Neuroanatomical circuitry mediating the sensory impact of nicotine in the central nervous system

Abstract

Direct actions of nicotine in the CNS appear to be essential for its reinforcing properties. However, activation of nicotinic acetylcholine receptors (nAChRs) on afferent sensory nerve fibers are important components of addiction to, and withdrawal from, cigarette smoking. The present study was to identify the neuroanatomical substrates activated by the peripheral actions of nicotine and to determine whether these sites overlap brain structures stimulated by direct actions of nicotine. Mouse brains were examined by immunohistochemistry for c-Fos protein after intraperitoneal injection of either nicotine (NIC, 30 and 40 µg/kg) and/or nicotine pyrrolidine methiodide (NIC-PM, 20 and 30 µg/kg). NIC-PM induced c-Fos immunoreactivity (IR) at multiple brain sites. In the brainstem, c-Fos IR was detected in locus coeruleus, laterodorsal tegmental nucleus and pedunculotegmental nucleus. In the midbrain, c-Fos IR was observed in areas overlapping the ventral tegmental area (VTA) which includes paranigral nucleus, parainterfascicular nucleus, parabrachial pigmental area and rostral VTA. Other structures of the nicotine brain-reward circuitry activated by NIC-PM included hypothalamus, paraventricular thalamic nucleus, lateral habenular nucleus, hippocampus, amygdala, accumbens nucleus, piriform cortex, angular insular cortex, anterior olfactory nucleus, lateral septal nucleus, bed nucleus of stria terminalis, cingulate and medial prefrontal cortex, olfactory tubercle, medial and lateral orbital cortex. Nicotine, acting through central and peripheral nAChRs, produced c-Fos IR in areas that overlapped NIC-PM induced c-Fos expressing sites. These neuroanatomical data are the first to demonstrate that the CNS structures which are the direct targets of nicotine are also anatomical substrates for the peripheral sensory impact of nicotine.

Involvement of the rostral agranular insular cortex in nicotine self-administration in rats

“…A single acute injection of either nicotine or its peripherally-limited analog, nicotine pyrrolidine methiodide, have been observed to induce neural activity, confirmed through c-Fos immunoreactivity, in the RAIC but not the CGIC of mice [33]. Yet interestingly, the ␣7 subtype of the nicotinic acetylcholine receptor has been found within the CGIC but not the RAIC of rats [34].…”

“…As it receives afferents from the high-order [28] medial subdivision of the mediodorsal thalamic nucleus [29,30], along with those from multiple medial thalamic nuclei conveying motivational/affective aspects of peripheral stimuli, the RAIC is considered a high-order multimodal cortical region. The involvement of the RAIC has also been observed in certain models of nicotine addiction [16,31] and neural responses to nicotine exposure [32,33] in rodents.…”

Limbic thalamus and state-dependent behavior: The paraventricular nucleus of the thalamic midline as a node in circadian timing and sleep/wake-regulatory networks

“…The action of orexin in PVT has been implicated in the effects of nicotine on arousal and cognition and in nicotine addiction: peripheral nicotine administration increases Fos expression in orexin neurons projecting to PVT, as reported in the rat (Pasumarthi and Fadel, 2008), and increases of Fos expression in PVT neurons, as reported in the mouse (Dehkordi et al, 2014). Data in rat prefrontal cortical slices have shown that orexin and nicotine excite the same thalamocortical synapses (Lambe et al, 2005), pointing out a direct interaction of orexin and nicotine with thalamic midline terminals in the prefrontal cortex, besides their actions on PVT neurons.…”

The Sensory Impact of Nicotine on Noradrenergic and Dopaminergic Neurons of the Nicotine Reward - Addiction Neurocircuitry

“…The direct effects of nicotine on CNS neurons are critical for its reward and addiction properties [5-9]. Additionally, the sensory impacts of nicotine, mediated by exteroceptive and interoceptive sensory nerve endings in the gustatory, respiratory and circulatory systems, are important components of the nicotine reward-addiction circuitry [10-17]. The importance of the peripheral sensory impact of nicotine in its reward and addiction properties is documented in recent animal studies from our laboratory [17].…”

“…Additionally, the sensory impacts of nicotine, mediated by exteroceptive and interoceptive sensory nerve endings in the gustatory, respiratory and circulatory systems, are important components of the nicotine reward-addiction circuitry [10-17]. The importance of the peripheral sensory impact of nicotine in its reward and addiction properties is documented in recent animal studies from our laboratory [17]. We demonstrated that nicotine pyrrolidine methiodide (NIC-PM), a peripherally-acting analog of nicotine, that does not cross the blood brain barrier, activates virtually all the CNS sites that are direct targets of nicotine.…”