Peter B. Hedlund

5-HT7 Receptor Inhibition and Inactivation Induce Antidepressantlike Behavior and Sleep Pattern

BACKGROUND The 5-hydroxytryptamine7 receptor (5-HT7) is implicated in circadian rhythm phase resetting, and 5-HT7 receptor-selective antagonists alter rapid eye movement (REM) sleep parameters in a pattern opposite from those in patients with clinical depression. METHODS As sleep, circadian rhythm, and mood regulation are related, we examined 5-HT7 receptor knockout mice in two behavioral models of depression. The forced swim and tail suspension tests are highly predictive for antidepressant drug activity. RESULTS Unmedicated 5-HT7-/- mice showed decreased immobility in both tests, consistent with an antidepressantlike behavior. The selective 5-HT7 receptor antagonist SB-269970 also decreased immobility. The selective serotonin reuptake inhibitor citalopram, a widely used antidepressant, decreased immobility in both 5-HT7+/+ and 5-HT7-/- mice in the tail suspension test, suggesting that it utilizes an independent mechanism. The 5-HT7-/- mice spent less time in and had less frequent episodes of REM sleep, also consistent with an antidepressantlike state. CONCLUSIONS The 5-HT7 receptor might have a role in mood disorders and antagonists might have therapeutic value as antidepressants.

Amisulpride is a potent 5-HT7 antagonist: relevance for antidepressant actions in vivo

RationaleAmisulpride is approved for clinical use in treating schizophrenia in a number of European countries and also for treating dysthymia, a mild form of depression, in Italy. Amisulpride has also been demonstrated to be an antidepressant for patients with major depression in many clinical trials. In part because of the selective D2/D3 receptor antagonist properties of amisulpride, it has long been widely assumed that dopaminergic modulation is the proximal event responsible for mediating its antidepressant and antipsychotic properties.ObjectivesThe purpose of these studies was to determine if amisulpride’s antidepressant actions are mediated by off-target interactions with other receptors.Materials and MethodsWe performed experiments that: (1) examined the pharmacological profile of amisulpride at a large number of central nervous system (CNS) molecular targets and, (2) after finding high potency antagonist affinity for human 5-HT7a serotonin receptors, characterized the actions of amisulpride as an antidepressant in wild-type and 5-HT7 receptor knockout mice.ResultsWe discovered that amisulpride was a potent competitive antagonist at 5-HT7a receptors and that interactions with no other molecular target investigated in this paper could explain its antidepressant actions in vivo. Significantly, and in contrast to their wild-type littermates, 5-HT7 receptor knockout mice did not respond to amisulpride in two widely used rodent models of depression, the tail suspension test and the forced swim test.ConclusionsThese results indicate that 5-HT7a receptor antagonism, and not D2/D3 receptor antagonism, likely underlies the antidepressant actions of amisulpride.

The 5-HT7 receptor and disorders of the nervous system: an overview

RationaleThe 5-HT7 receptor is a more recently discovered G-protein-coupled receptor for serotonin. The functions and possible clinical relevance of this receptor are not yet fully understood.ObjectiveThe present paper reviews to what extent the use of animal models of human psychiatric and neurological disorders have implicated the 5-HT7 receptor in such disorders. The studies have used a combination of pharmacological and genetic tools targeting the receptor to evaluate effects on behavior.ResultsModels of anxiety and schizophrenia have yielded mixed results with no clear role for the 5-HT7 receptor described in these disorders. Some data are available for epilepsy, migraine, and pain but it is still very early to draw any definitive conclusions. There is a considerable amount of evidence supporting a role for the 5-HT7 receptor in depression. Both blockade and inactivation of the receptor have resulted in an antidepressant-like profile in models of depression. Supporting evidence has also been obtained in sleep studies. Especially interesting are the augmented effects achieved by combining antidepressants and 5-HT7 receptor antagonists. The antidepressant effect of amisulpride has been shown to most likely be mediated by the 5-HT7 receptor.ConclusionsThe use of pharmacological and genetic tools in preclinical animal models strongly supports a role for the 5-HT7 receptor in depression. Indirect evidence exists showing that 5-HT7 receptor antagonism is clinically useful in the treatment of depression. Available data also indicate a possible involvement of the 5-HT7 receptor in anxiety, epilepsy, pain, and schizophrenia.

