Combination of escitalopram and a 5-HT(₁A) receptor antagonist selectively decreases the extracellular levels of dopamine in the nucleus accumbens relative to striatum through 5-HT(₂C) receptor stimulation; suggestive of antipsychotic potential

Serotonin 5-HT_2C receptors are widely distributed throughout the brain located on GABAergic interneurons and afferent neurons in the ventral tegmental area and substantia nigra. Consequently, activation of this receptor modulates the dopaminergic neurotransmission. The antipsychotic potential of the combined treatment with escitalopram, in therapeutic relevant doses, and the 5-HT_1A receptor antagonist, WAY-100635, has been evaluated by assessment of conditioned avoidance (CAR) behaviour and the use of microdialysis in freely moving rats. The combined treatment was found to decrease both CAR behaviour without affecting escape failures and the basal extracellular levels of dopamine (DA) in the nucleus accumbens (NAc) acutely without affecting DA levels in the striatum, suggesting an antipsychotic-like effect with mesolimbic selectivity. The escitalopram/WAY-100635-induced changes in CAR behaviour and DA were prevented by pretreatment with the 5-HT_2C receptor antagonist, SB242084, indicating that the effects are mediated by stimulation of the 5-HT_2C receptor. Thus, indirect activation of the 5-HT_2C receptor may induce antipsychotic-like effects. The observations on DA levels were in line with the findings made with the selective 5-HT_2C receptor agonist, vabicaserin, which was also shown to produce a mesolimbic selective decrease in DA levels in the present study. In addition, it was demonstrated that escitalopram, in combination with the partial 5-HT_1A agonist, (-)-pindolol, decreased basal DA levels in the NAc. A potential therapeutic effect could readily be assessed, since both escitalopram and (-)-pindolol are already on the market.     

Differences in ligand binding profiles between cloned rabbit and human 5-HT1Dα and 5-HT1Dβ receptors: ketanserin and methiothepin distinguish rabbit 5-HT1D receptor subtypes

The study of serotonin receptor function has been complicated by the extreme molecular diversity of serotonin receptor subtypes, the lack of selective agonists and antagonists for many of the subtypes, and divergence in the pharmacological properties of a single receptor subtype across different animal species. An example of this pharmacological diversity between species homologues is provided by the 5-HT_1D receptor subfamily. To further advance the ability to characterize and pharmacologically compare functional responses mediated by native 5-HT_1D receptors, we have cloned the 5-HT_1D and 5-HT_1D receptor subtypes from the rabbit and evaluated their pharmacological profiles using radioligand binding assays. The deduced amino acid sequences of the rabbit 5-HT_1D and 5-HT_1D receptor genes displayed 60% overall identity [75% transmembrane (TM) identity] to each other and > 90% overall identity (95% TM identity) to their corresponding human homologues. Two compounds were identified in binding assays which discriminated between the closely-related 5-HT_1D receptors. Ketanserin exhibited high affinity (pK_i = 7.66) and selectivity ( > 20-fold) for the 5-HT_1D receptor while methiothepin displayed high affinity (pK_i = 7.86) and selectivity (16-fold) for the 5-HT_1D receptor subtype. The rabbit and human recombinant 5-HT_1D receptors showed significant intraspecies (rabbit 5-HT_1D vs. 5HT_1D) and interspecies (i.e. rabbit vs. human 5-HT_1D) similarities in their ligand binding profiles. These data suggest that 5-HT_1D-mediated responses in rabbit preparations may provide information relevant to the pharmacology of the 5-HT_1D receptor subtypes in humans.     

