Abstract
Nicotine, the main addictive component of tobacco smoke, has both rewarding and aversive properties. Recent studies have suggested that GABAergic neurons, one of the main neurochemical components of the reward-addiction circuitry, may also play a role in the aversive responses to nicotine. In the present study of transgenic mice expressing Green Fluorescent Protein (GFP) in Glutamate Decarboxylase 67 (GAD67) neurons, we hypothesized that a subpopulation of GABAergic neurons in the Ventral Tegmental Area (VTA) are the targets of aversive doses of nicotine in the CNS. We tested this hypothesis using c-Fos immunohistochemical techniques to identify GAD67-GFP positive cells within the VTA, that are activated by a single intraperitoneal (i.p.) injection of a low (40 ug/kg) or a high (2 mg/kg) dose of nicotine. We also assessed the anatomical location of GAD67-GFP positive cells with respect to tyrosine hydroxylase (TH) Immunoreactive (IR) dopaminergic cells in VTA. Consistent with our previous studies low- and high-dose nicotine both induced c-Fos activation of various intensities at multiple sites in VTA. Double labeling of c-Fos activated cells with GAD67-GFP positive cells identified a subpopulation of GABAergic neurons in Substantia Nigra Compact part Medial tier (SNCM) that were activated by high- but not by low-dose nicotine. Of 217 GABAergic cells counted at this site, 48.9% exhibited nicotine induced c-fos immunoreactivity. GAD67-GFP positive cells in other regions of VTA were not activated by the nicotine doses tested. Double labeling of GAD67-GFP positive cells with TH IR cells showed that the GABAergic neurons that were activated by high-dose nicotine were located in close proximity to the dopaminergic neurons of substantia nigra compact part and VTA. Dose-dependent activation of GAD67-GFP positive neurons in SNCM, by a nicotine dose known to produce aversive responses, implies that GABAergic neurons at these sites may be an important component of the nicotine aversive circuitry.
Highlights
Nicotine, the main addictive component of cigarette smoke, acts on various nicotinic acetylcholine receptors of the mesolimbic reward pathways to facilitate dopamine (DA) release in nucleus accumbens [1,2,3,4,5]
In rostral Ventral Tegmental Area (VTA), corresponding to bregma −3.15 to −3.07 mm, Glutamate Decarboxylase 67 (GAD67)-Green Fluorescent Protein (GFP) positive cells were seen in areas overlapping Substantia Nigra Reticular part (SNR), Substantia Nigra Compact part, Medial tier (SNCM) and Red nucleus Parvocellular part (RPC) (Figure 1: Panels A–C)
In caudal VTA, corresponding to bregma −3.87 to −3.63 mm, GAD67-GFP positive cells were seen in areas that were ventral, lateral and rostral to Paranigral Nucleus (PN), Parabrachial pigmented nucleus (PBP) and to Parainterfascicular Nucleus (PIF) of VTA and at sites that correspond to Interpeduncular
Summary
The main addictive component of cigarette smoke, acts on various nicotinic acetylcholine receptors (nAChRs) of the mesolimbic reward pathways to facilitate dopamine (DA) release in nucleus accumbens [1,2,3,4,5]. The precise mechanism by which nicotine acts to regulate the activity of DA signaling is not clear. Multiple biochemical studies have demonstrated that the activity of dopaminergic neurons in ventral tegmental area (VTA) is regulated by glutamatergic and GABAergic interneurons, as well as by projections from other brain regions [6,7,8]. Electrophysiological studies have shown that a single exposure to nicotine causes a transient increase in GABAergic transmission [8]. This response is followed by a persistent depression of the inhibitory GABAergic signal, caused by desensitization of the nAChRs [8,9,10]. Nicotine enhances glutamatergic transmission, via nAChRs which desensitize less than the nAChRs on GABAergic neurons, thereby, shifting the balance toward excitation [8,11,12,13]
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