Measurement of anxiety in transgenic mice.

A wide range of approaches has been used to study anxiety in mice. All presuppose that aversive stimuli, such as foot shock or novelty, induce a central state of fear, which can be quantified through specific behavioural and physiological measures. This review discusses the validity of the various approaches in terms of their similarity to different human anxiety disorders, their ability to detect compounds which modulate human anxiety, and their relevance to animal defensive processes. The most commonly used models of anxiety suitable for screening transgenic and knockout mice are discussed, with an emphasis placed on controlling for factors which could confound results. As all models used to date have limitations and no single paradigm adequately models all aspects of anxiety, this review recommends the use of a broad range of anxiety models in order to provide a comprehensive characterisation of the behavioural phenotype of transgenic mice.

Activation of 5-HT2B receptors in the medial amygdala causes anxiolysis in the social interaction test in the rat.

In a recent study, we reported the presence of neurones expressing 5-HT2B receptor protein in the medial amygdaloid nucleus of the adult rat brain. In the present study, bilateral micro-injection of the 5-HT2B receptor agonist 1-[5-(2-thienylmethoxy)-1H-3-indolyl]propan-2-amine hydrochloride (BW 723C86, 0.09 and 0.93 nmol, 5 min pretest) into the medial amygdaloid nuclei increased the total interaction time of a pair of male rats in the social interaction test, to a comparable extent to chlordiazepoxide (5 mg/kg p.o., 1 hr pretest) without altering locomotor activity; indicative of anxiolytic activity. The increase in social interaction was prevented by pretreatment with the 5-HT2C/2B receptor antagonist N-(1-methyl-5-indoyl)-N'-(3-pyridyl) urea hydrochloride (SB 200646A, at 2 but not 1 mg/kg p.o., 1 hr pretest), which did not alter behaviour when given alone. Intra-amygdala BW 723C86 (0.09, 0.31 and 0.93 nmol, 5 min pretest) did not significantly alter the number of punished responses made when the same rats were examined seven days later in a Vogel punished drinking test, although chlordiazepoxide (5 mg/kg p.o., 1 hr pretest) produced the expected anxiolytic profile. The results are consistent with the proposal that activation of 5-HT2B receptors in the medial amygdala induces anxiolysis in the social interaction model but has little effect on behaviour in a punished conflict model of anxiety. These data suggest that serotonergic neurotransmission in this nucleus may selectively affect specific kinds of anxiety generated by different animal models.

Effect of chronic administration of selective 5-hydroxytryptamine and noradrenaline uptake inhibitors on a putative index of 5-HT2C/2B receptor function.

Chronic treatment with selective 5-HT reuptake inhibitors (SSRI) are therapeutic in obsessive compulsive disorder, depression, anxiety, bulimia nervosa and migraine. In the present study the possibility that SSRI's act by desensitizing 5-HT2C/5-HT2B receptors was assessed using a putative in vivo model of 5-HT2C/5-HT2B receptor function, mCPP-induced hypolocomotion. mCPP (2, 4 and 6 mg/kg i.p. 20 min pretest) reduced locomotion and rears in rats treated acutely or chronically with saline. Acute oral administration of the SSRI's fluoxetine (10 mg/kg), paroxetine (10 mg/kg), or clomipramine (70 mg/kg) or the noradrenaline reuptake inhibitor, desipramine (10 mg/kg), all 1 hr pretest, did not prevent mCPP-induced hypolocomotion. In contrast, chronic treatment with the SSRI's paroxetine and fluoxetine (both 10 mg/kg p.o. daily x 21 days), significantly attenuated the effect of mCPP (4 and 6 mg/kg i.p.) on locomotion and rears 24 hr after the last pretreatment dose. Chronic clomipramine (70 mg/kg p.o. daily x 21 days) also significantly attenuated the effect of mCPP (4 mg/kg i.p.) on rears and tended to reduce the hypolocomotor response. However, chronic treatment with desipramine, (10 mg/kg p.o. daily x 21) had no effect on any of the parameters measured. As chronic fluoxetine and paroxetine did not reduce brain mCPP levels (determined by HPLC 30 min after 4 mg/kg i.p.) the results suggest that chronic SSRI's, but not desipramine, reduce 5-HT2C/5-HT2B receptor responsivity. If this occurs in man, it may mediate or contribute to their reported therapeutic efficacy in depression, anxiety, bulimia, migraine and alcoholism. It may also be of particular relevance to their unique efficacy in OCD.