Predicting dopamine D₂ receptor occupancy from plasma levels of antipsychotic drugs: a systematic review and pooled analysis

Measuring dopamine D? receptor occupancy levels using positron emission tomography (PET) is still widely unavailable. The objective of this study was to evaluate the accuracy of predicting D2 occupancy from the antipsychotic plasma level in patients with schizophrenia. Positron emission tomographic studies that measured plasma levels of antipsychotics and their corresponding D? occupancy levels were identified, using MEDLINE and EMBASE (last search: March 2010). Antipsychotics that were investigated in a total of 20 subjects or more were included. All data points for each antipsychotic were fit to a one-site binding model to estimate the total plasma concentration of each antipsychotic associated with a 50% occupancy (ED??) of brain D? receptors. The mean prediction error and the root mean squared prediction error were used to measure the predictive performance of individual D? receptor occupancies from plasma drug levels derived from a one-site occupancy model using an ED?? value calculated for each data point. A total of 34 treatment arms from 23 studies involving 281 subjects were included. The mean (95% confidence interval) prediction errors and root squared prediction errors were as low as 0.0 (-1.8 to 1.8) and 8.9 (7.6-10.2) for risperidone (n = 98); 0.0 (-3.5 to 3.5) and 15.1 (12.9-17.3) for clozapine (n = 75); -0.1 (-1.2 to 1.2), 0.0 (-1.9 to 1.9), and 4.6 (3.5-5.8) for olanzapine (n = 42); 0.1 (-3.4 to 3.5) and 9.9 (7.3-12.5) for haloperidol (n = 35); and -0.1 (-3.3 to 3.1) and 12.3 (8.8-15.7) for ziprasidone (n = 31), respectively. These findings suggest that D? occupancy of antipsychotics could be estimated with a high degree of accuracy using widely available plasma levels.     

SDZ 216–525, a selective and potent 5-HT1A receptor antagonist

The pharmacological properties of SDZ 216–525, methyl 4-{4-[4(1,1,3-trioxo-2H,1,2-benzoisothiazol-2-yl)butyl]-1-piperazinyl}1H-indole-2-carboxylate, a new selective and potent 5-HT_1A receptor antagonist, are described in vitro (and comparisons made with those of MDL 73005 and NAN 190, two putative for 5-HT_1A receptor antagonists) and in vivo. In radioligand binding studies, SDZ 216–525 showed high affinity and selectivity for 5-HT_1A sites (pK_D = 9.2) as compared to 5-HT_1B, 5-HT_1C, 5-HT_1D, 5-HT₂ and 5-HT₃ sites (pK_D= 6.0, 7.2, 7.5, 5.2 and 5.4, respectively). The affinity of the compound for α₁, α₂, β₂ and β₂ adrenoceptors. and dopamine D₂ receptors was at least 50–100 times lower than for 5-HT_1A sites. The effects of SDZ 216–525, MDL 73005 and NAN 190 on 5-HT₁ receptor-linked second messengers were characterized in the following tests: inhibition of forskolin-stimulated adenylate cyclase activity in calf hippocampus (5-HT_1A), rat substantia nigra (5-HT_1B) and calf substantia nigra (5-HT_1D) and stimulation of inositol phosphate production in pig choroid plexus (5-HT_1C). SDZ 216–525 potently antagonised the effects of 8-OH-DPAT (8-hydroxy-2[N-diprophyl-amino]-tetralin) on 5-HT_1A receptors (pK_B = 10) and displayed no intrinsic activity in this test, whereas it behaved at best as a weak antagonist on the other receptor models pK_B values < 6.9). NAN 190 also behaved as a potent antagonist at 5-HT_1A receptors (pK_B = 8.7), whereas MDL 73005 displayed potent and nearly full agonism at 5-HT_1A receptors (pEC₅₀ = 7.3, E_max = 92%). Both compounds behaved broadly similarly to SDZ 216–525 in the other models. In vivo, SDZ 216–525 did not induce forepaw treading or flat body posture in lighlty44 reserpinies rats at up to 1 mg/kg s.c., whereas the behavioural responses to a submaximal dose of 8-OH-DPAT (0.25 mg/kg s.c.) were inhibited dose dependently by SDZ 216–525 over the range 0.03−1 mg/kg s.c. Similarly, SDZ 216–525 over the same dose range suppressed dose dependently the hypothermic effects of 8-OH-DPAT. These data demonstrate SDZ 216–525 to be a potent and selective 5-HT_1A receptor antagonist in vitro and in vivo.     

