Dynamics Of Da Release

Although the studies cited above suggest that the nicotine-evoked release of DA from terminals of mesocorticolimbic and nigrostriatal neurons is primarily a direct result of the stimulation of postsynaptic receptors in the VTA and NA, respectively, the evidence indicates that nicotine's effect at the nerve terminals is modulated by the firing pattern of dopaminergic neurons which, in turn, is affected by amino acid neurotransmitter actions. In the early 1980s, electrophysiological measurements of the activity of dopaminergic neurons in the SN found that, in addition to spontaneous single depolarizations, characteristic bursting patterns of multiple spikes were also observed (Grace and Bunney, 1983, 1984). It was soon discovered that neurons in the VTA had higher burst firing activity than those in the SN (Grenhoff et al., 1986, 1988; Clark and Chiodo, 1988) and the administration of nicotine to animals dramatically increased the amount of burst firing in both of these dopaminergic pathways (Grenhoff et al., 1986).

Evidence that burst firing is controlled by excitatory amino acid neurotransmit-ters was demonstrated by the finding that the administration of NMDA agonists produced an increase in neuronal firing whereas the administration of NMDA antagonists dramatically reduced this activity (Overton and Clark, 1991, 1992; Chergui et al., 1993, Christoffersen and Meltzer, 1995). Further experiments have determined that the origin of the glutamatergic neurons responsible for input to the SN and VTA is primarily from the prefrontal cortex, although several other minor excitatory amino acid pathways to nigrostriatal and mesolimbic neurons have been described (Meltzer et al., 1997; Overton and Clark, 1997). In contrast to the facilitatory effect of glutamate on burst firing, it has been shown that GABAergic input can depress burst firing in nigrostriatal and mesolimbic neurons (Suaud-Chagny et al., 1992; Engberg et al., 1993; Erhardt et al., 1998; Paladini et al., 1999; Celada et al., 1999; Yin and French, 2000). Therefore, it appears that the firing of dopaminergic neurons is modulated in vivo by both excitatory and inhibitory amino acid neurotransmitters.

More direct measurements of glutamatergic modulation of nigrostriatal and mesolimbic neurotransmission come from in vivo microdialysis experiments in which the levels of DA in the striatum and NAc have been determined. It has been shown that stimulation of NMDA receptors at the terminals of the NAc and striatum results in an enhancement of DA release (Overton and Clark, 1992; Asencio et al., 1991). The local application of nicotine in the striatum also increases DA release, as expected; however, nicotine also produces a large increase in glutamate release, and nicotine-stimulated DA release is partially blocked by NMDA receptor antagonists (Toth et al., 1992; Kaiser and Wonnacott, 2000). Thus, nicotine-stimulated DA release in the striatum can occur by a direct and an indirect action. The direct action would be the result of nicotine's interaction with presynaptic nAChRs located on striatal nerve endings, whereas the indirect action would be produced by the stimulation of glutamate release which, in turn, would evoke DA release in the tissue (Vizi and Lendvai, 1999; Wonnacott et al., 2000; Kaiser and Wonnacott, 2000).

It is likely that this same dual action occurs at mesolimbic dopaminergic terminals in the NAc and in the cell bodies of the VTA as well. In the VTA it has been shown that NMDA receptor stimulation leads to an enhanced release of DA from the NAc (Suaud-Chagny et al., 1992; Gonon and Sundstrom, 1996; Westerink et al., 1996; Schilstrom et al., 1998a; Kretschmer, 1999). Also, the elevation of DA release produced by nicotine can be attenuated by the coadministration of NMDA antagonists into the VTA (Schilstrom et al., 1998a), suggesting that cholinergic and glutamatergic neurons act in concert within the VTA to stimulate accumbens DA levels. It has also been shown that the sensitization of both locomotor activity and accumbens DA release, which occurs as a result of subchronic nicotine administration, is decreased by NMDA antagonists (Balfour et al., 1996, 1998; Shoaib et al., 1997b; Svensson et al., 1998). Interestingly, it appears that this decrease in nicotine's effect may be partially due to blockade of nAChR upregulation in the presence of NMDA antagonism (Shoaib et al., 1997b), although the specificity of the MK-801 on NMDA receptors in this latter study is open to question.

