Nicola B. Mercuri⁽¹⁾, Pernilla Grillner^(2)
(1)IRCCS Santa Lucia, University of Rome Tor Vergata - Rome. Italy
⁽²⁾Dept Physiology and Pharmacology. Karolinska Institutet - Stockholm. Sweden

	[Cell Biology & Cytology]	[Neuroscience]

INTRODUCTION

A. Dopaminergic systems of the midbrain

1. Anatomy

Dopamine was discovered as an independent neurotransmitter in the 1950´s (Carlsson et al. 1958). The description of the neuronal populations containing dopamine and their anatomical distribution was subsequently made possible by the introduction of the histochemical formaldehyde fluorescence technique by Falck and Hillarp (Falck et al. 1962) by which the monoaminergic neurones in the brain could be visualised. Dahlström and Fuxe (1964) subsequently provided a more detailed description of the dopaminergic systems in the rat brain. The dopamine neurones of the midbrain are mainly located in three distinct areas, the retrorubral field (A8), the substantia nigra pars compacta (SNPC; A9) and the ventral tegmental area (VTA; A10), which contain 70-75% of the dopamine neurones in the brain. They are organised in two principal dopaminergic systems that are named according to their respective projection areas (see for review Ungerstedt 1971, Björklund and Lindvall 1984). The nigrostriatal system thus originates in the SNPC and projects to the dorsal striatum, i.e. caudate and putamen (Andén et al. 1964), and the mesolimbocortical system projects from the VTA to the limbic areas of the ventral striatum (i.e. nucleus accumbens), amygdala and olfactory tubercle, as well as limbic cortices such as the medial prefrontal, cingulate and entorhinal (Andén et al. 1966, Ungerstedt 1971, Björklund and Lindvall 1984). The dopamine neurones of the retrorubral field (A8) also project to the dorsal striatum and can be viewed as a caudal extension of SNPC (Ungerstedt 1971, Nauta 1978).

 

2. Physiological characteristics of the midbrain dopamine neurones

The dopaminergic neurones of the SNPC and VTA have been well characterised by the use of electrophysiological methods both in vivo and in vitro combined with immunohistochemical techniques (Aghajanian and Bunney 1973, Grace and Bunney 1983, Grace and Onn 1989, Lacey et al. 1989, Johnson and North 1992b). The dopamine neurones described in vivo by intracellular or extracellular recordings in anaesthetised rats have a typical firing pattern that is irregular and usually consists of bursts of action potentials riding on a depolarising wave. The action potential has a characteristic shape with a long duration of the depolarising phase (>2 ms) (Aghajanian and Bunney 1973, Grace and Bunney 1983, 1984). The burst firing activity of dopamine neurones recorded in vivo has been shown to be more efficient in increasing the dopamine efflux in the terminal areas than regular firing activity (Gonon and Buda 1985, Gonon 1988, Bean and Roth 1991, Chergui et al. 1996, 1997). In vitro studies from neurones of the SNPC and VTA in a rat brain slice preparation has revealed the existence of two neuronal types with distinct electrophysiological characteristics (Lacey et al. 1989, Johnson and North 1992b). One class, called principal neurones, consists of neurones with immunoreactivity for the dopamine synthesising enzyme tyrosine hydroxylase and is thus regarded as dopaminergic (Grace and Onn 1989). The other class, named secondary neurones, is considered to be g-aminobutyric acid (GABA)ergic (Mugnaini and Oertel 1985) and/or enkephalinergic (Finley et al. 1981) interneurones. The dopaminergic neurones in vitro display a spontaneous, relatively slow and highly regular firing activity of 0.5-4 Hz. They have action potentials with a long duration (>2ms), a pronounced afterhyperpolarisation (AHP), show an inward current in response to hyperpolarising pulses, and respond with hyperpolarisation to dopamine application (Grace and Onn 1989, Johnson and North 1992b; Mercuri et al., 1995). When recorded in vitro the dopamine neurones can display burst activity if NMDA is applied together with the Ca²⁺-dependent K⁺ channel (K_Ca) blocker apamine (see Seutin et al. 1993). The dopamine cells are readily distinguished from the presumed GABAergic interneurones, which in contrast display an irregular or silent firing activity, with action potentials of shorter duration (<1.5 ms) and show no inhibitory response to dopamine but are inhibited by opiates (Lacey et al. 1989, Johnson and North 1992b). The dopamine neurones in the two different areas have been shown to markedly differ in vitro neither in their physiological properties nor in their response to various pharmacological manipulations. However, in vivo a difference in sensitivity to pharmacological agents is often present and may be explained by the absence of active afferent inputs in vitro.