The 5-HT7 receptor: a target for novel therapeutic avenues?

The 5-HT(7) receptor is currently receiving widespread attention, and growing efforts are being made to understand its physiological/ pathophysiological significance. Evidence has accumulated which suggests that this receptor is involved in the regulation of limbic processes, circadian rhythm and sensory processing. Interest in the 5-HT(7) receptor may increase further as new findings suggest its implication in the pathogenesis of migraine and the modulation of sympathetic afferent pathways. At this stage, however, the involvement of this receptor in human pathology and therapeutics can only be inferred. This review discusses the current knowledge of the 5-HT(7) receptor in terms of its characteristics, and potential physiological and/or pathophysiological relevance. A brief overview of some high-affinity 5-HT(7) receptor ligands, some of which are currently used as therapeutics, is also provided.     

The 5-HT1A receptor in schizophrenia: a promising target for novel atypical neuroleptics?

Increasing attention is being directed towards the role of the serotonergic system in the neurochemistry of schizophrenia and antipsychotic drug treatment. This review considers the 5-HT1A receptor in this context. In patients with schizophrenia, the majority of post-mortem studies have reported increases in 5-HT1A receptor density in the prefrontal cortex in the approximate range 15-80%. Although the pathophysiological significance of this finding is unclear, given the location of a major proportion of these receptors on pyramidal cells, it may reflect an abnormal glutamatergic network. In terms of drug treatment, 5-HT1A agonists clearly display anticataleptic activity in rats. In addition, 5-HT1A agonists consistently increase dopamine release in the prefrontal cortex in rodents, which is an effect that might be predicted to improve negative symptoms. 5-HT1A agonists augment classical neuroleptics in some rat models of antipsychotic action and may be capable of modulating the glutamatergic network therapeutically. Despite the encouraging preclinical data, there is a paucity of clinical studies of 5-HT1A agonist augmentation of neuroleptics in the treatment of schizophrenia. However, the clinical relevance may be clarified by the atypical antipsychotic drugs clozapine, quetiapine and ziprasidone which combine D2 receptor antagonism and 5-HT1A agonism. In conclusion, given the increased prefrontal 5-HT1A receptor density in the illness, and the anticataleptic activity of 5-HT1A agonists combined with their ability to evoke prefrontal dopamine release, there is now a sufficient rationale to examine thoroughly the role of the 5-HT1A receptor in schizophrenia and antipsychotic drug treatment.     

How selective is GR 43175? Interactions with functional 5-HT1A, 5-HT1B, 5-HT1C and 5-HT1D receptors

Summary GR 43175 (3-[2-dimethylamino]ethyl-N-methyl-1H-indole-5 methane sulphonamide) is a novel 5-HT₁-like receptor-selective agonist which was reported to be active in the treatment of migraine attacks. The effects of the compound were investigated in radioligand binding studies and in functional models for 5-HT_1A, 5-HT_1B, and 5-HT_1D receptors (inhibition of forskolin-stimulated adenylate cyclase activity in calf hippocampus, rat and calf substantia nigra, respectively) and 5-HT_1C receptors (stimulation of inositol phosphate production in pig choroid plexus).GR 43175 displayed the following order of affinity for 5-HT recognition sites (pK_D values, -log mol/l, in parentheses): 5-HT_1D (7.54) > 5-HT_1B (6.35) > 5-HT_1A (6.13) 5-HT_1C (4.13) > 5-HT₂ (3.67). The same order of potency was observed at functional 5-HT₁ receptors, at which GR 43175 acted as a full agonist, with the exception of the 5-HT_1C receptor, where the compound was a weak antagonist (pEC₅₀ or pK_B values, -log mol/l, in parentheses): 5-HT_1D (6.28) > 5-HT_1B (6.03) > 5-HT_1A (5.57) > 5-HT_1C (4.25).The present data show that GR 43175 interacts preferentially as an agonist with 5-HT_1B and 5-HT_1D receptors. Since 5-HT_1B receptors have not yet been identified in human brain, it seems possible that it is the 5-HT_1D receptor which is relevant to the reported antimigraine effects of this compound.Send offprint requests to D. Hoyer at the above address     