No hypothermic response to serotonin in 5-HT7 receptor knockout mice

With data from recently available selective antagonists for the 5-HT7 receptor, it has been hypothesized that 5-hydroxytryptamine (5-HT)-induced hypothermia is mediated by the 5-HT7 receptor, an effect previously attributed to other receptor subtypes. It has been established that the biologically active lipid oleamide allosterically interacts with the 5-HT7 receptor to regulate its transmission. The most well characterized effects of oleamide administration are induction of sleep and hypothermia. Here, we demonstrate, by using mice lacking the 5-HT7 receptor, that 5-HT-induced hypothermia is mediated by the 5-HT7 receptor. Both 5-HT and 5-carboxamidotryptamine, a 5-HT1 and 5-HT7 receptor agonist, in physiological doses fail to induce hypothermia in 5-HT7 knockout mice. In contrast, oleamide was equally effective in inducing hypothermia in mice lacking the 5-HT7 receptors as in wild-type mice. When administered together, 5-HT and oleamide showed additive or greater than additive effects in reducing body temperature. Taken together, the results show that 5-HT-induced hypothermia is mediated by the 5-HT7 receptor, and that oleamide may act through an independent mechanism as well as at an allosteric 5-HT7 receptor site to regulate body temperature.

Serotonin 5-HT7 receptor agents: structure-activity relationships and potential therapeutic applications in central nervous system disorders

Since its discovery in the 1940s in serum, the mammalian intestinal mucosa, and in the central nervous system, serotonin (5-HT) has been shown to be involved in virtually all cognitive and behavioral human functions, and alterations in its neurochemistry have been implicated in the etiology of a plethora of neuropsychiatric disorders. The cloning of 5-HT receptor subtypes has been of importance in enabling them to be classified as specific protein molecules encoded by specific genes. The 5-HT(7) receptor is the most recently classified member of the serotonin receptor family. Since its identification, it has been the subject of intense research efforts driven by its presence in functionally relevant regions of the brain. The availability of some selective antagonists and agonists, in combination with genetically modified mice lacking the 5-HT(7) receptor, has allowed for a better understanding of the pathophysiological role of this receptor. This paper reviews data on localization and pharmacological properties of the 5-HT(7) receptor, and summarizes the results of structure-activity relationship studies aimed at the discovery of selective 5-HT(7) receptor ligands. Additionally, an overview of the potential therapeutic applications of 5-HT(7) receptor agonists and antagonists in central nervous system disorders is presented.

Mice lacking 5-HT7 receptors show specific impairments in contextual learning

Using 5‐HT7 receptor knockout mice it has been shown that the 5‐HT7 receptor is the main mediator of serotonin‐induced hypothermia but very little is known about the relevance of 5‐HT7 receptors in behaviour. We here report that lack of 5‐HT7 receptors leads to a specific learning deficit that is not due to general sensory or behavioural deficits. The knockout mice show impaired contextual fear conditioning but no significant deficits in motor and spatial learning or cued and operant conditioning. In addition, we demonstrate that 5‐HT7 receptor knockout mice display decreased long‐term synaptic plasticity within the CA1 region of the hippocampus. The results indicate an important role for the 5‐HT7 receptor in contextual hippocampal‐dependent learning and suggest a possible neuronal correlate for such a role is present within the CA1 region of the hippocampus.

Receptor-receptor interactions as an integrative mechanism in nerve cells

Several lines of evidence indicate that interactions among transmission lines can take place at the level of the cell membrane via interactions among macromolecules, integral or associated to the cell membrane, involved in signal recognition and transduction. The present view will focus on this last subject, i.e., on the interactions between receptors for chemical signals at the level of the neuronal membrane (receptor-receptor interaction). By receptor-receptor interaction we mean that a neurotransmitter or modulator, by binding to its receptor, modifies the characteristics of the receptor for another transmitter or modulator. Four types of interactions among transmission lines may be considered, but mainly intramembrane receptor-receptor interactions have been dealt with in this article, exemplified by the heteroregulation of D2 receptors via neuropeptide receptors and A2 receptors. The role of receptor-receptor interactions in the integration of signals is discussed, especially in terms of filtration of incoming signals, of integration of coincident signals, and of neuronal plasticity.