3. Afferent input to the midbrain dopamine neurones

The SNPC and VTA receive glutamatergic, GABAergic, cholinergic, serotoninergic and noradrenergic afferent inputs.

The glutamatergic afferents to midbrain dopamine neurones arise mainly from the prefrontal cortex, the subthalamic, laterodorsal- (LDTg) and pedunculopontine (PPTg) tegmental nuclei. The glutamatergic input is believed to regulate the firing activity, in particular burst firing, seen in vivo (Grenhoff et al. 1988, Svensson and Tung 1989, Charléty et al. 1991) particularly through activation of ionotropic glutamate receptors of the N-methyl-D-aspartate (NMDA)-type (Chergui et al. 1993, 1994). By electrical stimulation of the afferents in a brain slice preparation, synaptic potentials can be elicited in dopamine neurones that are mediated through activation of predominantly a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainate receptors and to a smaller extent through NMDA receptor activation (Mereu et al. 1991, Johnson and North 1992b). Metabotropic glutamate receptors (mGluRs) have also been shown to mediate a slow excitatory (Shen and Johnson 1997) as well as an inhibitory synaptic potential (Fiorillo and Williams 1998). Bath application of a metabotropic agonist induces an excitatory current in the dopamine neurones (Mercuri et al.1993). The presence of glutamate in the dopamine neurones themselves has recently been reported (Sulzer et al. 1998). It was shown that cultured midbrain dopamine neurones form functional glutamatergic synapses, so-called autapses.

The GABAergic input to the midbrain dopamine neurones originates in the striatum and pallidum (Fonnum et al. 1978, Bolam and Smith 1990, Smith and Bolam 1990) and from intrinsic GABAergic interneurones of the midbrain (Di Chiara et al. 1979, Grofova et al. 1982, Stanford and Lacey 1996). Both GABA_A- and GABA_B-mediated synaptic potentials can be evoked by focal stimulation of the slice preparation (Johnson and North 1992b). Bath application of GABA induces a hyperpolarisation mediated through both GABA_A and GABA_B receptor activation. The GABA_B-mediated responses are G-protein mediated causing an increase in K⁺ conductance (Lacey et al. 1988).

The cholinergic input to the dopamine neurones arises in the PPTg and in the adjacently located LDTg (Beninato and Spencer 1987, Clarke et al. 1987, Bolam et al. 1991). The LDTg predominantly projects to VTA while PPTg projects to SNPC (Oakman et al. 1995). These pontine nuclei thus provide both glutamatergic and cholinergic innervation to the dopamine neurones as revealed by immunocytochemical labelling for choline-acetyltransferase and glutamate combined with anterograde tracing techniques (Lavoie and Parent 1994a, c). The PPTg sends an extensive projection to the SNPC, where the terminals closely surround the soma and proximal dendrites of the dopamine neurones (Lavoie and Parent 1994b). Both muscarinic and nicotinic receptors are present on dopamine neurones (Clarke et al. 1985, Cortès and Palacios 1986, Schwartz 1986, Wada et al. 1989) and pharmacological activation of these receptors leads to excitation of the dopamine neurones in vitro (Calabresi et al. 1989, Lacey et al. 1990). Nicotine, administered systemically in vivo, increases the burst firing activity of VTA dopamine neurones (Grenhoff et al. 1986, Mereu et al. 1987) associated with an increased release of dopamine in the nucleus accumbens (Imperato et al. 1986, Damsma et al. 1989), that is blocked by local application into the VTA, but not into the nucleus accumbens, of the nicotinic receptor antagonist mecamylamine (Nisell et al. 1994). Furthermore, chemical stimulation of the PPTg excites the dopamine neurones of SNPC, an effect that is blocked by local application of mecamylamine in the SNPC (Clarke et al. 1987). However, synaptic potentials mediated through activation of cholinergic receptors have, as yet, not been convincingly demonstrated in dopamine neurones.

Also the raphe nuclei and the locus coeruleus provide serotoninergic (Dray et al. 1976, Fibiger and Miller 1977, Phillipson 1979, Hervé et al. 1987, van Bockstaele et al. 1994) and noradrenergic (Phillipson 1979, Grenhoff et al. 1993, 1995) afferent inputs to dopamine neurones.