Search for correlations between serotonin 5-HT1A receptor expression and cognitive functions—a strategy in translational psychopharmacology

Rationale Animal studies and studies of human aging have suggested that the serotonin 5-HT_1A receptor may serve as a biomarker for cognitive functioning and a target for pharmacological treatment of cognitive deficits.Objectives The purpose of this positron emission tomography (PET) study was to search for relationships between interindividual variability in serotonin 5-HT_1A receptor binding potential (BP) and cognitive functioning.Materials and methods Twenty-four male control subjects, age 20–55 years, were examined with [¹¹C]WAY100635 PET and a battery of cognitive tests. 5-HT_1A receptor binding potential were calculated for the raphe nuclei, the hippocampus and the neocortex. Correlation coefficients between BP and cognitive performance were obtained for each region.Results There was a severalfold of variability in 5-HT_1A BP between individuals. We found no significant correlation between regional [¹¹C]WAY100635 binding and cognitive performance.Conclusions The results do not provide support for involvement of the 5-HT_1A receptor in cognitive functioning in man and question the predictive validity of some currently used animal models in translational neuroscience.     

Sensitization to MDMA locomotor effects and changes in the functionality of 5-HT(2A) and D₂ receptors in mice

The behavioral and neurochemical adaptations related to chronic 3,4-methylenedioxymethamphetamine (MDMA) treatment are largely unknown. In this study, we assessed whether repeated administration of MDMA would induce (a) context-dependent locomotor sensitization in mice and (b) changes in serotonin 5-HT(2A) and dopamine D? receptor functionality as measured by [3?S]GTPγS binding. Mice were treated with MDMA (10 mg/kg, intraperitoneally) or saline every other day for 11 days either in their home cages or in the environment where locomotor activity was measured. After a 10-day withdrawal period, mice were challenged with MDMA (5 and 10 mg/kg) and saline before locomotor activity measurements. During repeated MDMA treatment, locomotion was progressively enhanced, indicating the development of behavioral sensitization. The MDMA challenge at a dose of 5 mg/kg increased locomotor activity to a greater extent in mice pretreated with MDMA in the testing apparatus than in mice pretreated in the home cages, revealing that contextual cues paired with repeated drug exposure can enhance the expression of behavioral sensitization to MDMA. In contrast, a challenge administration of MDMA at 10 mg/kg induced similar locomotor sensitization in mice pretreated in both environments. An increase in the functionality of cortical 5-HT(2A) receptors was observed in mice pretreated with MDMA compared with mice pretreated with saline, but this activation was significantly greater in mice pretreated in the locomotor environment. In contrast, the functional activity of striatal D? receptors was significantly decreased only in mice pretreated with MDMA in the testing apparatus. These results reveal neuroadaptations in cortical 5-HT(2A) and striatal D? receptors after MDMA-induced behavioral sensitization in mice.     

The N-terminal region of the human 5-HT₂C receptor has as a cleavable signal peptide

