Inhibition of Monoamine Oxidases Desensitizes 5-HT_1AAutoreceptors and Allows Nicotine to Induce a Neurochemical and Behavioral Sensitization

Abstract

Although nicotine is generally considered to be the main compound responsible for addictive properties of tobacco, experimental data indicate that nicotine does not exhibit all the characteristics of other substances of abuse. We recently showed that a pretreatment with mixed irreversible monoamine oxidases inhibitors (MAOIs), such as tranylcypromine, triggers a locomotor response to nicotine in mice and allows maintenance of behavioral sensitization to nicotine in rats. Moreover, we showed by microdialysis in mice that behavioral sensitization induced by compounds belonging to main groups of drugs of abuse, such as amphetamine, cocaine, morphine, or alcohol, was underlain by sensitization of noradrenergic and serotonergic neurons. Here, this neurochemical sensitization was tested after nicotine, tranylcypromine, or a mixture of both compounds. Data indicate that, whereas neither repeated nicotine nor repeated tranylcypromine alone has any effect by itself, a repeated treatment with a mixture of nicotine and tranylcypromine induces both behavioral sensitization and sensitization of noradrenergic and serotonergic neurons.

Nicotinic excitation of serotonergic projections from dorsal raphe to the nucleus accumbens

“…In support of that idea, behavioral sensitization to repeated nicotine exposure was enhanced when inhibitory 5-HT 1A autoreceptors were blocked or desensitized, and this correlated with increased release of serotonin (Lanteri et al 2009). Intracranial self-stimulation studies indicate that chronic nicotine lowers the brain reward thresholds, suggesting increased reward, whereas withdrawal from nicotine has the opposite effect .…”

Tranylcypromine Reduces Herpes Simplex Virus 1 Infection in Mice

“…We used TCP at a dose of about 10 mg/kg/day to treat HSV-1-infected mice, because previous neuroscience reports found promising in vivo results in mice with 10 to 6 mg/kg/day of TCP (47)(48)(49)(50). The TCP dose used for our mouse study is higher than those used for humans but is less than the acyclovir dose (10 to 20 mg/kg every 8 h) used to treat HSV-1-infected patients by intravenous injection (51).…”

How Much Serotonin in the CNS is Too Much?

“…Clinically, while SRIs are widely used as a first-line drug to treat depression, MAOIs are often recommended for treatment-resistant depression. Similar to SRIs, the MAOI-evoked increase in 5HT ext is also regulated by feedback mechanisms involving 5HT 1A Rs (Lanteri et al, 2009). Hence, like SRIs, MAOIs could produce relatively higher increases after the feedback inhibition mechanism is eliminated or desensitized, showing a maximum elevation of 5-10 fold above baseline (Tao et al, 1994).…”