 

4. Functional role of the midbrain dopamine neurones

The dopamine neurones of the midbrain are implicated in motor tasks related to normal movements, motivational as well as reward-related behaviour and cognitive functions (see for review Le Moal and Simon 1991, Schultz 1997, 1998, Koob et al. 1998).

The nigrostriatal dopamine neurones are critically involved in the pathophysiology of Parkinson´s disease (Carlsson et al. 1959, Ehringer and Hornykiewicz 1960), and degeneration of the dopamine neurones in the ventrolateral part of SNPC and to a lesser degree also in the VTA is responsible for the typical symptoms of Parkinson´s disease, namely, bradykinesia, rigidity and tremor. The degeneration of the dopamine neurones leads to a reduced dopamine output to neostriatum (e.g. caudate-putamen), increasing the activity in the indirect loop to globus pallidus internal and substantia nigra pars reticulata (SNPR) of the basal ganglia leading to an increased inhibition of motor output from thalamus (see for review DeLong 1990). As proposed by Carlsson (1959) the dopamine precursor L-DOPA was shown to provide the first effective treatment for the disease by Birkmayer and Hornykiewicz in 1961, and is still the most effective treatment of Parkinson´s disease despite severe side effects affecting up to 75% of the patients after five years treatment.

The mesolimbocortical dopamine neurones are profoundly implicated in reward-related behaviour (see for review Koob et al. 1998, Robbins and Everitt 1999) and many drugs of abuse including cocaine, amphetamine, opiates, ethanol and nicotine are known to directly or indirectly cause an increased release of dopamine in terminal areas (di Chiara and Imperato 1988, see for review Di Chiara 1995). Moreover, specific lesions of nucleus accumbens projecting dopamine neurones reduce self-administration of nicotine (see Corrigall et al. 1992), cocaine and amphetamine (see Roberts et al. 1980, Wise and Bozarth 1987). Rats can also learn to electrically self-stimulate the dopaminergic neurones of the VTA (Corbett and Wise 1980, Wise and Rompre 1989, Wolske et al. 1993, Garris et al. 1999). The cholinergic input to the dopamine neurones has been shown to be implicated in mediating rewarding brain stimulation of the lateral hypothalamus (Yeomans et al. 1985, 1993, 1997). In several in vitro studies nicotine has been shown to excite dopamine neurones (Calabresi et al. 1989, Pidiplicko et al. 1997, Picciotto et al. 1998) whereas opiates have been shown to inhibit the GABAergic input to dopamine neurones, leading to a disinhibition of the dopamine neurones (Johnson and North 1992a).

Studies in the monkey (Schultz et al. 1993, 1998) have further analysed the role of the midbrain dopamine neurones in reward-related tasks and demonstrated that the dopamine neurones are, indeed, activated by a primary reward and especially if it is unexpected. If the reward is coupled to a conditioning signal (visual or auditory), the increased firing of the dopamine neurones will switch from the moment of appearance of the reward to the instant when the conditioning stimulus appears, and not when the actual reward is delivered. Moreover, if the conditioning stimulus is not followed by the expected reward the dopamine neurones decrease their firing. The dopamine neurones can thus detect deviations from the expected reward so that a positive signal is delivered to the brain if the reward is better than expected, no change if the reward is just as expected, and negative if less than expected.

Therefore, it has been suggested that the midbrain dopamine neurones serve two functions: ⁽¹⁾ to provide a tonic, generally enabling input on postsynaptic neurones in terminal fields, and ⁽²⁾ to send a phasic, global reinforcement or teaching signal to the brain, which helps to adapt behaviour and motor acts according to the motivational value of environmental stimuli (see for review Schultz 1997, 1998, Schultz et al. 1997, 1998, Redgrave et al. 1999).

The prefrontal projection of the mesocortical dopamine neurones from VTA are considered to modulate neuronal activity in the prefrontal cortex related to cognitive functions such as working memory, planning and execution of behaviour, inhibitory response control and maintenance of focused attention (see Le Moal and Simon 1991). Also reward-related stimuli increase dopaminergic activity in this region (Taber and Fibiger 1997). In particular, D₁ receptor activation has been demonstrated to be required for the adequate performance of working memory tasks (Sawaguchi and Goldman-Rakic 1994).