The 5-hydroxytryptamine 2C (5-HT(2C)) receptor has a single nucleotide polymorphism (SNP) site at amino acid position 23 in its N-terminal tail. The polymorphism involves conversion of a cysteine to serine. The site, designated C23S, is located within a 32 amino acid long predicted signal peptide. The aim of the present study was to investigate whether the 5-HT(2C) receptor indeed has a functional cleavable signal peptide. For this purpose, ten N-terminally modified 5-HT(2C) receptors were constructed. Modifications included addition of the influenza virus hemagglutinin signal peptide, addition of a FLAG epitope, truncation of the N-terminal tail, and combinations of these changes. The receptors were transiently expressed in COS-7 cells. The relative amounts of receptors expressed at the membranes were quantified by [(3)H]-mesulergine radioligand binding. In one of the receptor constructs the FLAG epitope was inserted just after the endogenous putative signal peptide. Immunostaining with the M1 antibody, which recognizes the FLAG epitope only as free N-terminal entity, was used to detect whether the putative signal peptide preceding the FLAG epitope was cleaved off. The results suggest the following conclusions. The predicted signal peptide in the N-terminal tail of the 5-HT(2C) receptor acts as a cleavable signal peptide. Cleaving of the signal peptide is important for translocation of the wild type receptor to the plasma membrane. The two amino acids differentially encoded by the C23S SNP are likely absent from the mature 5-HT(2C) receptor.     

Effects of acute selective 5-HT1, 5-HT2, 5-HT3 receptor andα 2 adrenoceptor blockade on naloxone-induced antinociception

Several studies have demonstrated a paradoxical form of antinociception induced by the repeated administration of opioid antagonists accompanied by exposure to a painful stimulus. The underlying mechanism of this naloxone-induced antinociception (NIA) is still unknown, but the results of several studies suggest that it is a non-opioid response. This study was designed to investigate serotonergic and noradrenergic involvement in NIA. Rats were treated daily with systemic injections of 5 mg/kg naloxone, followed by a 45-s hot plate test of nociception (temperature=51.5 ± 0.5°C). After rats reached plateau levels of NIA, they received a test trial in which they were treated with various doses of different selective 5-HT or ₂ adrenoceptor antagonists in addition to naloxone before the hot plate test. Rats treated with 0.16, 0.32 and 0.63 mg/kg pirenperone or 2.5 mg/kg ritanserin showed significant reductions in paw lick latency with respect to rats treated with vehicle. In addition, high doses of yohimbine (7.5–10 mg/kg) also effectively reversed NIA. In contrast, NIA was not affected by acute blockade of 5-HT₁ or 5-HT₃ receptors by methiothepin or MDL 72222, respectively, or by the ₂ adrenoceptor blocker idazoxan. None of the 5-HT or ₂ adrenoceptor antagonists had any effect on the paw lick latencies of saline-treated rats. A possible role of 5-HT₂ receptors in the antinociception induced by opioid receptor blockade is discussed.     

Concurrent stimulation of cannabinoid CB1 and dopamine D2 receptors enhances heterodimer formation: a mechanism for receptor cross-talk?

Dopamine and endogenous cannabinoids display complex interactions in the basal ganglia. One possible level of interaction is between CB1 cannabinoid and D2 dopamine receptors. Here, we demonstrate that a regulated association of CB1 and D2 receptors profoundly alters CB1 signaling. This provides the first evidence that CB1/D2 receptor complexes exist, are dynamic, and are agonist-regulated with highest complex levels detected when both receptors are stimulated with subsaturating concentrations of agonist. The consequence of this interaction is a differential preference for signaling through a "nonpreferred" G protein. In this case, D2 receptor activation, simultaneously with CB1 receptor stimulation, results in the receptor complex coupling to G alpha s protein in preference to the expected G alpha i/o proteins. The result of this interaction is an increase in the second messenger cAMP, reversing an initial synergistic inhibition of adenylyl cyclase activity seen at subthreshold concentrations of cannabinoid agonist. Additionally, a pertussis toxin insensitive component in the activation of extracellular signal-regulated kinase (ERK) 1/2 kinases by the cannabinoid agonist CP 55,940 [(1R,3R,4R)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl)cyclohexan-1-ol] is revealed in cells stably expressing both CB1 and D2 receptors. Thus, concurrent receptor stimulation promotes a heterooligomeric receptor complex and an apparent shift of CB1 signaling from a pertussis toxin-sensitive inhibition to a partly pertussis toxin-insensitive stimulation of adenylyl cyclase and ERK 1/2 phosphorylation.     