The 5-HT7 receptor is involved in allocentric spatial memory information processing

The hippocampus has been implicated in aspects of spatial memory. Its ability to generate new neurons has been suggested to play a role in memory formation. Hippocampal serotonin (5-HT) neurotransmission has also been proposed as a contributor to memory processing. Studies have shown that the 5-HT(7) receptor is present in the hippocampus in relatively high abundance. Thus the aim of the present study was to investigate the possible role of the 5-HT(7) receptor in spatial memory using 5-HT(7) receptor-deficient mice (5-HT(7)(-/-)). A hippocampus-associated spatial memory deficit in 5-HT(7)(-/-) mice was demonstrated using a novel location/novel object test. A similar reduction in novel location exploration was observed in C57BL/6J mice treated with the selective 5-HT(7) receptor antagonist SB-269970. These findings prompted an extended analysis using the Barnes maze demonstrating that 5-HT(7)(-/-) mice were less efficient in accommodating to changes in spatial arrangement than 5-HT(7)(+/+) mice. 5-HT(7)(-/-) mice had specific impairments in memory compilation required for resolving spatial tasks, which resulted in impaired allocentric spatial memory whereas egocentric spatial memory remained intact after the mice were forced to switch back from striatum-dependent egocentric to hippocampus-dependent allocentric memory. To further investigate the physiological bases underlining these behaviors we compared hippocampal neurogenesis in 5-HT(7)(+/+) and 5-HT(7)(-/-) mice employing BrdU immunohistochemistry. The rate of cell proliferation in the dentate gyrus was identical in the two genotypes. From the current data we conclude that the 5-HT(7)(-/-) mice performed by remembering a simple sequence of actions that resulted in successfully locating a hidden target in a static environment.

Evidence for specific N-terminal galanin fragment binding sites in the rat brain

The existence and widespread distribution of specific [125I]galanin-(1-15) fragment binding sites in the rat brain was demonstrated by using [125I]galanin-(1-15) as a radioligand in quantitative receptor autoradiographical studies. These binding sites were also present in several areas lacking or having very few [125I]galanin-(1-29) binding sites, such as the dorsal hippocampal formation, the neocortex and the neostriatum. [125I]Galanin-(1-15) binding sites showed a high selectivity for the fragment, since galanin-(1-15) could displace 80% of the binding whereas porcine galanin-(1-29) could only displace 30%. The binding was saturable with a Kd of 0.63 +/- 0.02 nM and a Bmax of 15.3 +/- 1.7 fmol/mg in sections from the dorsal hippocampal formation. Thus, a new type of galanin receptor selective for N-terminal galanin fragments may exist in the rat brain.

Contribution of spinal 5-HT1A and 5-HT7 receptors to locomotor-like movement induced by 8-OH-DPAT in spinal cord-transected mice

Growing evidence from in vitro studies suggests that spinal serotonin (5‐HT) receptor subtypes 5‐HTR1A and 5‐HTR7 are associated with an induction of central pattern generator activity. However, the possibility of a specific role for these receptor subtypes in locomotor rhythmogenesis in vivo remains unclear. Here, we studied the effects of a single dose (1 mg/kg, i.p.) of 8‐hydroxy‐2‐(di‐N‐propylamino)‐tetralin (8‐OH‐DPAT), a potent and selective 5‐HTR1A/7 agonist, in mice spinal cord transected at the low‐thoracic level (Th9/10). The results show that 8‐OH‐DPAT acutely induced, within 15 min, hindlimb movements that share some characteristics with normal locomotion. Paraplegic mice pretreated with the selective 5‐HTR1A antagonists, WAY100,135 or WAY100,635, displayed significantly less 8‐OH‐DPAT‐induced movement. A similar reduction of 8‐OH‐DPAT‐induced movements was found in animals pretreated with SB269970, a selective 5‐HTR7 antagonist. Moreover, a near complete blockade of 8‐OH‐DPAT‐induced movement was obtained in wild‐type mice pretreated with 5‐HTR1A and 5‐HTR7 antagonists, and in 5‐HTR7–/– mice pretreated with 5‐HTR1A antagonists. Overall, these results clearly demonstrate that 8‐OH‐DPAT potently induces locomotor‐like movement in the previously paralysed hindlimbs of low‐thoracic‐transected mice. The results, with selective antagonists and knockout animals, provide compelling evidence of a specific contribution of both receptor subtypes to spinal locomotor rhythmogenesis in vivo.