In addition to their implication in reward-related behaviour and cognitive functioning, the mesolimbocortical dopamine neurones are considered to be involved in the symptomatology of schizophrenia (see Carlsson 1988). The `dopamine hypothesis of schizophrenia´ was based on the fact that: ⁽¹⁾ all effective neuroleptic drugs used for treatment of schizophrenia share antidopaminergic activity and ⁽²⁾ drugs which directly or indirectly facilitates dopaminergic neurotransmission in brain, e.g. amphetamine or L-DOPA, can precipitate or aggravate psychosis. However, this classical hypothesis has been challenged by the relative lack of effect of the typical neuroleptics on negative symptoms, by the difficulties to find unequivocal evidence for dopaminergic hyperactivity in the brains of schizophrenic patients and by the fact that the atypical antipsychotic drug clozapine, despite its lower occupancy of D₂ receptors, has a significantly higher efficacy and a better effect on negative symptoms (Farde et al. 1988, 1992, Kane et al. 1988, Nordström et al. 1995). Clozapine is not only a D₂ receptor antagonist but has also affinity for D_1,4, a_1,2-adrenergic, 5-HT_2A,6,7, muscarinic and histaminergic receptors (see for review Seeman 1990, Roth et al. 1998), and in contrast to classical neuroleptic drugs it increases dopamine efflux in the prefrontal cortex (Moghaddam and Bunney 1990, Nomikos et al. 1994). This is of particular interest in view of the role of prefrontal dopamine in cognitive functioning and may have bearing on its effectiveness against cognitive and negative symptoms (Hertel et al. 1999). Consequently, the original dopamine hypothesis of schizophrenia, proposing a global hyperactivity of brain dopaminergic systems needs to be revised. A differential dysfunctioning of the dopaminergic systems with hyperactivity or hyperreactivity in some areas and hypofunction in others (Weinberger et al. 1986, Svensson et al. 1993) seems more likely. Such a dysfunction of brain dopamine systems may, in turn, rather be related to alterations in the input neurones to the dopamine neurones (Nauta 1976, Svensson et al. 1995).

 

B. Synaptic transmission and its modulation

The neuronal activity of individual neurones and the accompanying release of neurotransmitter are determined by the intrinsic firing activity and by the afferent control of the neurone. Synaptic transmission can be either fast or slow. In fast synaptic transmission the released neurotransmitter activates ligand-gated ion channels leading to a direct opening of the channel and a flux of ions across the cell membrane. In slow synaptic transmission the transmitter released activates G-protein-coupled receptors that induce opening or closure of ion channels. Glutamate and GABA are the predominant neurotransmitters of the brain and can mediate both fast and slow transmission. Acetylcholine (ACh) and serotonin (5-HT) can also mediate both fast and slow neurotransmission but only few examples of fast neurotransmission have been reported for these transmitters in the brain (see Roerig et al. 1997, Ullian et al. 1997, Alkondon et al. 1998). Noradrenalin and dopamine act exclusively on G-protein-coupled receptors. In addition to their postsynaptic effects these neurotransmitters can also modulate synaptic transmission through activation of various receptors located at the presynaptic terminal.

1. Involvement of voltage-gated Ca²⁺ channels in synaptic transmission

The synaptic release of neurotransmitters from their vesicles in the nerve terminal to the synaptic cleft requires an increase in Ca²⁺ concentration in the terminal. The opening of voltage-gated Ca²⁺ channels provides this Ca²⁺ increase as the action potential invades the presynaptic terminal, leading to Ca²⁺ influx from the extracellular space.

The voltage-gated Ca²⁺ channels are divided into two groups, low voltage activated (LVA) channels that are activated by small membrane depolarisations and high voltage activated (HVA) channels that require a larger depolarisation for their activation. The different types of channels are named after their characteristic properties (Nowycky et al. 1985, Llinás et al. 1992, see for review Tsien et al. 1988, Snutch and Reiner 1992, Hille 1992). LVA channels also called T-type channels, inactivate rapidly and induce a transient current. HVA channels consists of the L-type channels that are large and long lasting, are abundant in all excitable tissue (the heart, smooth muscle and in the nervous system) and are sensitive to 1,4-dihydropyridines (DHPs), N-type channels that were described first in neuronal tissue and are blocked by w-conotoxin GVIA (w-CTX GVIA), P/Q-type channels which are predominant in cerebellar Purkinje cells and have a slow inactivation and are blocked by w-Agatoxin IVA (w-Aga IVA), and finally R-type channels which conduct the residual current remaining after blockade of all other HVA Ca²⁺ channels. The different Ca²⁺ channels can thus be identified using specific pharmacological tools (Nowycky et al. 1985, Fox et al 1987, Tsien et al 1988, Llinás et al 1992, Mintz et al. 1992, Pearson et al. 1995, Randall and Tsien 1995).