An in vivo pharmacological evaluation of pardoprunox (SLV308) — A novel combined dopamine D2/D3 receptor partial agonist and 5-HT1A receptor agonist with efficacy in experimental models of Parkinson's disease

Partial D_2/3 dopamine (DA) receptor agonists provide a novel approach to the treatment of the motor symptoms of Parkinson's disease (PD) that may avoid common dopaminergic side-effects, including dyskinesia and psychosis. The present study focussed on the in vivo pharmacological and therapeutic characterisation of the novel D_2/3 receptor partial agonist and full 5-HT_1A receptor agonist pardoprunox (SLV308; 7-[4-methyl-1-piperazinyl]-2(3H)-benzoxazolone monochloride). Pardoprunox induced contralateral turning behaviour in rats with unilateral 6-hydroxydopamine-induced lesions of the substantia nigra pars compacta (SNpc) (MED = 0.03 mg/kg; po). In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets, pardoprunox dose-dependently increased locomotor activity (MED = 0.03 mg/kg; po) and decreased motor disability (MED = 0.03 mg/kg; po). The effects of pardoprunox were reversed by the D₂ antagonist sulpiride. In contrast pardoprunox attenuated novelty-induced locomotor activity (MED = 0.01 mg/kg; po), (+)-amphetamine-induced hyperlocomotion (MED = 0.3 mg/kg; po) and apomorphine-induced climbing (MED = 0.6 mg/kg; po) in rodents. Pardoprunox also induced 5-HT_1A receptor-mediated behaviours, including flat body posture and lower lip retraction (MED = 0.3 mg/kg; po) and these were reversed by the 5-HT_1A receptor antagonist WAY100635. Collectively, these findings demonstrate that pardoprunox possesses dopamine D2/3 partial agonist effects, 5-HT1A agonist effects and reduces parkinsonism in animal models. functional DA D₂ receptor partial agonist activity and is effective in experimental models predictive of efficacy in PD. The presence of functional 5-HT_1A agonist activity might confer anti-dyskinetic activity and have effects that control neuropsychiatric components of PD.     

5-HT1-like receptor mediated changes in porcine carotid haemodynamics: are 5-HT1D receptors involved?

Summary 5-Hydroxytryptamine (5-HT) reduces porcine arteriovenous shunting in the carotid vascular bed by stimulation of both 5-HT₁-like and 5-HT₂ receptors and increases capillary flow to some tissues, like the skin and ears, by different 5-HT₁-like receptors. In view of the heterogeneous nature of the 5-HT₁-like receptors and the relative selectivity for the 5-HT_1D binding sites of sumatriptan, which also reduces porcine arteriovenous shunting and slightly increases capillary blood flow towards skin and ears by 5-HT₁-like receptors, we have attempted to determine whether one or both of these carotid 5-HT₁-like receptors belong to the 5-HTID subtype.Pentobarbitone anaesthetized pigs, subjected to bilateral cervical vagosympathectomy, received either 5-HT (2 g · kg^–1 · min^–1) in the carotid artery or cumulative i.v. doses of sumatriptan (10, 30, 100 and 300 g · kg^–1). Their effect on the total carotid blood flow and its distribution into capillary and arteriovenous anastomotic parts was determined with radioactive microspheres. The effect of metergoline (1 mg·kg^–1), a substance with a very high affinity for the 5-HT_1D receptor as well as for the 5-HT_1A, 5-HT_1B, 5-HT_1C and 5-HT₂ receptors, was studied on the responses to 5-HT and sumatriptan.Both 5-HT and sumatriptan reduced carotid arteriovenous anastomotic blood flow. 5-HT and, to a lesser extent, sumatriptan also increased capillary blood flow towards some tissues. Metergoline by itself did not affect the distribution of porcine carotid blood flow. It attenuated the constrictor response, but increased the vasodilator response to 5-HT, in a manner similar to the 5-HT₂ receptor antagonists cyproheptadine, ketanserin and WAL 1307 in our former experiments. These effects seem, therefore, to be related to the blockade of 5-HT₂ receptors by metergoline. On the other hand, metergoline had no significant effect against the responses to sumatriptan.It is concluded that neither the constrictor nor the dilator carotid 5-HT₁-like receptors seem to be related to the known 5-HT₁ binding subtypes, including the 5-HT_1D subtype. Send offprint requests to M. O. Den Boer at the above address     

