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

Abstract

McGehee DS. Nicotinic excitation of serotonergic projections from dorsal raphe to the nucleus accumbens. J Neurophysiol 106: 801-808, 2011. First published May 18, 2011 doi:10.1152/jn.00575.2010.-Tobacco use is a major public health problem, and although many smokers report that they want to quit, only a small percentage succeed. Side effects associated with nicotine withdrawal, including depression, anxiety, and restlessness, certainly contribute to the low success rate. The dorsal raphe nucleus (DRN) is a serotonergic center with many functions, including control of mood and emotional state. We investigated the effect of nicotine on DRN neurons that project to the nucleus accumbens (NAc), an area involved in reward-related behaviors. Using a retrograde labeling method, we found that 75% of DRN-NAc projection neurons are serotonergic. In coronal slices that include the DRN, whole cell recordings were conducted on neurons identified by fluorescent backlabeling from NAc or randomly selected within the nucleus. Nicotine increased action potential firing rates in a subset of DRN neurons. Voltage-clamp recording revealed nicotinic acetylcholine receptor (nAChR)-mediated inward currents that contribute to the nicotineinduced excitation. Nicotinic receptors also indirectly affect excitability by modulating synaptic inputs to these neurons. Nicotine enhanced excitatory glutamatergic inputs to a subset of DRN-NAc projection neurons, while inhibitory ␥-aminobutyric acid (GABA)ergic inputs were modulated either positively or negatively in a subset of these neurons. The net effect of nAChR activation is enhancement of serotonergic output from DRN to the NAc, which may contribute to the effects of nicotine on mood and affect. nicotine; dorsal raphe nucleus; addiction; serotonin; nicotine withdrawal

Presynaptic α4β2 Nicotinic Acetylcholine Receptors Increase Glutamate Release and Serotonin Neuron Excitability in the Dorsal Raphe Nucleus

“…In fact, nicotinic effects on glutamate transmission lasted longer and had a higher prevalence than reported previously by Chang et al (2011). These discrepancies could be attributed to animal age or strain or the fact that they performed all physiology experiments at room temperature, whereas our experiments were done at 33°C.…”

“…One of the most common presynaptic effects of nicotine is to increase glutamate release (McGehee et al, 1995). Taking into account these data, we hypothesized that nicotine increases glutamate release in the DRN, which explains in part the nicotinic stimulatory effects on the firing rate of 5-HT DRN neurons reported previously (Mihailescu et al, 1998(Mihailescu et al, , 2002Chang et al, 2011).…”

“…Postsynaptic effects are short lasting because of nAChRs desensitization, whereas presynaptic effects are long lasting because of glutamate release potentiation. These combined presynaptic and postsynaptic effects of nicotine would increase firing frequency of DRN neurons (Mihailescu et al, 2001(Mihailescu et al, , 2002Chang et al, 2011), which in turn would change the levels of 5-HT in the brain. Contrary to our findings, systemic nicotine administration in rats transiently inhibited 5-HT DRN neurons (Engberg et al, 2000).…”

“…These effects could rely on the ability of glutamatergic neurotransmission to change the circuits regulating the serotonergic tone within the DRN and other brain regions. For example, it has been proposed that an increase of DRN serotonergic output to the nucleus accumbens could partially explain the rewarding and addictive effects of nicotine (Chang et al, 2011).…”

“…Data obtained in our laboratory revealed that postsynaptic nAChRs of 5-HT and non-5-HT DRN neurons are functional (Galindo-Charles et al, 2008) and that nicotine increases the firing frequency of ϳ80% of 5-HT DRN neurons (Mihailescu et al, 1998(Mihailescu et al, , 2002. Accordingly, a recent study has demonstrated the presence of functional somatic and presynaptic nAChRs in DRN neurons that project to the nucleus accumbens (Chang et al, 2011). Nicotine stimulatory effect on 5-HT DRN neurons has been explained previously through presynaptic release of noradrenaline from afferents originating in locus ceruleus (Li et al, 1998).…”