SB-243213; a selective 5-HT2C receptor inverse agonist with improved anxiolytic profile: lack of tolerance and withdrawal anxiety.

SB-243213 (5-methyl-1-[[-2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-6-trifluoromethylindoline hydrochloride) is a new, selective 5-hydroxytryptamine (5-HT)2C receptor inverse agonist. SB-243213 has high affinity for the human 5-HT2C receptor (pK(i) 9.37) and greater than a 100-fold selectivity over a wide range of neurotransmitter receptors, enzymes and ion channels. In in vitro functional studies, SB-243213 acted as an inverse agonist at the human 5-HT2C receptor with a pK(b) of 9.8. In in vivo studies, SB-243213 was a potent inhibitor of central 5-HT2C receptor-mediated function in rats, blocking meta-chlorophenylpiperazine-induced hypolocomotion with an ID50 of 1.1 mg/kg p.o. and a long duration of action (>8 h). In rats, SB-243213 exhibited anxiolytic-like activity in both the social interaction and Geller-Seifter conflict tests. Importantly, unlike diazepam, chronic administration of SB-243213 did not result in the development of either tolerance to the anxiolytic-like effects or withdrawal anxiogenesis. Furthermore, in rodents, SB-243213 did not affect seizure threshold, did not increase body weight or induce catalepsy, but attenuated the haloperidol-induced catalepsy. SB-243213 did not affect amphetamine-, MK-801- or phencyclidine-induced hyperactivity. In conclusion, SB-243213 may possess an improved anxiolytic profile compared to benzodiazepines. SB-243213 also modulates dopaminergic transmission, lacks pro-psychotic properties and may have utility in the treatment of schizophrenia and motor disorders.

Biarylcarbamoylindolines are novel and selective 5-HT(2C) receptor inverse agonists: identification of 5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]- 5-pyridyl]carbamoyl]-6-trifluoromethylindoline (SB-243213) as a potential antidepressant/anxiolytic agent.

The evolution, synthesis, and biological activity of a novel series of 5-HT(2C) receptor inverse agonists are reported. Biarylcarbamoylindolines have been identified with excellent 5-HT(2C) affinity and selectivity over 5-HT(2A) receptors. In addition, (pyridyloxypyridyl)carbamoylindolines have been discovered with additional selectivity over the closely related 5-HT(2B) receptor. Compounds from this series are inverse agonists at the human cloned 5-HT(2C) receptor, completely abolishing basal activity in a functional assay. The new series have reduced P450 inhibitory liability compared to a previously described series of 1-(3-pyridylcarbamoyl)indolines (Bromidge et al. J. Med. Chem. 1998, 41, 1598) from which they evolved. Compounds from this series showed excellent oral activity in a rat mCPP hypolocomotion model and in animal models of anxiety. On the basis of their favorable biological profile, 32 (SB-228357) and 40 (SB-243213) have been selected for further evaluation to determine their therapeutic potential for the treatment of CNS disorders such as depression and anxiety.

Postnatal development of the T calcium current in cat thalamocortical cells.

