A review of central 5-HT receptors and their function

Context Existing therapies for major depression have a lag of onset of action of several weeks, resulting in considerable morbidity. Exploring pharmacological strategies that have rapid onset of antidepressant effects within a few days and that are sustained would have an enormous impact on patient care. Converging lines of evidence suggest the role of the glutamatergic system in the pathophysiology and treatment of mood disorders. Objective To determine whether a rapid antidepressant effect can be achieved with an antagonist at theN-methyl-D-aspartate receptor in subjects with major depression. Design A randomized, placebo-controlled, double-blind crossover study from November 2004 to September 2005. Setting Mood Disorders Research Unit at the National Institute of Mental Health. Patients Eighteen subjects withDSM-IVmajor depression (treatment resistant). Interventions After a 2-week drug-free period, subjects were given an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days, a week apart. Subjects were rated at baseline and at 40, 80, 110, and 230 minutes and 1, 2, 3, and 7 days postinfusion. Main Outcome Measure Changes in scores on the primary efficacy measure, the 21-item Hamilton Depression Rating Scale. Results Subjects receiving ketamine showed significant improvement in depression compared with subjects receiving placebo within 110 minutes after injection, which remained significant throughout the following week. The effect size for the drug difference was very large (d = 1.46 [95% confidence interval, 0.91-2.01]) after 24 hours and moderate to large (d = 0.68 [95% confidence interval, 0.13-1.23]) after 1 week. Of the 17 subjects treated with ketamine, 71% met response and 29% met remission criteria the day following ketamine infusion. Thirty-five percent of subjects maintained response for at least 1 week. Conclusions Robust and rapid antidepressant effects resulted from a single intravenous dose of anN-methyl-D-aspartate antagonist; onset occurred within 2 hours postinfusion and continued to remain significant for 1 week. Trial Registration clinicaltrials.gov Identifier:NCT00088699.

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A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression

The chronic mild stress (CMS) model of depression has high validity but has in the past been criticized for being difficult to replicate. However, a large number of recent publications have confirmed

Chronic Mild Stress (CMS) Revisited: Consistency and Behavioural-Neurobiological Concordance in the Effects of CMS

Cannabis sativa is the source of a unique set of compounds known collectively as plant cannabinoids or phytocannabinoids. This review focuses on the manner with which three of these compounds, (-)-trans-delta9-tetrahydrocannabinol (delta9-THC), (-)-cannabidiol (CBD) and (-)-trans-delta9-tetrahydrocannabivarin (delta9-THCV), interact with cannabinoid CB1 and CB2 receptors. Delta9-THC, the main psychotropic constituent of cannabis, is a CB1 and CB2 receptor partial agonist and in line with classical pharmacology, the responses it elicits appear to be strongly influenced both by the expression level and signalling efficiency of cannabinoid receptors and by ongoing endogenous cannabinoid release. CBD displays unexpectedly high potency as an antagonist of CB1/CB2 receptor agonists in CB1- and CB2-expressing cells or tissues, the manner with which it interacts with CB2 receptors providing a possible explanation for its ability to inhibit evoked immune cell migration. Delta9-THCV behaves as a potent CB2 receptor partial agonist in vitro. In contrast, it antagonizes cannabinoid receptor agonists in CB1-expressing tissues. This it does with relatively high potency and in a manner that is both tissue and ligand dependent. Delta9-THCV also interacts with CB1 receptors when administered in vivo, behaving either as a CB1 antagonist or, at higher doses, as a CB1 receptor agonist. Brief mention is also made in this review, first of the production by delta9-THC of pharmacodynamic tolerance, second of current knowledge about the extent to which delta9-THC, CBD and delta9-THCV interact with pharmacological targets other than CB1 or CB2 receptors, and third of actual and potential therapeutic applications for each of these cannabinoids.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1038/sj.bjp.0707442

The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin

Conditioned place preference (CPP) continues to be one of the most popular models to study the motivational effects of drugs and non-drug treatments in experimental animals. This is obvious from a steady year-to-year increase in the number of publications reporting the use this model. Since the compilation of the preceding review in 1998, more than 1000 new studies using place conditioning have been published, and the aim of the present review is to provide an overview of these recent publications. There are a number of trends and developments that are obvious in the literature of the last decade. First, as more and more knockout and transgenic animals become available, place conditioning is increasingly used to assess the motivational effects of drugs or non-drug rewards in genetically modified animals. Second, there is a still small but growing literature on the use of place conditioning to study the motivational aspects of pain, a field of pre-clinical research that has so far received little attention, because of the lack of appropriate animal models. Third, place conditioning continues to be widely used to study tolerance and sensitization to the rewarding effects of drugs induced by pre-treatment regimens. Fourth, extinction/reinstatement procedures in place conditioning are becoming increasingly popular. This interesting approach is thought to model certain aspects of relapse to addictive behavior and has previously almost exclusively been studied in drug self-administration paradigms. It has now also become established in the place conditioning literature and provides an additional and technically easy approach to this important phenomenon. The enormous number of studies to be covered in this review prevented in-depth discussion of many methodological, pharmacological or neurobiological aspects; to a large extent, the presentation of data had to be limited to a short and condensed summary of the most relevant findings.

