Presynaptic nAChR

The consequences of nicotinic signalling are dictated by the subcellular localisation of nAChRs (Fig. 2). It was clear from early studies that a significant proportion of nAChRs in the brain are presynaptic (Wonnacott 1997). Presynaptic nAChRs can directly influence transmitter release. Preterminal nAChRs located at the neck of a synaptic bouton can promote transmitter release by initiating action potentials, and are therefore sensitive to tetrodotoxin (Lena et al. 1993 Dani and Bertrand 2007). 

Responses in the dopamine system are more complex (see chapter by Balfour, this volume). Repeated nicotine injections resulted in enhanced extracellular DA levels in the NAc (Benwell and Balfour 1992, 1997), but not in the striatum (Benwell and Balfour 1997). Analysis of the precise placement of dialysis probes has revealed differential responses to drugs of abuse, including nicotine, between the NAc core (ventral striatum) and shell (Di Chiara 2002 Balfour 2004 Wonnacott et al. 2005 see chapter by Balfour, this volume). Moreover, the sensitised neurotransmitter responses observed in the hippocampus and NAc were markedly attenuated if rats received a constant infusion of a low level of nicotine (Benwell and Balfour 1997). Thus, transient peaks of nicotine appear capable of sensitising some brain pathways with respect to catecholamine release, but the responses may be mitigated by lower sustained plasma concentrations, possibly due to desensitisation. The extent that presynaptic nAChRs contribute to this process in vivo is unclear presynaptic a7 nAChRs on glutamatergic afferents to the VTA merit attention as potential mediators of sensitisation (see Sect. 2.2.2). 

In the peripheral (Wessler 1989) as well as central (Wonnacott 1997) nervous system, presynaptic nicotinic autoreceptors were reported to control the release of acetylcholine. In both locations, the consequence of presynaptic nAChR activation most commonly is an increase in both spontaneous and evoked acetylcholine release (MacDermott et al. 1999), whereas presynaptic muscarinic receptors mediate the opposite effect, an autoinhibition. Recent studies have focused on the composition of presynaptic nAChRs (Table 2). In the hippocampus, nicotinic autoreceptors were suggested to be a3/p4 receptors (Tani et al. 1998), but a role of p2 subunits has also been implicated (Lloyd et al. 1998). Likewise, in the neocortex, presynaptic nicotinic autoreceptors are likely to be 04/ p2 receptors (Marchi et al. 2002). In contrast, in the interpeduncular nucleus the autoreceptors were suggested to mainly contain a3 and p4 subunits (Grady et al. 2001). 

The control of dopamine release via presynaptic nAChRs has been investigated in great detail. Originally, modulation of dopamine release via nAChRs has been revealed in striatal synaptosomes (Rapier et al. 1990). More recently, the receptors involved have been documented to contain 0C4, 0C5, a, P2, and p3 subunits (Luetje 2004 Salminen et al. 2004). Although 0C7 containing receptors were found to contribute to the facilitation of dopamine release, this was due to an indirect effect mediated by increases in glutamate release (Kaiser and Wonnacott 2000). In other... 

In the motor endplate, the excitatory A2a receptors regulate the autofacilitation of ACh rclca.se by interaction with the presynaptic nAChR. This probably occurs through an adenylate cyclase cAMP-dependent mechanism (Correira-de-Sa and Ribeiro, 1994). Blockade of A2 receptors potentiated, and blockade of AI prevented the effect of the presynaptic nAChRs on Ach relea.se. The nAChR agonist dimethyl-4-pheny piperazinium causes facilitation of ACh release when applied for a short time and inhibition when applied for a long time. This change from facilitation to inhibition is prevented if endogenous extracellular adenosine is removed. 

Nicotinic receptors (nicotinic acetylcholine receptors, nACHR) exist not only in the membrane of vertebrate skeletal muscle at the synapse between nerve and muscle (muscle-type nAChR) but also at various synapses throughout the brain, mainly at presynaptic positions (neuronal-type nAChR). Whereas the muscle-type nAChR is precisely composed of two a 1-subunits, one (3 -subunit, one y -subunit and one y -subunit (adult)... 

Central nervous system (CNS A, top). NAChR are involved in various functions. They have a predominantly presynaptic location and promote transmitter release from innervated axon terminals by means of depolarization. Together with ganglionic NAChR they belong to the neuronal type, which differs from the motor type in terms of the composition of its five subunits. 

In the CNS, the nAChRs are located mainly at the presynaptic nerve terminals where they modulate the synaptic activity by regulating the neurotransmitter release. Multiple populations of nAChRs exist, with a largely diverse subunit composition. 

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