The burst firing of thalamic cells in the adult cat is mainly controlled by a voltage-dependent membrane current that has recently been characterized as being similar to the low voltage-activated (i.e. low threshold), T-type, Ca2+ current originally described in sensory neurons. In those neurons so far studied, as well as in skeletal muscle, the low threshold Ca2+ current has been shown to decrease in amplitude or even disappear during embryogenesis or the first few weeks of postnatal life. We have now investigated the in vivo postnatal development of the low threshold Ca2+ current present in thalamocortical cells of the dorsal lateral geniculate nucleus of cats aged four to 100 days. The results show that the amplitude of the low threshold Ca2+ current triples from 0.5 nA in the first few days after birth to over 1.5 nA in the adult. However, this increase in amplitude is not accompanied by any change in its inactivation and activation properties, its latency to peak and the time dependence of inactivation removal. Because of these similarities during development and in adulthood it is likely that a major role of the low threshold Ca2+ current during neuronal development is the generation of oscillatory activities similar to those observed in adult thalamocortical cells.

On the properties and origin of the GABAB inhibitory postsynaptic potential recorded in morphologically identified projection cells of the cat dorsal lateral geniculate nucleus.

Intracellular recordings were performed from projection cells of the cat dorsal lateral geniculate nucleus in vitro to investigate the properties and origin of optic tract evoked inhibitory postsynaptic potentials mediated by GABAB receptors and their relationship to the physiologically different cell classes present in this nucleus. In all three main laminae of the dorsal lateral geniculate nucleus, stimulation of the optic tract evoked an excitatory postsynaptic potential followed by two inhibitory postsynaptic potentials. The first is a GABAA receptor mediated inhibitory postsynaptic potential since it was blocked by bicuculline, reversed in polarity following intracellular Cl- injection and had a reversal potential similar to the bicuculline sensitive hyperpolarizing effect of GABA. The second is a GABAB receptor mediated inhibitory postsynaptic potential. Its amplitude was not linearly related to membrane potential (maximal amplitude at -60 mV), it decreased when using frequencies of stimulation higher than 0.05 Hz and it was reversibly increased by addition of bicuculline to the perfusion medium. The reversal potential of GABAB inhibitory postsynaptic potentials was dependent on the extracellular K+ concentration but did not change in the presence of bicuculline or when recording with Cl- filled microelectrodes. While GABAA inhibitory postsynaptic potentials always abolished repetitive firing of projection cells, GABAB inhibitory postsynaptic potentials were able to block weak firing but unable to decrease strong activation of projection cells evoked by direct current injection. Optic tract evoked GABAB (as well as GABAA) inhibitory postsynaptic potentials could be recorded in slices which did not include the perigeniculate nucleus, thus indicating that they are generated by the interneurons of the dorsal lateral geniculate nucleus. Using intracellular injection of horseradish peroxidase, we have found that the GABAB inhibitory postsynaptic potentials are present in projection cells showing many different types of neuronal morphologies. In conclusion, GABA released from interneurons in the dorsal lateral geniculate nucleus is capable of evoking an early, short-lasting GABAA and a late, long-lasting GABAB inhibitory postsynaptic potential in projection cells with diverse morphology, indicating that the late inhibition in the dorsal lateral geniculate nucleus can no longer be associated exclusively with the recurrent inhibitory pathway through the perigeniculate nucleus.

Optic tract stimulation evokes GABAA but not GABAB IPSPs in the rat ventral lateral geniculate nucleus.

The inhibitory postsynaptic potentials (IPSPs) evoked in neurons of the rat ventral geniculate nucleus (vLGN) by electrical stimulation of the optic tract and the action of GABA and baclofen on the same cells were studied using intracellular recording technique in an in vitro slice preparation. A short latency short duration IPSP always followed the monosynaptic excitatory postsynaptic potential (EPSP). This IPSP reversed in polarity at about -65 mV and was reversibly blocked by bicuculline (50 microM) thus indicating that it represents a GABAA receptor-mediated IPSP. No long-lasting IPSP was evoked in vLGN cells by stimulation of the optic tract, while in the same slice, long-lasting GABAB IPSPs were routinely recorded in the dorsal lateral geniculate nucleus. GABA applied by ionophoresis evoked a hyperpolarization that had a reversal potential close to -70 mV and was antagonized by bicuculline. Baclofen hyperpolarized vLGN neurons and its action was reversibly blocked by the selective GABAB antagonist phaclofen (1 mM). In the presence of bicuculline GABA also produced a hyperpolarization that had properties similar to that evoked by baclofen. These results indicate that, although functional GABAA and GABAB receptors are present on vLGN neurons, stimulation of the optic tract evokes only GABAA but not GABAB mediated IPSPs. The lack of long-lasting GABAB IPSPs could explain the absence of long-lasting inhibition observed in vLGN neurons in vivo following stimulation of the optic tract.

