The selective 5-HT2A receptor antagonist M100907 enhances antidepressant-like behavioral effects of the SSRI fluoxetine.

The addition of low doses of atypical antipsychotic drugs, which saturate 5-HT(2A) receptors, enhances the therapeutic effect of selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs) in patients with major depression as well as treatment-refractory obsessive-compulsive disorder. The purpose of the present studies was to test the effects of combined treatment with a low dose of a highly selective 5-HT(2A) receptor antagonist (M100907; formerly MDL 100,907) and low doses of a SSRI using a behavioral screen in rodents (the differential-reinforcement-of low rate 72-s schedule of reinforcement; DRL 72-s) which previously has been shown to be sensitive both to 5-HT(2) antagonists and SSRIs. M100907 has a approximately 100-fold or greater selectivity at 5-HT(2A) receptors vs other 5-HT receptor subtypes, and would not be expected to appreciably occupy non-5-HT(2A) receptors at doses below 100 microg/kg. M100907 increased the reinforcement rate, decreased the response rate, and shifted the inter-response time distributions to the right in a pattern characteristic of antidepressant drugs. In addition, a positive synergistic interaction occurred when testing low doses of the 5-HT(2A) receptor antagonist (6.25-12.5 microg/kg) with clinically relevant doses of the SSRI fluoxetine (2.5-5 mg/kg), which both exerted minimal antidepressant-like effects by themselves. In vivo microdialysis study revealed that a low dose of M100907 (12.5 microg/kg) did not elevate extracellular 5-HT levels in the prefrontal cortex over those observed with fluoxetine alone (5 mg/kg). These results will be discussed in the context that the combined blockade of 5-HT(2A) receptors and serotonin transporters (SERT) may result in greater efficacy in treating neuropsychiatric syndromes than blocking either site alone.

Modulation of serotonergic function in rat brain by VN2222, a serotonin reuptake inhibitor and 5-HT1A receptor agonist.

VN2222 (1-(benzo[b]thiophen-3-yl)-3-[4-(2-methoxiphenyl piperazin-1-yl]propan-1-ol) is a potential antidepressant with high affinity for the serotonin transporter and 5-HT(1A) receptors. Locally applied, VN2222 enhanced the extracellular 5-hydroxytryptamine (5-HT) concentration (5-HT(ext)) in rat striatum to 780% of baseline whereas its systemic administration (1-10 mg/kg s.c.) reduced 5-HT(ext). In the presence of citalopram, 8-OH-DPAT or VN2222 applied in medial prefrontal cortex reduced 5-HT(ext). Fluoxetine, VN2222, and 8-OH-DPAT suppressed the firing rate of dorsal raphe 5-HT neurons (ED(50): 790, 14.9, and 0.8 microg/kg i.v., respectively). These effects were antagonized by WAY 100635. Administration of VN2222 for 2 weeks desensitized 5-HT(1A) receptors as assessed by microdialysis and single-unit recordings (ED(50) values for 8-OH-DPAT were 0.45 and 2.34 microg/kg i.v. for controls and rats treated with 6 mg/kg day VN2222). These results show that VN2222 is a mixed 5-HT reuptake inhibitor/5-HT(1A) agonist that markedly desensitizes 5-HT(1A) autoreceptors. These properties suggest that it may be a clinically effective dual action antidepressant drug.

Control of the serotonergic system by the medial prefrontal cortex: potential role in the etiology of PTSD and depressive disorders.

The prefrontal cortex is involved in an array of higher brain functions that are altered in psychiatric disorders. Serotonergic neurons of the midbrain rapbe nuclei innervate the prefrontal cortex and are the cellular target for drugs used to treat mood disorders such as the selective serotonin (5-HT) reuptake inhibitors. Anatomical evidence supports the existence of projections from the medial prefrontal cortex (mPFC) to the dorsal raphe nucleus (DR). We report on a functional control of the activity of DR 5-HT neurons by projection neurons in the mPFC. The stimulation of the mPFC elicits two types of responses in DR 5-HT neurons, orthodromic excitations and inhibitions. Excitations are mediated by AMPA/KA and NMDA receptors whereas inhibitions are mediated by GABA(A) and 5-HT(1A) receptors. The activation of a subgroup of 5-HT neurons increases 5-HT release which subsequently activates 5-HT(1A) autoreceptors on other 5-HT neurons. GABA(A)-mediated inhibitions involve GABAergic elements in the DR or adjacent areas. Pyramidal neurons of the mPFC co-express postsynaptic 5-HT(1A) (inhibitory) and 5-HT(2A) (excitatory) receptors. Consistent with the above observations, the selective activation of both receptors in mPFC reduced and increased, respectively, the firing activity of DR 5-HT neurons and the 5-HT release in mPFC. Overall, these data indicate that the activity of the 5-HT system is strongly controlled by the mPFC. Thus, the abnormal prefrontal function in post-traumatic stress disorder and depressive patients may induce a disregulation of 5-HT neurons projecting to other brain areas that can underlie the existing symptomatology in these psychiatric disorders.

Endogenous cannabinoids: a new system involved in the homeostasis of arterial pressure in experimental cirrhosis in the rat.

BACKGROUND & AIMS: Recent studies have described the existence of endogenous cannabinoids with vasodilator activity because of their interaction with peripheral CB1 receptors, anandamide being the most extensively investigated. The study investigated whether endogenous cannabinoids are involved in the pathogenesis of the cardiovascular disturbances in experimental cirrhosis. METHODS: Arterial pressure, cardiac output, and total peripheral resistance were measured before and after the administration of a cannabinoid CB1 receptor antagonist to cirrhotic rats with ascites and to control rats. Blood pressure was also assessed in normotensive recipient rats after the intravenous administration of blood cells or isolated monocytes obtained from cirrhotic and control rats. Moreover, the endogenous content of anandamide was measured in circulating monocytes of cirrhotic and control rats by gas chromatography/mass spectrometry. RESULTS: CB1 receptor blockade did not modify systemic hemodynamics in control rats, but significantly increased arterial pressure and peripheral resistance in cirrhotic animals. Blood cell suspension or monocytes from cirrhotic animals, but not from controls, induced arterial hypotension in recipient rats. Finally, anandamide was solely detected in monocytes of cirrhotic animals. CONCLUSIONS: Monocytes of cirrhotic rats with ascites are activated to produce anandamide and this substance contributes to arterial hypotension in experimental cirrhosis.