The voltage-gated Ca²⁺ channels preferentially involved in synaptic transmission in the mammalian brain are the N- and P/Q-type channels (Takahashi and Momiyama 1993, Regehr and Mintz 1994, Wheeler et al. 1994, Wu and Sagau 1994, see for review Dunlap et al. 1995, Reuter 1996), since blockade of L-type channels does not affect synaptic transmission in the hippocampus, nucleus accumbens, cerebellum and striatum (Kamiya et al. 1988, Horne and Kemp 1991, Regehr and Mintz 1994, Turner et al. 1993, Wheeler et al. 1994). However, L-type channels have been shown to regulate release of catecholamines from chromaffin cells, neuropeptides from the neurohypophysis and hippocampal granule cells and excitatory amino acids in the retina (Lemos and Nowycky 1989, Takibana et al. 1993, Lopez et al. 1994, Simmons et al. 1995, von Gersdorff and Matthews 1996). DHPs have also been shown to inhibit the spontaneous firing of dopamine neurones in vitro (Mercuri et al. 1994).

 

2. Glutamate-mediated synaptic transmission

Glutamate can activate both ligand-gated ion channels, i.e. ionotropic glutamate receptors, and G-protein-coupled receptors, i.e metabotropic glutamate receptors (mGluRs) and synaptic transmission can be mediated through both types.

Ionotropic glutamate receptors are mainly of three types: AMPA, kainate and NMDA receptors. AMPA and kainate receptors are permeable mainly to Na⁺ and K⁺, whereas NMDA receptors, in addition, are permeable to Ca²⁺ and have a particular characteristic of being both ligand-gated and voltage-dependent. Mg²⁺ that blocks the NMDA channel pore only at a more negative potential controls the voltage dependence. In addition, the receptor is also allosterically modulated by glycine. NMDA receptor activation is critical for the induction of long term potentiation (LTP) - a plasticity phenomenon in many systems which has been implicated in memory formation (Bliss and Lomo 1973, see for review Bliss and Collingridge 1993). Whereas AMPA-mediated synaptic transmission is of shorter duration, NMDA receptors mediate a slower synaptic event. Until quite recently the physiological role of kainate receptors was unclear, but it has recently been reported that they can mediate a slow synaptic potential in the mossy fibre pathway of the hippocampus (Castillo et al. 1997, Vignes and Collingridge 1997). At about the same time it was shown that kainate receptors could mediate presynaptic inhibition of GABA release also in the hippocampal formation (Clarke et al. 1997). Moreover, the belief that the AMPA and kainate act exclusively on ionotropic receptors had to be modified, since it has recently been shown that they may also act through G-proteins and affect second-messenger pathways (Wang et al. 1997, Rodriguez-Moreno and Lerma 1998).

The mGluRs are divided into three groups (I, II and III) based on their molecular sequence homology, transduction mechanism and pharmacology. Group I mGluRs (mGluR1 and 5) are coupled to phospholipase C, whereas group II (mGluR 2 and 3) and III (mGluR4, 6, 7 and 8) are negatively coupled to adenylate cyclase. The different groups can be distinguished from each other using specific pharmacological tools. The functional role of mGluRs described so far is to presynaptically modulate GABA and glutamate release and to be involved in synaptic plasticity, for example LTP in hippocampus (see for review Pin and Bockaert, 1995, Pin and Duvoisin 1995, Pin 1998).

In midbrain dopamine neurones application of the mGluR agonist trans-(±)-1-amino-1,3-cyclopentanedicarboxylic acid (t-ACPD) exerts an excitatory action inducing an inward current (Mercuri et al. 1993). It has also been demonstrated that slow excitatory synaptic currents can be evoked by a repetitive stimulation of afferents to dopamine neurones (Shen and Johnson 1997). This effect was suggested to be mediated through group I mGluR activation. In the same preparation also an inhibitory synaptic current mediated through mGluRs can be elicited by a shorter repetitive stimulation (Fiorillo and Williams 1998). This effect is also due to activation of group I mGluRs, which instead of inducing an excitation increases the release of Ca²⁺ from internal stores leading to activation of K_Ca, and thereby hyperpolarising the membrane potential.

