NLX-101 (also known as F15599) exhibits nanomolar affinity, exceptional selectivity and biased agonist activation of serotonin 5-HT1A receptors. Given systemically, it displays antidepressant-like activity in the rat forced swim test (FST), and preferentially activates 5-HT1A post-synaptic heteroreceptors in the prefrontal cortex (PFC), a brain region involved in the control of mood. Here, we assessed the ability of NLX-101 to produce antidepressant-like activity in the FST following in-situ PFC unilateral microinjection. (+)8-OH-DPAT and F13714, two 5-HT1A receptor agonists that do not display cortical biased agonism, were tested as comparators. NLX-101 decreased time spent in immobility in a bi-modal manner, with a first MED of 0.25 μg (immobility reduced from 160 to 80 s) but immobility returned to control levels at the next dose (1 μg). At higher doses, immobility decreased monotonically, with a second MED of 16 μg and a maximal effect (36 s) at 32 μg. (+)8-OH-DPAT and F13714 also diminished immobility but, unlike NLX-101, they did so in a unimodal manner, with MEDs of 1 and 4 μg, and maximal responses of 31 and 4 s, for (+)8-OH-DPAT and F13714, respectively. The effects of (+)8-OH-DPAT (16 μg) and of both active doses of NLX-101 (0.25 and 16 μg) were prevented by the 5-HT1A receptor antagonist WAY-100,635 (0.63 mg/kg s.c.). In conclusion, activation of 5-HT1A receptors in the PFC by NLX-101 produces robust antidepressant-like effects in the rat FST, with a distinctive bimodal dose-response pattern. These data suggest that NLX-101 may target specific 5-HT1A receptor subpopulations in PFC, likely located on GABAergic and/or glutamatergic neurons.

Levomilnacipran (LVM; F2695) is the more active enantiomer of the serotonin/norepinephrine (5-HT/NE) reuptake inhibitor (SNRI) milnacipran and is currently under development for the treatment of major depressive disorder. LVM was benchmarked against two other SNRIs, duloxetine and venlafaxine, in biochemical, neurochemical and pharmacological assays. LVM exhibited high affinity for human NE (Ki = 92.2 nM) and 5-HT (11.2 nM) transporters, and potently inhibited NE (IC50 = 10.5 nM) and 5-HT (19.0 nM) reuptake (human transporter) in vitro. LVM had 2-fold greater potency for norepinephrine relative to serotonin reuptake inhibition (i.e. NE/5-HT potency ratio: 0.6) and 17 and 27 times higher selectivity for NE reuptake inhibition compared with venlafaxine and duloxetine, respectively. LVM did not exhibit affinity for 23 off-target receptors. LVM (i.p.) increased cortical extracellular levels of 5-HT, and NE (minimal effective doses: MEDs = 20 and 10 mg/kg, respectively). In anti-depressive/anti-stress models, i.p. LVM diminished immobility time in the mouse forced swim (MED = 20 mg/kg) and tail suspension (MED = 2.5 mg/kg) tests, and reduced shock-induced ultrasonic vocalizations in rats (MED = 5 mg/kg). Duloxetine and venlafaxine were less potent (MEDs ≥ 10 mg/kg). At doses active in these three therapeutically-relevant models, LVM (i.p.) did not significantly affect spontaneous locomotor activity. In summary, LVM is a potent, selective inhibitor of NE and 5-HT transporters with preferential activity at the former. It is efficacious in models of anti-depressive/anti-stress activity, with minimal potential for locomotor side effects.

Background and purpose: The D-2/D-3 receptor antagonist, D-4 receptor partial agonist, and high efficacy 5-HT1A receptor agonist F15063 was shown to be highly efficacious and potent in rodent models of activity against positive symptoms of schizophrenia. However F15063 induced neither catalepsy nor the 'serotonin syndrome'. Here, we evaluated its profile in rat models predictive of efficacy against negative symptoms/ cognitive deficits of schizophrenia.Experimental approach: F15063, given i.p., was assessed in models of behavioural deficits induced by interference with the NMDA/glutamatergic ( phencyclidine: PCP) or cholinergic ( scopolamine) systems.Key results: Through 5-HT1A activation, F15063 partially alleviated ( MED: 0.04 mgkg(-1)) PCP-induced social interaction deficit between two adult rats, without effect by itself, underlining its potential to combat negative symptoms. At doses above 0.16 mgkg(-1), F15063 reduced interaction by itself. F15063 ( 0.16 mgkg(-1)) selectively re-established PCP-impaired 'cognitive flexibility' in a reversal learning task, suggesting potential against adaptability deficits. F15063 ( 0.04-0.63 mgkg(-1)) also reversed scopolamine-induced amnesia in a juvenile-adult rat social recognition test, indicative of a pro-cholinergic influence. Activity in this latter test is consistent with its D-4 partial agonism, as it was blocked by the D-4 antagonist L745,870. Finally, F15063 up to 40 mgkg(-1) did not disrupt basal prepulse inhibition of startle reflex in rats, a marker of sensorimotor gating.Conclusions and implications: The balance of D-2/D-3, D-4 and 5-HT1A receptor interactions of F15063 yields a promising profile of activity in models of cognitive deficits and negative symptoms of schizophrenia.

