Long-Lasting Enhancement of Glutamatergic Synaptic Transmission by Acetylcholine Contrasts with Response Adaptation after Exposure to Low-Level Nicotine

Abstract

Attempts to mimic synaptic delivery of acetylcholine (ACh) with brief, repetitive pulses of high concentration ACh at synapses of medial habenula (MHN) and interpeduncular nucleus (IPN) neurons in vitro elicited temporally distinct facilitation and inhibition of glutamate secretion via nicotinic and muscarinic ACh receptor-mediated pathways, respectively. ACh-induced nicotinic facilitation was sustained for up to 2 hr, whereas muscarinic inhibition was transient. Prolonged exposure to nicotine inactivated nicotinic receptors selectively, thus decreasing the relative contribution of the facilitatory versus inhibitory influences of ACh. The net effect of ACh in modulating glutamatergic transmission at MHN-IPN synapses may be determined by pre-exposure to nicotine, because the drug appears to switch the balance between the facilitatory and inhibitory actions of ACh.Key words: neuromodulation; glutamate; acetylcholine; nicotine; presynaptic; nicotinic acetylcholine receptors; medial habenula; interpeduncular nucleusThe cholinergic system in the brain has been implicated in a variety of behavioral and cognitive functions, such as working memory, aspects of learning, attention, and arousal. These actions underlie the interaction of the endogenous neurotransmitter ACh with a variety of receptors that modulate neuronal excitability in networks that receive cholinergic afferents (Wainer et al., 1993;Sarter and Bruno, 1997). However, the cellular mechanisms underlying this neuromodulation are poorly understood. Although muscarinic acetylcholine receptors (mAChRs) are renowned for their effects in cortical regions affected in Alzheimer's disease, nicotinic acetylcholine receptors (nAChRs) may also contribute to cholinergic signaling in the normal and aging brain. Nicotine alters a variety of cognitive and behavioral functions through its specific interaction with nAChRs found within the diffuse terminal fields of central cholinergic projections (Woolf, 1991;Levin, 1992). Activation of nAChRs in circuits related to behavioral reinforcement may underlie the renowned effects of nicotine as an addictive drug (Stolerman and Shoaib, 1991;Schelling, 1992;Stolerman and Jarvis, 1995;Rose and Corrigall, 1997;Mansvelder and McGehee, 2000).Nicotinic receptors are found in the cell bodies, dendrites, and within the presynaptic domains of neurons. Recent electrophysiological studies have provided direct evidence that nAChRs mediate synaptic transmission at central synapses (for review, see Jones et al., 1999). In addition, nAChRs are targeted to synaptic terminal and preterminal domains, consistent with demonstrated effects of ACh and nicotine on the release of a wide variety of neurotransmitters (Rapier et al., 1990;Grady et al., 1992;McGehee et al., 1995;Dani and Heinemann, 1996;Gray et al., 1996;McGehee and Role, 1996;Role and Berg, 1996;Wonnacott, 1997;MacDermott et al., 1999).Nicotine interaction with nAChRs facilitates the induction of long-term potentiation of glutamatergic neurotransmission in the hippocampus (Fujii et al., 1999...

Mecamylamine Attenuates Cue-Induced Reinstatement of Nicotine-Seeking Behavior in Rats

“…Second, ample evidence has shown desensitization, an inactive conformation of nicotinic receptors after nicotine exposure (Lukas et al, 1996;Mansvelder et al, 2002). For example, it was shown that six daily nicotine injections resulted in the development of tolerance to its antinociception actions (McCallum et al, 2000) and that nicotinic receptor function could be lost for 424 h following chronic nicotine exposure (Girod and Role, 2001). In the present study, self-administration tests were conducted daily and it might be expected that nicotinic receptors might have remained in a partially desensitized state due to the extended and regular daily exposure to nicotine.…”

Desensitization of neuronal nicotinic receptors

“…While controversy exists over whether prolonged agonist exposure results in up-or down-regulation of receptor function (Buisson and Bertrand, 2002), recovery from this "state," whether it requires purely time (slow transition rates) or de novo receptor synthesis (Boyd, 1987;Hsu et al, 1996), likely influences synaptic transmission for prolonged periods. Girod and Role (2001) recently observed that presynaptic nAChR function could be lost for Ͼ24 h following 24 -72 h treatment with low levels of nicotine (Fig. 5), which implies that desensitized/inactive nAChR conformations may have a critical role in addiction.…”

“…For convenience, upward columns illustrate the percentage of synapses that were facilitated in each condition, whereas downward columns illustrate the percentage of synapses that were inhibited. Reprinted with permission from Girod and Role (2001) ing) the voltage-gated Na ϩ channels that underlie the action potential (Hodgkin and Huxley, 1952). A similar straightforward physiological role for desensitization of ligand-gated ion channels is far from apparent-neurotransmitter is generally not around long enough to provide the continuous stimulation necessary to desensitize these receptors under physiological conditions (Clements, 1996).…”

Cellular and synaptic mechanisms of nicotine addiction

“…In hippocampal slice recordings, Ji et al (2001) found that focal application of ACh to the dendritic region of CA1 pyramidal neurons leads to LTP induction by a weak stimulus that only induces STP without nAChR activation. In addition, focal ACh application induces persistent enhancement of glutamatergic contacts between medial habenula and interpeduncular neurons (Girod and Role, 2001). Together, these findings highlight cellular mechanisms that may contribute to the prolonged excitatory effects on DA release following nicotine exposure (Mansvelder and McGehee, 2000).…”