Effects of RO 60 0175, a 5-HT(2C) receptor agonist, in three animal models of anxiety.

There is some controversy as to whether 5-HT(2C) receptor agonists are anxiogenic or anxiolytic. The effects of the novel 5-HT(2C) receptor agonist, (S)-2-chloro-5-fluoro-indol-1-yl)-1-methyl ethylamine fumarate (RO 60 0175), in three models of anxiety were therefore tested. RO 60 0175 was found to induce hypolocomotion in rats at doses greater than 0.5 mg/kg s.c., an effect reversed by the selective 5-HT(2C) receptor antagonist, SB-242084. RO 60 0175 did not elicit anxiolytic-like responses in the social interaction test under high light unfamiliar conditions, but suppressed both time spent in social interaction and locomotion at doses of 1 and 3 mg/kg s.c., suggesting a sedative response. In the Vogel conflict test, RO 60 0175 had no significant action on the number of shocks taken. In the Geller-Seifter test, RO 60 0175 (0.3 and 1 mg/kg s.c.) simultaneously reduced both unpunished and punished lever pressing, a profile consistent with sedation. Finally, RO 60 0175 was tested in a rat social interaction test under low light familiar conditions optimal for the detection of anxiogenic-like responses. At 1 and 3 mg/kg s.c., RO 60 0175 reduced both time spent in social interaction and concurrent locomotion, a profile more consistent with sedation than anxiogenesis. In conclusion, RO 60 0175 induced sedative-like responses via 5-HT(2C) receptor activation, but was neither anxiolytic, nor clearly anxiogenic at the doses tested.

An investigation of the mechanism responsible for fluoxetine-induced hypophagia in rats.

The effect of fluoxetine on feeding in p-chlorophenylalanine (PCPA) pretreated rats and the nature of its interaction with 5-HT2C receptors have been investigated. Animals that received 3 days PCPA (150 mg/kg i.p.) pretreatment and vehicle on the test day consumed a similar amount as control, saline pretreated animals under the test paradigm used in this study. Fluoxetine (20 and 30 mg/kg p.o.) significantly reduced food intake in PCPA and control pretreated animals to a similar extent, despite an approximately 90% reduction in the levels of brain 5-hydroxytryptamine (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) in the PCPA-pretreated animals. Thus, hypophagia is unlikely to be caused by inhibition of 5-HT reuptake. In the pig choroid plexus in vitro, fluoxetine and norfluoxetine inhibited specific [3H] mesulergine binding with pKI's (+/- S.E.M.) of 6.45 +/- 0.09 (n = 4) and 6.05 +/- 0.05 (n = 3), and slope factors (+/- S.E.M.) of 1.06 +/- 0.14 and 0.99 +/- 0.13, respectively. In slices of piglet choroid plexus fluoxetine (1, 10 and 33 microM) caused a rightward shift in the dose-response curve produced by 5-HT with no effect on the maximal response, and a mean pKB of 5.94 +/- 0.09. Norfluoxetine (10 microM) also produced a rightward shift in the 5-HT dose-response curve with no effect on the maximal response, and a pKB of 6.20. Thus, both compounds acted as surmountable antagonists with no agonist efficacy at 5-HT2C receptors present in choroid plexus. The hypophagic effect of fluoxetine (20 mg/kg p.o.) was also unaffected by the non-specific 5-HT2C receptor antagonist metergoline (2 and 5 mg/kg i.p.). These findings suggest that the hypophagic effect of fluoxetine is not likely to be dependent upon intact brain 5-hydroxytryptaminergic presynaptic function, nor is it mediated by an agonist action at the 5-HT2C receptor, but by an additional, unknown mechanism.