Background and purpose: F15063 is a high affinity D-2/D-3 antagonist, D-4 partial agonist, and high efficacy 5-HT1A agonist, with little affinity ( 40-fold lower than for D-2 receptors) at other central targets. Here, the profile of F15063 was evaluated in models of positive symptoms of schizophrenia and motor side-effects.Experimental approach: Rodent behavioural tests were based on reversal of hyperactivity induced by psychostimulants and on measures of induction of catalepsy and 'serotonin syndrome'.Key results: F15063 potently ( ED(50)s: 0.23 to 1.10 mg kg(-1) i.p.) reversed methylphenidate-induced stereotyped behaviors, blocked d-amphetamine and ketamine hyperlocomotion, attenuated apomorphine-induced prepulse inhibition ( PPI) deficits, and was active in the conditioned avoidance test. In mice, it reversed apomorphine-induced climbing ( ED50 = 0.30 mg kg(-1) i.p.). F15063, owing to its 5-HT1A agonism, did not produce ( ED50 > 40 mg kg(-1) i.p.) catalepsy in rats and mice, a behavior predictive of occurrence of extra-pyramidal syndrome ( EPS) in man. This absence of cataleptogenic activity was maintained upon sub-chronic treatment of rats for 5 days at 40 mg kg(-1) p.o. Furthermore, F15063 did not induce the 'serotonin syndrome' in rats ( flat body posture and forepaw treading: ED50 > 32 mg kg(-1) i.p.).Conclusions and implications: F15063 conformed to the profile of an atypical antipsychotic, with potent actions in models of hyperdopaminergic activity but without inducing catalepsy. These data suggest that F15063 may display potent antipsychotic actions with low EPS liability. This profile is complemented by a favourable profile in rodent models of negative symptoms and cognitive deficits of schizophrenia ( companion paper).

The effects of CCK-8, ceruletide, their non-sulfated forms and CCK-4 on locomotor activity and rearing in mice were examined. CCK-8 and ceruletide, but not their non-sulfated forms and CCK-4, significantly inhibited the behavioral parameters dose-dependently. The inhibitory effects of CCK-8 and ceruletide were similar, but ceruletide acted more slowly and its inhibitory effect continued much longer than CCK-8, suggesting a difference in stability with the chemical structure. The antagonistic effects of ceruletide on behavioral changes induced by DA agonists were also examined. Peripherally injected ceruletide antagonized both methylphenidate- and methamphetamine-induced hyperactivity in mice dose-dependently, whereas it had no dose-related antagonistic effect on methylphenidate-induced stereo-typed behavior. Ceruletide also significantly inhibited apomorphine-induced hyperactivity when injected peripherally. However, no obvious dose-response relationship was observed in either intensity or duration of inhibitory action of ceruletide. These findings suggest that ceruletide does not interfere with dopaminergic transmission due to the blockade of postsynaptic DA receptors in the brain. In conclusion, peripheral injection of CCK-8 and ceruletide may affect directly or indirectly dopamine function producing behavioral changes that resemble those of neuroleptics in some respects.

NT69L is a novel neurotensin (8–13) analog that produces atypical antipsychotic-like effects in animal models. Because atypical antipsychotic drugs increase dopamine (DA) and acetylcholine (ACh) efflux in the medial prefrontal cortex and DA efflux in the nucleus accumbens, the present study sought to further evaluate the putative antipsychotic-like effects of NT69L by assessing DA and ACh efflux in these regions. Dual probe microdialysis was conducted in awake freely moving male rats, without using an acetylcholinesterase inhibitor in the perfusion medium. NT69L (1.0 and 3.0 mg/kg) produced significant increases in extracellular DA and ACh efflux in the medial prefrontal cortex. NT69L (1.0 mg/kg, but not 3.0 mg/kg) produced a significant increase of DA, but not ACh, efflux in the nucleus accumbens. Pretreatment with the serotonin (5-HT)1A receptor antagonist WAY100635 (0.2 mg/kg) significantly attenuated the 3.0 mg/kg NT69L-induced increase in medial prefrontal cortical DA efflux. Pretreatment with NT69L (1.0 mg/kg) significantly potentiated the effects of the atypical antipsychotic drug risperidone (0.1 mg/kg) on DA, but not ACh, efflux in the medial prefrontal cortex, while pretreatment with NT69L 1.0 mg/kg failed to alter the effects of haloperidol (0.1 mg/kg) on DA or ACh efflux in either region. These findings further suggest that NT analogs may be useful alone or adjunctively for the treatment of schizophrenia.