The nAChR subtypes responsible for these direct and indirect actions of nicotine have been discussed in detail in preceding chapters. Nevertheless, a few comments are in order as they relate to nicotine-stimulated DA release. The nAChRs which are present on dopaminergic neurons appear to consist primarily of the a3P2 and a4P2 subtypes. At striatal terminals, the application of the relatively selective a3P2 antagonists, neuronal bungarotoxin (Grady et al., 1992) or a conotoxin MII (Kulak et al., 1997; Kaiser et al., 1998) produces a substantial blockade of release, although a significant component of the release appears to be mediated by a4P2 nAChRs as well (Kaiser et al., 1998; Sharples et al., 2000). In any case, the direct actions of nicotine appear to involve nAChRs containing the P2 subunit (Grady et al., 1992; Wonnacott et al., 2000), although a small proportion of receptors at the terminals may contain the P4 subunit based on the activity of cytisine (Reuben et al., 2000).

At the cell bodies of these nigrostriatal neurons, it has been shown that mRNA for the a4 subunit (Sorenson et al., 1998; Arroyo-Jim nez et al., 1999) and a6 subunit (Le Novere et al., 1996; Goldner et al., 1997) predominate. A prominent localization of the mRNA for the a6 subunit along with P3 has also been found in the VTA (Le Novere et al., 1996). These studies suggest that a mixture of nAChR subtypes exist at the cell bodies of nigrostriatal and mesocorticolimbic dopaminergic neurons resulting in complex dynamics for nicotinic stimulation.

In addition to these nAChRs on dopaminergic neurons, it appears that the predominant receptors on the terminals of neighboring neurons which indirectly mediate the release of DA are of the a7 subtype. A discussion of the localization and pharmacology of the nAChRs in the striatum is found in Chapter 2 and has been characterized in recent studies by Wonnacott and coworkers (Wonnocott et al., 2000; Kaiser and Wonnacott, 2000). In the VTA, a7 nAChRs also appear to mediate DA release from the NAc (Schilstrom et al., 1998b). Within the NAc, while the local administration of mecamylamine almost completely blocks nicotine-stimulated DA release (Marshall et al., 1997; Fu et al., 1999), the a7 antagonists, methylcacaconite and a-bungarotoxin, are able to decrease part of the response to nicotine if the mecamylamine blockade is submaximal (Fu et al., 1999), indicating that, as in the striatum, a7 receptors at mesolimbic nerve terminals are involved in modulating the release of DA as well. The a7 receptors have also been implicated in the activation of glutamatergic neurons in the VTA which indirectly stimulate DA release by an action on NMDA and/or AMPA receptors (Desce et al., 1991; Pidoplichko et al., 1997).

From this information it is apparent that the effect of nicotine on dopaminergic neurotransmission is a complex process. At the dopaminergic terminal regions, nAChRs appear to be present on glutamatergic nerve endings in the NAc and CP such that DA levels are enhanced via nicotine-stimulated glutamate release. Nicotinic receptors are clearly present on the dopaminergic terminal as well so nicotine can directly modulate DA release at the synapse. Nicotine's primary activity following systemic administration appears to result from the stimulation of presynaptic nAChR on glutamatergic nerve terminals in the VTA and SN which causes an increase in burst firing of dopaminergic neurons projecting to the NAc and CP. The ability of nicotine to produce a more direct depolarization of dopaminergic neurons in the

VTA and SN via postsynaptic nAChRs on the dendrites and soma of these nerves may contribute to this effect.

Cigarette Crusher

Cigarette Crusher

Get All The Support And Guidance You Need To Permanently STOP Being A Slave To Nicotine And Cigarettes. This Book Is One Of The Most Valuable Resources In The World When It Comes To Easy Ways To Eliminate Smoking Addiction And Revitalize Your Body.

Get My Free Ebook


Post a comment