Schizophrenia is a chronic, severe and highly complex mental illness. Current treatments manage the positive symptoms, yet have minimal effects on the negative and cognitive symptoms, two prominent features of the disease with critical impact on the long-term morbidity. In addition, antipsychotic treatments trigger serious side effects that precipitate treatment discontinuation. Here, we show that activation of the trace amine-associated receptor 1 (TAAR1), a modulator of monoaminergic neurotransmission, represents a novel therapeutic option. In rodents, activation of TAAR1 by two novel and pharmacologically distinct compounds, the full agonist RO5256390 and the partial agonist RO5263397, blocks psychostimulant-induced hyperactivity and produces a brain activation pattern reminiscent of the antipsychotic drug olanzapine, suggesting antipsychotic-like properties. TAAR1 agonists do not induce catalepsy or weight gain; RO5263397 even reduced haloperidol-induced catalepsy and prevented olanzapine from increasing body weight and fat accumulation. Finally, TAAR1 activation promotes vigilance in rats and shows pro-cognitive and antidepressant-like properties in rodent and primate models. These data suggest that TAAR1 agonists may provide a novel and differentiated treatment of schizophrenia as compared with current medication standards: TAAR1 agonists may improve not only the positive symptoms but also the negative symptoms and cognitive deficits, without causing adverse effects such as motor impairments or weight gain.
Trace amines (TAs) such as β-phenylethylamine, p-tyramine, or tryptamine are biogenic amines found in the brain at low concentrations that have been implicated in various neuropsychiatric disorders like schizophrenia, depression, or attention deficit hyperactivity disorder. TAs are ligands for the recently identified trace amine-associated receptor 1 (TAAR1), an important modulator of monoamine neurotransmission. Here, we sought to investigate the consequences of TAAR1 hypersignaling by generating a transgenic mouse line overexpressing Taar1 specifically in neurons. Taar1 transgenic mice did not show overt behavioral abnormalities under baseline conditions, despite augmented extracellular levels of dopamine and noradrenaline in the accumbens nucleus (Acb) and of serotonin in the medial prefrontal cortex. In vitro, this was correlated with an elevated spontaneous firing rate of monoaminergic neurons in the ventral tegmental area, dorsal raphe nucleus, and locus coeruleus as the result of ectopic TAAR1 expression. Furthermore, Taar1 transgenic mice were hyposensitive to the psychostimulant effects of amphetamine, as it produced only a weak locomotor activation and failed to alter catecholamine release in the Acb. Attenuating TAAR1 activity with the selective partial agonist RO5073012 restored the stimulating effects of amphetamine on locomotion. Overall, these data show that Taar1 brain overexpression causes hyposensitivity to amphetamine and alterations of monoaminergic neurotransmission. These observations confirm the modulatory role of TAAR1 on monoamine activity and suggest that in vivo the receptor is either constitutively active and/or tonically activated by ambient levels of endogenous agonist(s).
5-HT(2C) receptors are predominantly localised in the brain and their dysregulation may contribute to particular symptoms of anxiety and depression. The marked affinity of several clinically established psychotropic agents sites (e.g., tricyclic antidepressants, clozapine, fluoxetine) for 5-HT(2C) receptor has generated interest in the therapeutic potential of selective, high affinity 5-HT(2C) receptor ligands. Like the selective serotonin re-uptake inhibitor (SSRI) fluoxetine, high affinity selective agonists such as Ro 60-0175 and Ro 60-0332 have potent in vivo activity in animal models suggestive of therapeutic action against depression, obsessive-compulsive disorder (OCD) and panic disorders. In contrast, 5-HT(2C) receptor antagonists such as SB-200646A or SB-221284 show signs of anxiolytic-like activity in tests for conditioned and phobic-like anxiety in rodents whereas they are inactive in tests indicative of antidepressant, antiOCD and antipanic activity. These results are consistent with an important hypothesis proposing that 5-HT has a complex, dual action on the neural mechanism of anxiety by either facilitating or inhibiting different kinds of anxiety in different brain regions. They also suggest that 5-HT(2C) receptor subtypes play an important role in the therapeutic properties of SSRIs. Certain 5-HT(2C) receptor antagonists may possess negative efficacy at 5-HT(2C) receptors and, as inverse agonists, may control constitutive receptor activity possibly characterising some psychopathological states. Receptor variants exist in the human population and indicate possible associations between somatic mutations in the 5-HT(2C) receptor and psychopathology or response to drug treatment. Selective 5-HT(2C) receptor ligands may offer innovative and improved therapeutic opportunities for the biological treatment of specific aspects of psychiatric syndromes.
Regulated binding of TBP to a promoter is a key event in transcriptional regulation. We show here that on glucose depletion, the S. cerevisiae Isw1 chromatin remodeling complex is required for the displacement of TBP from the PHO8 promoter. Displacement of TBP also requires the sequence-specific bHLH-LZ factor Cbf1p that targets Isw1p to the PHO8 UAS. Cbf1p- and Isw1p-dependent displacement of TBP is also observed at the PHO84 promoter, but not at the ADH1 promoter, where loss of TBP is Cbf1p- and Isw1p independent. The results point to a promoter-specific Isw1p-dependent mechanism for targeted regulation of basal transcription by displacement of TBP from a promoter.
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