Anxiolytic effects of 5-HT₁A receptors and anxiogenic effects of 5-HT₂C receptors in the amygdala of mice

The aim of the present study is to test a hypothesis that 5-HT(1A) and 5-HT(2C) receptors in the amygdala play an important role in the regulation of anxiety behaviors. We examined alterations in anxiety-like behaviors after manipulation of the expression of 5-HT(1A) and 5-HT(2C) receptors in the amygdala using recombinant adenovirus approaches. Recombinant adenoviruses containing a 5-HT(1A) promoter-controlled 5-HT(1A) antisense sequence or a 5-HT(2C) promoter-controlled 5-HT(2C) sense sequence were injected into the amygdala. Elevated plus-maze (EPM) and open field tests were conducted to determine anxiety-like behavior and locomotor activity. Reductions in the expression of 5-HT(1A) receptors in the amygdala significantly attenuated the time spent in the open arms of EPM and time spent in the center of an open field. Reduction in the percent of time spent in the open arms of EPM is negatively correlated with the density of 5-HT(1A) receptors in the central amygdala. On the other hand, increased expression of 5-HT(2C) receptors reduced the time spent in the open arms of EPM and time spent in the center of an open field. The reductions in the time spent and distance traveled in the open arms of EPM were correlated to the density of 5-HT(2C) receptors in the basolateral nucleus of amygdala. These data suggest that amygdaloid 5-HT(1A) receptors produce anxiolytic and 5-HT(2C) receptors produce anxiogenic effects. Together, the present results demonstrate the important role of the amygdaloid 5-HT(1A) and 5-HT(2C) receptors in the regulation of anxiety-like behaviors. This article is part of a Special Issue entitled 'Anxiety and Depression'.     

Comparison of D₂ dopamine receptor occupancy after oral administration of quetiapine fumarate immediate-release and extended-release formulations in healthy subjects

Quetiapine is an established drug for treatment of schizophrenia, bipolar disorder, and major depressive disorder. While initially manufactured as an immediate-release (IR) formulation, an extended-release (XR) formulation has recently been introduced. Pharmacokinetic studies show that quetiapine XR provides a lower peak and more stable plasma concentration than the IR formulation. This study investigated if the pharmacokinetic differences translate into different time curves for central D? dopamine receptor occupancy. Eleven control subjects were examined with positron emission tomography (PET) and the radioligand [11C]raclopride. Eight subjects underwent all of the scheduled PET measurements. After baseline examination, quetiapine XR was administered once-daily for 8 d titrated to 300 mg/d on days 5-8, followed by 300 mg/d quetiapine IR on days 9-12. PET measurements were repeated after the last doses of quetiapine XR and IR at predicted times of peak and trough plasma concentrations. Striatal D? receptor occupancy was calculated using the simplified reference tissue model. Peak D? receptor occupancy was significantly higher with quetiapine IR than XR in all subjects (50 ± 4% and 32 ± 11%, respectively), consistent with lower peak plasma concentrations for the XR formulation. Trough D? receptor occupancy was similarly low for both formulations (IR 7 ± 7%, XR 8 ± 6%). The lower peak receptor occupancy associated with quetiapine XR may explain observed pharmacodynamic differences between the formulations. Assuming that our findings in control subjects are valid for patients with schizophrenia, the study supports the view that quetiapine, like the prototype atypical antipsychotic clozapine, may show antipsychotic effect at lower D? receptor occupancy than typical antipsychotics.