic systems, through the presence of inhibitory 5-HT 2 receptors on locus coeruleus cell bodies and the inhibitory effects of 0t2 adrenoceptors on activity in the dorsal raphe nucleus. This would suggest in some instances that the effects of forebrain NA and 5-HT depletion would be in opposing directions, as we have seen with the opposite effects of forebrain NA and 5-HT depletion on the acquisition of the CVD described above. Some evidence also supports the hypothesis that there is a special interaction between 5-HT and ACh in tests of learning and memory. Studies of the functions of forebrain 5-HT systems are at a crucial stage and have yet to result in encompassing functional hypotheses. The requirements of such hypotheses will be discussed in this presentation.
Functional investigation in psychiatry using single photon emission tomography with 99mTc-exametazime
Goodwin, G.M. MRC Brain Metabolism Unit, Royal Edinburgh Hospital, Morningside Park, Edinburgh, EHIO 5HF, U.K. Key words: Affective disorders; 5-Hydroxytryptamine; Single photon emission tomography (SPET or SPECT)
The demand for metabolic substrate of different brain regions is usually yoked tightly to regional cerebral blood flow. A tomographic estimate of regional cerebral blood flow in man can be made by single photon emission tomography (SPET or SPECT) with 99mTc-cxametazime, an intravenous ligand taken into brain in proportion to local tissue perfusion. Accordingly, the method provides a measure of regional brain function. Together with selective SPET ligands for receptor binding sites, the approach comprises a two-pronged technique for pharmacological investigation in man. It allows the identification of the regional topography characteristic of particular psychiatric syndromes and promises to shed light on how treatments serve to modify function in these and other brain areas. In principle, it promises to allow a much more rigorous examination of theories that propose the involvement of an individual neurotransmitter such as 5-hydroxytryptamine (5-HT) in the expression or treatment of particular diseases or their component symptoms. For example, 40 patients with a major depressive episode were investigated at rest using SPET. All patients ere unipolar and were rated on the Newcastle scale and with the 17-item Hamilton scale. They also completed a range of neuro-