Executive and social behaviors under nicotinic receptor regulation

Abstract

Nicotine enhances several cognitive and psychomotor behaviors, and nicotinic antagonists cause impairments in tasks requiring cognitive effort. To explore the contribution of nicotinic receptors to complex cognitive functions, we developed an automated method to investigate sequential locomotor behavior in the mouse and an analysis of social behavior. We show that, in the ␤2 ؊/؊ mutant, the high-order spatiotemporal organization of locomotor behavior, together with conflict resolution and social interaction, is selectively dissociated from low-level, more automatic motor behaviors. Such deficits in executive functions resemble the rigid and asocial behavior found in some psychopathological disorders such as autism and attention deficit hyperactivity disorder. N icotine and nicotinic agonists enhance cognitive and psychomotor behaviors in various species (1-5). Conversely, nicotinic antagonists (6, 7) and loss of nicotinic acetylcholine receptors (nAChRs) under various pathological conditions impair cognitive performance (8-10). These pharmacological actions of nicotine are mediated by a variety of nAChR subtypes with different distribution patterns in the brain (11,12). To unravel their respective contribution to brain functions, mice lacking defined nAChR subunits have been generated (for a review see ref. 13).Brain nAChRs are pentameric oligomers composed of protein subunits arranged in various combinations of ␣ (2-9) and ␤ (2-4). The principal combinations that predominate in the brain are ␣4␤2 and ␣7 subunits (13,14). Mice lacking the ␤2 subunits show abnormal passive avoidance (15) and impaired nicotine self-administration (16) and drug discrimination (17) and exhibit a reduced nociceptive response to nicotine (18) and decreased visual acuity (19). On the other hand, general spatial memory tested in the water-maze task is not affected (9).The aim of this article is to explore the contribution of nAChRs to complex cognitive functions referred to as executive processes. The management of these processes provides the maintenance of goal representation, the appropriate adaptation of behavior in a changing environment, the organization of sequences of actions over time, and the inhibition of prepotent or previous responses (20). Former work in humans and animals has shown that these processes require prefrontal and͞or cingulate activation (21-24). Behavioral protocols known to rely on the integrity of these structures were adapted to mice.We developed an automated analytical procedure for locomotor behavior (25) in the mouse. This method makes possible the distinction and quantitative evaluation of high-level executive components from low-level motor behavior. Furthermore, to study an index of adapted responses to a context that potentially leads to conflict resolution, we designed a procedure aimed at the distinction between several types of sequential behaviors in a social context. Interestingly, the ''supervisory planning'' organization of mouse locomotor behavior and conflict resolution were found selectivel...

A neurocomputational hypothesis for nicotine addiction

“…This action is progressively robustly selected, and the neutral choice declines. The initial latency decrease corresponds to the motor activational effects of nicotine observed experimentally (45,46), and the differential responding for the armed vs. the neutral action choice is in direct concordance with experimental results on nicotine self-administration (27).…”

Effects of Topiramate on the Prepulse Inhibition of the Acoustic Startle in Rats

“…More interestingly, PPI enhancements might reflect an improvement in preattentional and executive functions. In support of this possibility, such a phenomenon has been consistently shown for nicotine (Acri et al, 1994;Kumari et al, 1996), a well known enhancer of executive behaviors (Granon et al, 2003). Further studies are warranted to qualify the significance of TPM-mediated PPI enhancement.…”

Concomitant alpha7 and beta2 nicotinic AChR subunit deficiency leads to impaired energy homeostasis and increased physical activity in mice

“…In fact, α7β2nAChR −/− mice showed enhanced motor performance on the rotarod [32] and β2nAChR −/− mice were described as hyperreactive to novelty, suggesting that endogenous nAChR stimulation may exert a tonic control on monoamine-mediated locomotor responses [8]. Hyperactivity associated to β2nAChR deficiency appeared to be linked to selective dissociation of the high-order spatiotemporal organization of locomotor behavior (involving conflict resolution/social interaction) from low-level (more automatic motor behaviors) [9] and to the absence of specific inactive states (corresponding to decision moments) allowing to scan the environment and organize sequences of behavior [10]. Interestingly, hyperactivity of β2nAChR −/− mice can be normalized by selective expression of β2nAChR in the nigrostriatal and mesolimbic brain regions [11].…”

“…Central nicotinic cholinergic signaling also regulates energy homeostasis through modulation of energy expenditure and control of spontaneous physical activity [6,7]. In this context, the β2nAChR −/− mice present an elevation in locomotor behavior but a dampened exploration behavior linked to alterations in the dopaminergic system [8][9][10][11]. In addition to these central roles in the brain, more subtle nAChR expression is detected in nonneuronal cell types throughout the body [12][13][14], suggesting a paracrine role for ACh.…”