Abstract
Addiction involves long-lasting maladaptive changes including development of disruptive drug-stimuli associations. Nicotine-induced neuroplasticity underlies the development of tobacco addiction but also, in regions such as the hippocampus, the ability of this drug to enhance cognitive capabilities. Here, we propose that the genetic locus of susceptibility to nicotine addiction, the CHRNA5/A3/B4 gene cluster, encoding the α5, α3 and β4 subunits of the nicotinic acetylcholine receptors (nAChRs), may influence nicotine-induced neuroadaptations. We have used transgenic mice overexpressing the human cluster (TgCHRNA5/A3/B4) to investigate hippocampal structure and function in genetically susceptible individuals. TgCHRNA5/A3/B4 mice presented a marked reduction in the dendrite complexity of CA1 hippocampal pyramidal neurons along with an increased dendritic spine density. In addition, TgCHRNA5/A3/B4 exhibited increased VGLUT1/VGAT ratio in the CA1 region, suggesting an excitatory/inhibitory imbalance. These hippocampal alterations were accompanied by a significant impairment in short-term novelty recognition memory. Interestingly, chronic infusion of nicotine (3.25 mg/kg/d for 7 d) was able to rescue the reduced dendritic complexity, the excitatory/inhibitory imbalance and the cognitive impairment in TgCHRNA5/A3/B4. Our results suggest that chronic nicotine treatment may represent a compensatory strategy in individuals with altered expression of the CHRNA5/A3/B4 region.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-014-0147-1) contains supplementary material, which is available to authorized users.
Highlights
It is generally accepted that addiction represents a neuropathology of learning and memory [1]
CHRNA5/A3/B4 overexpression leads to a reduced dendritic complexity in CA1 hippocampal pyramidal neurons that is rescued by nicotine treatment Using Lucifer Yellow (LY) injections and neuronal reconstruction techniques, we detected a reduction in the complexity of the apical dendritic tree in TgCHRNA5/A3/B4 CA1 pyramidal neurons, compared to wild type (WT) (p = 0.019, Figure 1a-b, Sholl analysis), with decreased number of nodes (p < 0.001, Additional file 1: Figure S1a)
We investigated if a chronic nicotine treatment in the adult brain affects the dendritic complexity of CA1 pyramidal neurons
Summary
It is generally accepted that addiction represents a neuropathology of learning and memory [1]. Drugs of abuse, including nicotine, induce neuroplasticity in areas involved in cognitive function, such as the hippocampus, a neuroadaptation assumed to contribute to the development of addiction by favoring associative memories [2,3,4,5,6] These neuroadaptations occur at the level of neuronal structure and synaptic strength and underlie the effects of the drug on cognitive performance [7,8,9,10,11]. Nicotinic acetylcholine receptors (nAChRs) are the main targets of nicotine They play a significant role in cognition and its disruption has been demonstrated in numerous psychiatric and neurological disorders that present cognitive alterations, including schizophrenia [13], attention deficit hyperactivity disorder [14] or Alzheimer’s disease [15]. Understanding the genetic influences on the effects of nicotine on cognition should contribute to the advancement of nicotine addiction treatment, this area of research is relatively new
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