Anxiolytic-like effect of paroxetine in a rat social interaction test.

The effects of short- and long-term administration of the selective serotonin reuptake inhibitor paroxetine were investigated in a rat social interaction test. A single administration of paroxetine at oral doses of 0.3, 1, 3 and 10 mg/kg had no effect on social interaction between pairs of male rats under bright light (high anxiety) conditions. After 21 days of daily administration, paroxetine given orally at 3 mg/kg significantly (p < 0.01) increased the time spent in social interaction by pairs of rats tested under the same conditions, with no effect on locomotor activity, indicating an anxiolytic-like effect. The magnitude of increase (+97%) was comparable to that seen after a single dose of chlordiazepoxide (4 mg/kg orally). Although there was also an increase in time spent in social interaction after 21 days of repeated oral administration of paroxetine at 0.3, 1, and 10 mg/kg (+44, +56, and +54% increases, respectively), statistical significance was not achieved. These results indicate that in the long term paroxetine has an anxiolytic action, and thus support the clinical evidence for its therapeutic use in the treatment of anxiety disorders in addition to its established role as an antidepressant.

A T-type Ca2+ current underlies low-threshold Ca2+ potentials in cells of the cat and rat lateral geniculate nucleus.

1. The characteristics of a transient inward Ca2+ current (IT) underlying low-threshold Ca2+ potentials were studied in projection cells of the cat and rat dorsal lateral geniculate nucleus (LGN) in vitro using the single-electrode voltage-clamp technique. 2. In cat LGN slices perfused at 25 degrees C with a solution which included 1 mM-Ca2+ and 3 mM-Mg2+, IT could be evoked by depolarizing voltage steps to -55 mV from a holding potential (Vh) of -95 mV and was abolished by reducing [Ca2+]o from 1 to 0.1 mM. IT was also blocked by 8 mM-Mg2+ and 500 microM-Ni2+, but 500 microM-Cd2+ was a significantly less effective antagonist. 3. The inactivation of IT, which occurred at Vh positive to -65 mV, was removed as Vh approached -100 mV. The process of inactivation removal was also time dependent, with 800-1000 ms needed for total removal. Activation curves for IT showed a threshold of -70 mV and illustrated that IT was extremely voltage sensitive over the voltage range from -65 to -55 mV. 4. The decay phase of IT followed a single-exponential time course with a time constant of decay which was voltage sensitive and ranged from 20 to 100 ms. The mean peak conductance increase associated with IT was 8.4 nS (+/-0.9, S.E.M.). 5. In more 'physiological' conditions (35 degrees C and 1.5 mM-Ca2+, 1 mM-Mg2+) the voltage dependence of activation and inactivation were unaffected. However, the development and decay of IT proceeded more rapidly and only 500-600 ms were needed for total removal of inactivation. Under these conditions, the use of voltage ramps showed that depolarization rates of greater than 30 mV/s were necessary for IT activation. 6. The use of multiple voltage-step protocols illustrated that the process of inactivation removal was rapidly reversed by brief returns to a Vh of -50 mV. Furthermore, any delay in IT activation, once the LGN cell membrane potential was in the IT activation range, resulted in a current of reduced amplitude. 7. Although IT in rat LGN cells was briefer and had a shorter latency to peak, it was otherwise similar to that seen in cat LGN cells. 8. The characteristics of IT are very similar to those of the T-type Ca2+ currents of other excitable membranes. The properties of IT are discussed with respect to its role in generating the low-threshold Ca2+ potentials which are central to the oscillatory behaviour of thalamic projection cells.

Low-frequency oscillatory activities intrinsic to rat and cat thalamocortical cells.