Measuring reward with the conditioned place preference (CPP) paradigm: update of the last decade.

During the last decade, serotonin (5-HT)1A receptors have been a major target for neurobiological research and drug development. 5-HT1A receptors have been cloned and a variety of selective agonists, such as the aminotetraline 8-OH-DPAT and the pyrimidinylpiperazine ipsapirone, have become available. Demonstrations of apparent intrinsic activity of these ligands at 5-HT1A receptors, however, depend highly on the particular assay system. This may be due to the possible existence of receptor subtypes and to assay (or brain region)-dependent differences in receptor reserve and the nature of receptor-effector coupling. Nevertheless, the apparent intrinsic activity of 8-OH-DPAT seems to be higher (although possibly not yet maximal) than that of the pyrimidinylpiperazines. In the brain, 5-HT1A receptors are located presynaptically as somatodendritic receptors on 5-HT neurons and postsynaptically in particular limbic and cortical regions. Although it is generally accepted that presynaptic 5-HT1A receptors control 5-HT neuronal activity, recent evidence suggests an additional role of postsynaptic 5-HT1A receptors in cortex as part of a negative feedback loop. Anxiolytic and antidepressive properties of selective 5-HT1A receptor agonists have now been confirmed by clinical studies. Although it is well established that the latter properties depend on the agonistic activity of these compounds, the optimal level of intrinsic activity is still a matter of debate and may be dependent on the clinical indication. Such compounds may also have antiaggressive effects, and possibly anticraving effects (manifested by their alcohol intake-reducing effects in dependent animals), but the specificity of these so-called anti-impulsivity effects is still controversial and not yet tested clinically. Anticataleptic, antiemetic and neuroprotective properties have been demonstrated in different species. Behavioral studies on the mechanisms underlying the anxiolytic and antidepressive effects have examined the relative contribution of pre- and postsynaptic 5-HT1A receptors by means of local cerebral application and lesion techniques. Most evidence points towards a critical involvement of presynaptic receptors in the anxiolytic effects of 5-HT1A receptor agonists (although a possible contribution of postsynaptic receptors cannot be excluded). With regard to the antidepressive properties, a case can be made for the reverse; i.e., a strong involvement of postsynaptic receptors and a questionable contribution of presynaptic receptors. However, as the therapeutic effects of those 5-HT1A receptor (partial) agonists which have been tested clinically require repeated administration, attention has been directed increasingly towards chronic studies.(ABSTRACT TRUNCATED AT 400 WORDS)

5-HT1A receptor agonists: recent developments and controversial issues

Effects of selected serotonin 5-HT(1) and 5-HT(2) receptor agonists on feeding behavior: possible mechanisms of action.

In order to create optimal conditions for the acquisition of i.v. cocaine self-administration in the rat, three groups of rats were deprived of food to different extents in order to obtain body weight reductions of 5 to 15, 15 to 25 and 25 to 35% of the pre-experimental body weights, and were tested for five consecutive 6-hr sessions in a continuous reinforcement procedure for self-administration of cocaine (0.12 mg/ml) or saline. Self-administration interacted with weight loss and indicated that: 1) a minimum level of 15 to 25% weight loss was required to obtain cocaine self-administration; 2) weight loss-induced potentiation of cocaine self-administration resulted from an interaction of increased nonspecific lever pressing activity and increased reinforcing effects of the compound; and 3) optimal differentiation between cocaine- and saline-induced responding was obtained at 15 to 25% weight loss. Daily pretreatment during the five test sessions, with 0.1 to 1.0 mg/kg of naltrexone or 43 to 375 micrograms/kg of haloperidol, dose-dependently decreased the number of cocaine (0.12 mg/ml) self-injections. Naltrexone pretreatment, and to a lesser extent haloperidol pretreatment, appeared to affect cocaine self-administration in a specific manner; both treatments affected responding on the reinforced lever, but not responding on the nonreinforced lever. Self-administration of 0.06 mg/ml of cocaine tended to be decreased by naltrexone (1 mg/kg) and haloperidol (375 micrograms/kg); whereas self-administration induced by 0.25 mg/ml of cocaine was not significantly affected by naltrexone or haloperidol. Both treatments failed to affect self-administration of saline.(ABSTRACT TRUNCATED AT 250 WORDS)

Food deprivation and acquisition of intravenous cocaine self-administration in rats: effect of naltrexone and haloperidol.

