Glutamate And Dopamine Interactions In The Motive Circuit

2.1. Glutamate and Dopamine Receptors

Extracellular dopamine binds to two major families of receptors; D1-like, which consists of D1 and D5 receptors, and D2-like, which consists of D2, D3, and D4 receptors. The receptor subtypes within each group share molecular and pharmacological properties but can differ in their anatomical distribution. The D1 receptor family is coupled to G proteins and is associated with the activation of adenylyl cyclase. In contrast, the family of D2 receptors are involved in inhibition of adenylyl cyclase activity, inhibition of phosphatidylinositol turnover, increased K+-channel activity, and modulating calcium conductances (26,27).

Glutamate receptors consists of ionotropic and metabotropic receptors. Ionotropic glutamate receptors are classified as N-methyl-d-aspartic (NMDA), a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), and kainate receptors. NMDA receptors are heteromerically formed by NRI and NR2 subunits. In addition to agonist binding, activation of NMDA receptors requires the depolarization of the postsynaptic membrane in order to overcome magnesium blockade of the ion channel; at which point, there is a relatively long lasting increase in Ca2+ efflux. AMPA receptors consist of GluRl GluR2, GluR3, and GluR4 subunits, whereas kainate receptors consist of GluR5-7, KA1, and KA2. Activation of AMPA and kainate receptors opens cation Na+ and Ca2+ channels resulting in a rapid rise and decay of synaptic currents. AMPA receptor activation, in particular, is thought to mediate most forms of fast glutamatergic neurotransmission (28,29).

In addition to the ionotropic receptors, eight metabotropic glutamate receptors (mGluR) have been cloned. The corresponding protein products are divided into three families: group I consists of mGluR1 and 5 receptors, group 2 consists of mGluR2 and 3 receptors, and group 3 consists of mGluR4, 6, 7, and 8 receptors. Group 1 receptors are coupled to phosphatidlylinositiol turnover. Group 2 receptors inhibit forskolin-stimulated formation of cAMP, and group 3 receptors are negatively coupled to adenylate cyclase (30).

2.2. Anatomy of the Motive Circuit

The circuitry outlined in Fig. 1 has been termed the motive circuit and is key in translating incoming stimuli into a behavioral response (31,32). A central component of the motive circuit is the meso-accumbens system. Although primarily a dopaminergic projection, as much as 20% of the meso-accumbens pathway contains y-aminobutyric acid (GABA) instead of dopamine (33). A second critical pathway originating in the VTA is the mesoprefrontal pathway, which sends dopamine projections to the PFC. A portion of these neurons synapse directly onto glutamatergic pyramidal neurons projecting to the nucleus accumbens. Surprisingly, almost 40% of these neurons contain GABAergic (33). In addition to the PFC, the nucleus accumbens receives glutamatergic afferents originating in the hippocampus, mediodorsal thalamus, and basolateral amygdala (34-37). The cells projecting from the nucleus accumbens terminate in the ventral pallidum and ventral mesencephalon and are GABAergic medium spiny neurons.

Ultrastructural anatomical studies indicate that dopamine and glutamate neurotransmission have numerous points of putative interaction within the motive circuit. Both the pyramidal cells in the PFC and medium spiny neurons in the nucleus accumbens are innervated by both transmitters. Within the nucleus accumbens, dopamine and glutamate afferents both synapse onto dendritic spines of the medium spiny neurons. Excitatory afferents synapse onto the head of the spine, whereas dopamine terminals synapse onto the neck of the spine (38,39). A similar orientation has been observed in the PFC, where dopamine synapses on more proximal portions of the pyramidal cell dendrite than glutamatergic afferents from the mediodorsal thalamus (40). Within the VTA, cortical glutamatergic afferents synapse onto both GABAergic and dopaminergic neurons projecting to the nucleus accumbens and PFC (41).

2.3. Neuronal Activity in Motive Circuit

Electrophysiological studies have been key in characterizing the contribution that individual nuclei make to the flow of information through the motive circuit. Given the anatomy of the circuit, the following subsections will review the contribution of glutamate and dopamine receptor stimulation in the nucleus accumbens PFC, and BLA to the activity of the medium spiny neurons in the nuecleus accumbens.