1. Low-frequency membrane potential oscillations recorded intracellularly from thalamocortical (TC) cells of the rat and cat dorsal lateral geniculate nucleus (dLGN) and of the rat ventrobasal nucleus (VB) maintained in vitro were investigated. On the basis of their electrophysiological and pharmacological properties, four types of activity were distinguished and named: the pacemaker oscillations, the spindle-like oscillations, the 'very slow' oscillations and the 'N-methyl-D-aspartate' (NMDA) oscillations. 2. The pacemaker oscillations (95 out of 173 cells) consisted of rhythmic, large-amplitude (10-30 mV) depolarizations which occurred at a frequency of 1.8 +/- 0.3 Hz (range, 0.5-2.9 Hz) and could often give rise to single or a burst of action potentials. Pacemaker oscillations were observed when the membrane potential was moved negative to -55 and positive to -80 mV, but in a given cell the upper and lower limits of this voltage range were separated by only 13.1 +/- 0.5 mV. Above -45 mV tonic firing consisting of single action potentials was seen in the cells showing this or the other types of low-frequency oscillations. 3. The spindle-like oscillations were observed in thirty-nine (out of 173) TC cells and consisted of rhythmic (2.1 +/- 0.3 Hz), large-amplitude depolarizations (and often associated burst firing) similar to the pacemaker oscillations but occurring in discrete periods every 5-25 s and lasting for 1.5-28 s. The spindle-like oscillations were observed when the membrane potential was moved negative to -55 and positive to -80 mV and in two cells they were transformed into continuous pacemaker oscillations by depolarization of the membrane potential to -60 mV. 4. Pacemaker and spindle-like oscillations were unaffected by tetrodotoxin (TTX) or by selective blockade of NMDA, non-NMDA, GABAA, GABAB, nicotinic, muscarinic, alpha- and beta-noradrenergic receptors. 5. The 'very slow' oscillations consisted of a TTX-insensitive, slow hyperpolarization-depolarization sequence (5-15 mV in amplitude) which lasted up to 90 s and was observed in nine dLGN cells and in two VB cells. The pacemaker and the spindle-like oscillations were recorded in one cell each which also showed the 'very slow' oscillations. 6. The 'NMDA' oscillations were observed only in a 'Mg(2+)-free' medium (0 mM-Mg2+, 2-4 mM-Ca2+; 64 out of 72 cells) and consisted of large-amplitude (10-25 mV) depolarizations that did not occur at regular intervals and were intermixed with smaller depolarizations present on the baseline and on the falling phase of the larger ones.(ABSTRACT TRUNCATED AT 400 WORDS)

Two inward currents and the transformation of low-frequency oscillations of rat and cat thalamocortical cells.

1. The contribution of a slow, mixed Na(+)-K+, inward rectifying current (Ih) and the T-type Ca2+ current (IT) (that underlies low-threshold Ca2+ potentials) to the low-frequency oscillations observed in rat and cat thalamocortical (TC) cells in vitro was studied using current clamp and single-electrode voltage clamp recordings. 2. From a holding potential of -50 mV, voltage steps negative to -60 mV showed the presence of a slow, non-inactivating inward current, Ih. This current was unaffected by Ba2+ (1-4 mM), tetrodotoxin (0.5-1 microM) and TEA (20 mM, n = 6), reversibly blocked by Cs+ (1-3 mM), and its reversal potential (-33.0 +/- 1.2 mV) followed changes in the extracellular Na+ and K+, but not Cl-, concentration. 3. Application of Cs+ (1-3 mM) abolished the pacemaker oscillations (n = 9), while in six cells that did not show any oscillatory activity Cs+ first evoked the spindle-like oscillations that, in the continuous presence of these ions, were then transformed into the pacemaker oscillations before all activities were finally blocked: all these effects were accompanied by a hyperpolarization and a progressive decrease and final blockade of Ih. Cs+ had no effect on the 'N-methyl-D-aspartate' (NMDA) oscillations (n = 5) and Ba2+ (2 mM, n = 8) did not block the pacemaker, the spindle-like and the 'NMDA' oscillations. 4. In ten cells that showed the pacemaker oscillations selective activation of beta-adrenoceptors by 10-50 microM-noradrenaline (in the presence of alpha-noradrenergic antagonists) or by 20 microM-isoprenaline first transformed the pacemaker oscillations into the spindle-like oscillations that, in the continuous activation of beta-receptors, were finally abolished: all these effects were accompanied by a depolarization and a progressive increase of Ih. 5. In TC cells that showed the pacemaker oscillations application of 1-octanol (50-100 microM), an antagonist of T-type Ca2+ currents, reversibly blocked this activity but concomitantly decreased (50%) the cell input resistance (n = 5). Application of Ni2+ (0.2-0.5 mM, n = 13), another antagonist of IT reversibly blocked the pacemaker, the spindle-like and the 'NMDA' oscillations. 7. In cells showing the pacemaker oscillations it was found that the current developing from the most hyperpolarized potential of an oscillation cycle was an inward relaxation whose time course differed from that of Ih evoked at the same potential.(ABSTRACT TRUNCATED AT 400 WORDS)