 

3. GABAergic neurotransmission

GABAergic neurotransmission is mediated through activation of the ionotropic GABA_A receptor that is permeable to Cl^- or through the GABA_B receptor that is a G-protein-coupled receptor activating K⁺ channels. The GABA_B receptor consists of two different subunits that form a heteromer. Without co-expression of the two different subunits functional receptors can not be formed (Jones et al. 1998, White et al. 1998, Kaupman et al. 1998, Kuner et al. 1999). In dopamine neurones synaptic potentials mediated through both types of receptors can be evoked, the GABA_A with a single electrical pulse and the GABA_B with a short train of repetitive stimulating pulses (Johnson and North 1992b). The two types of GABA mediated synaptic transmission to midbrain dopamine neurones have proved to be differentially modulated and their afferents might be distinct from each other (Johnson et al. 1992, Cameron and Williams 1993, Wu et al. 1995).

4. Cholinergic neurotransmission

Cholinergic neurotransmission is mediated through nicotinic and muscarinic receptors. Nicotinic acetylcholine receptors (nAChR) are ligand-gated ion channels formed by the assembly of 5 subunits. The subunits found in the central nervous system are of the a- or b- subtype. There are 8 different a-subunits (a_2-9) and 4 b-subunits (b_2-5) described in the CNS of vertebrates (Boulter et al. 1986, Sargent 1993). Functional nAChR can be formed by combinations of various a-and b-subunits, forming heteropentamers, or by the a_7-9 alone, forming homopentamers (Galzi and Changeux 1994). The nAChRs of the nervous system differ somewhat from the muscular types in respect to ion permeability. Neuronal nAChRs are permeable to Na⁺ as the muscular type but also to Ca²⁺ (see for review Vidal and Changeux 1996, Changeux et al. 1998).

Nicotinic receptors have only in a few cases been shown to mediate fast synaptic transmission in the brain (Roering et al. 1997, Ullian et al.1997, Alkondon et al. 1998, see for review Vidal and Changeux 1996). This is surprising since nicotine application clearly can induce excitation of many neuronal types in various regions of the brain (neocortex, VTA, SNPC, medial habenula, hippocampus etc; Calabresi et al. 1989, see for review Vidal and Changeux 1996). In recent years, attention has been focused on the role of nAChRs located presynaptically that are capable of facilitating synaptic release of both glutamate and GABA (Léna et al. 1993, Vidal and Changeux, 1993, McGehee et al. 1995, Gray et al. 1996). It was even hypothesised that the major role of nAChRs in the brain is that of a presynaptic modulator (McGehee et al. 1995).

In the VTA nicotine has been shown to excite dopamine neurones through a direct activation of nAChR on dopamine neurones. In addition, some evidence for a functional role of nicotinic receptors on glutamate afferents to the dopamine cells has recently been obtained in vivo by Schilström et al. (1998a).

Muscarinic receptors are all G-protein-coupled receptors. Five different subtypes have been cloned and are named m_1-5 and these correspond to the M_1-5 that can be distinguished using pharmacological tools (Bonner et al. 1987, Hulme et al. 1990). The m_1,3,5 are coupled to the inositol triphosphate (IP₃) system, whereas the m_2,4 are negatively coupled to adenylate cyclase (Hulme et al. 1990, Bonner et al. 1992). Muscarinic receptors can mediate slow synaptic transmission but also exert presynaptic modulation of synaptic transmission in various areas of the brain (Sugita et al. 1991, Hasselmo and Bower 1992, Hsu et al. 1995, Sim and Griffith 1996). In the midbrain dopamine neurones muscarine has previously been shown to exert an excitatory effect suggested to be M₁-mediated and the ionic mechanisms involved were suggested to be Ca²⁺- rather than K⁺-dependent (Lacey et al. 1990).

Discussion Board

Any Comment to this presentation?

[ABSTRACT] [INTRODUCTION] [MATERIAL & METHODS] [RESULTS] [DISCUSSION] [REFERENCES] [Discussion Board]

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	[Cell Biology & Cytology]	[Neuroscience]

Nicola B. Mercuri, Pernilla Grillner
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Last update: 4/01/00