Previous studies have shown that injection of 5-hydroxytryptamine (serotonin) receptor agonists in the dorsal raphe nucleus (DRN) to stimulate somatodendritic 5-HT1A autoreceptors or in the hippocampus to stimulate postsynaptic 5-HT1A receptors, induces anxiolytic-like effects in the rat. The mechanisms triggered by the latter treatment were investigated by measuring both the electrical activity of serotonergic DRN neurons and the anxiolytic response in rats receiving injections with 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) or ipsapirone into the dorsal hippocampus. Anxiety-related behavior was estimated by recording the time of ultrasonic vocalization (USV) due to electric foot shocks under standardized conditions. Intrahippocampal application of 8-OH-DPAT or ipsapirone produced a dose-dependent inhibition of the firing of serotonergic DRN neurons and of the shock-induced USV response. However, the range of efficient doses of 8-OH-DPAT via the intrahippocampal route (1-10 micrograms/rat) was larger than that using the i.v. route of injection (0.15-2.5 micrograms/rat). Furthermore, maximal inhibition of the firing of DRN serotonergic neurons occurred earlier when 8-OH-DPAT was injected i.v. (within 1-2 min) than when it was injected into the dorsal hippocampus (within 5 min). Interestingly, the injection of 8-OH-DPAT into the striatum, where 5-HT1A receptors are hardly detectable, or a lateral ventricle, also yielded dose-dependent reduction in both the firing rate of serotonergic DRN neurons and the USV response. Finally, local lesion with ibotenic acid to eliminate postsynaptic 5-HT1A receptors did not alter the inhibitory effects of intrahippocampal application of 8-OH-DPAT on the firing of serotonergic DRN neurons and the USV response. These data indicated that postsynaptic 5-HT1A receptors were not responsible for the inhibitory effects of 8-OH-DPAT and ipsapirone injected in forebrain areas on the electrical activity of serotonergic neurons and the USV response in rats. As shown by the autoradiographic labeling by [3H]8-OH-DPAT at distance from its injection site in the dorsal hippocampus, the diffusion of 5-HT1A receptor agonists (from injected areas in the forebrain to the DRN where they directly inhibit the electrical activity of serotonergic neurons) more likely accounted for their anxiolytic-like effects.

Are postsynaptic 5-HT1A receptors involved in the anxiolytic effects of 5-HT1A receptor agonists and in their inhibitory effects on the firing of serotonergic neurons in the rat?

The novel centrally acting analgesic tapentadol [(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride] combines two mechanisms of action, μ-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition (NRI), in a single molecule. Pharmacological antagonism studies have demonstrated that both mechanisms of action contribute to the analgesic effects of tapentadol. This study was designed to investigate the nature of the interaction of the two mechanisms. Dose-response curves were generated in rats for tapentadol alone or in combination with the opioid antagonist naloxone or the α2-adrenoceptor antagonist yohimbine. Two different pain models were used: 1) low-intensity tail-flick and 2) spinal nerve ligation. In each model, we obtained dose-effect relations to reveal the effect of tapentadol based on MOR agonism, NRI, and unblocked tapentadol. Receptor fractional occupation was determined from tapentadol's brain concentration and its dissociation constant for each binding site. Tapentadol produced dose-dependent analgesic effects in both pain models, and its dose-effect curves were shifted to the right by both antagonists, thereby providing data to distinguish between MOR agonism and NRI. Both isobolographic analysis of occupation-effect data and a theoretically equivalent methodology determining interactions from the effect scale demonstrated very pronounced synergistic interaction between the two mechanisms of action of tapentadol. This may explain why tapentadol is only 2- to 3-fold less potent than morphine across a variety of preclinical pain models despite its 50-fold lower affinity for the MOR. This is probably the first demonstration of a synergistic interaction between the occupied receptors for a single compound with two mechanisms of action.

https://jpet.aspetjournals.org/content/jpet/early/2011/01/24/jpet.110.175042.full.pdf

J. De Vry

Papers

5-HT1A receptor agonists: recent developments and controversial issues

Effects of selected serotonin 5-HT(1) and 5-HT(2) receptor agonists on feeding behavior: possible mechanisms of action.

Food deprivation and acquisition of intravenous cocaine self-administration in rats: effect of naltrexone and haloperidol.

Are postsynaptic 5-HT1A receptors involved in the anxiolytic effects of 5-HT1A receptor agonists and in their inhibitory effects on the firing of serotonergic neurons in the rat?

Synergistic Interaction between the Two Mechanisms of Action of Tapentadol in Analgesia