1-[2-[(Heteroaryloxy)heteroaryl]carbamoyl]indolines: novel and selective 5-HT2C receptor inverse agonists with potential as antidepressant/anxiolytic agents.

Bisaryl ethers have been identified with excellent 5-HT2C affinity and selectivity over both 5-HT2A and 5-HT2B receptors. Compounds such as 11, 27 and 38 have potent oral activity in a centrally mediated pharmacodynamic model of 5-HT2C function and their potential as novel non-sedating anxiolytic and antidepressants is under investigation.

1-[2-[(Heteroarylmethoxy)aryl]carbamoyl]indolines are selective and orally active 5-HT2C receptor inverse agonists.

Bisarylmethoxyethers have been identified with nanomolar 5-HT2C affinity and selectivity over both 5-HT2A and 5-HT2B receptors. Compounds such as 1, 2, 8, 12, 14 and 18 have potent oral activity in a centrally mediated pharmacodynamic model of 5-HT2C function and their therapeutic potential is currently under further investigation.

The muscarinic receptor agonist xanomeline has an antipsychotic-like profile in the rat.

The muscarinic receptor agonist xanomeline was examined and compared with the antipsychotics clozapine and/or haloperidol in the following in vivo rat models: apomorphine-induced disruption of prepulse inhibition (PPI), amphetamine-induced hyperlocomotion, and the conditioned emotional response (CER) test. The effects of xanomeline were also assessed ex vivo on dopamine turnover in the rat medial prefrontal cortex. Under conditions of varying dose and prepulse intensity, xanomeline, like haloperidol, had no effect on PPI. In contrast, the muscarinic receptor antagonist scopolamine and the muscarinic receptor agonist pilocarpine both induced significant dose-dependent deficits in PPI. Haloperidol and xanomeline, but not pilocarpine, dose dependently reversed apomorphine-induced disruption of PPI. Thus, xanomeline induced a clear antipsychotic-like effect in PPI, whereas pilocarpine appeared to induce a psychotomimetic-like effect. Xanomeline attenuated amphetamine-induced hyperactivity at doses that had no effect on spontaneous activity, possibly indicating a separation between attenuation of limbic hyperdopaminergic function and the induction of hypolocomotion. Haloperidol and clozapine also reversed amphetamine-induced hyperlocomotion, but at similar doses to those that reduced spontaneous locomotion. Clozapine, but not haloperidol had an anxiolytic-like effect in the CER test. The effects of xanomeline in the CER test were similar to those of clozapine, although at the anxiolytic dose it tended to disrupt baseline levels of lever pressing. Finally, haloperidol, clozapine, pilocarpine, and xanomeline, all induced an increase in dopamine turnover in medial prefrontal cortex. The antipsychotic-like effects of xanomeline in the animal models used here suggest that it may be a useful treatment for psychosis.