2.3.1. Nucleus Accumbens

Through a series of experiments over the last decade, Grace and colleagues presented compelling evidence that excitatory afferents to spiny cells from the hippocampus and amygdala serve to gate activity of glutamatergic afferents originating in the PFC (42). The activity of medium spiny neurons exhibit biphasic states characterized by a depolarized state in which the cell is more excitable and a hyperpolarized nonfiring state in which the cell is unlikely to fire (19,43). Hippocampal glutamatergic afferents appear to regulate the transition to the up (relatively depolarized) state. Specifically, stimulation of fimbria fornix produced a long-lasting duration of the up state (19). Similarly, stimulation of BLA resulted in a brief transition to the depolarized state. (44). Conversely, PFC glutamatergic afferents to the accumbens do not appear to alter the frequency of up or down states, but, instead produce action potentials in medium spiny neurons provided the cell is in the up state (19). Stimulation of either NMDA or AMPA receptors in the accumbens produces excitation in medium spiny neuron; however, AMPA but not NMDA receptor antagonists block glutamate-induce excitation of medium spiny neurons (45).

Dopamine neurotransmission in the accumbens also modulates the biphasic states observed in medium spiny neurons. Stimulation of D1 receptor in the NAc is thought to promote a voltage-dependent calcium conductance that prolongs the duration of the up state (46,47) However, this occurs only when the neuron is in the up state because the calcium conductance is voltage dependent. In contrast, stimulation of D2-like receptors in the accumbens supports the duration of the down state, as well as decreasing the frequency of transition from the down state to the up state (42). Taken together, this compound effect of dopamine transmission serves to increase the signal-to-noise ratio by supporting either the up or down state. Thus, if there is more depolarizing glutamatergic input, dopamine transmission will increase the duration of depolarization by increasing calcium conductance, and in the relative absence of depolarizing input, dopamine will support an inactive state. This dopaminergic filter on the transit of information is consistent with behavioral studies that have concluded that dopamine serves to "gate" information through the nucleus accumbens (17).

2.3.2. Ventral Tegmental Area

The activity of meso-accumbens dopamine neurons is differentially modulated by stimulation of glutamatergic and dopaminergic receptors in the VTA. Meso-accumbens dopaminergic neurons are characterized by long-duration action potentials, irregular- and burst-firing patterns, and slow conduction velocities. Stimulation of NMDA receptors in the VTA regulates burst firing (48,49), whereas stimulation of AMPA receptors appears to regulate the overall firing rate (50) Conversely, stimulation of dopamine receptors in the VTA produces an inhibition of activity modulated by D2 autoreceptors. The role of D1 receptor stimulation is unclear because these receptors are located on glutamatergic terminals and GABAergic interneurons. Thus although stimulation of D1 receptors fails to directly alter the activity of meso-accumbens DA neurons (51,52) it would be expected to affect overall excitatory and inhibitory tone to the cells.

2.3.3. Prefrontal Cortex

Similar to medium spiny neurons in the accumbens, projection (pyramidal) cells in the PFC also exhibit biphasic states (53,54), although the regulation of these states is not well understood. Interestingly, however, several studies have shown that dopamine projections from the VTA modulate this pathway. Ultrastructural studies indicate that glutamate and DA afferents to the PFC synapse directly onto dendritic spines and shafts of pyramidal neurons (38,39). Dopamine neurotransmission in the PFC is thought to inhibit PFC efferents, in part due to observations that stimulation of the VTA decreases cell firing in the PFC (55,57), and this is attenuated by blockade of D2-like DA receptors (57). However, the inhibition of cell firing observed following stimulation of the VTA may also involve GABA release, consistent with the aforementioned anatomical studies indicating that approx 40% of neurons from VTA to PFC are GABAergic (58). More recently, it has been suggested that DA in the PFC, similar to the NAc, acts as a state stabilizer. This conclusion was based on the observation that, akin to the spiny cells in the nucleus accumbens (see above), stimulation of the VTA produces an increase in duration of the pre-existing state of the cell (42). In fact, also similar to the nucleus accumbens, stimulation of D1-like dopamine receptors in the PFC increases cell excitability but only when the cells are in the depolarized state (59).

2.3.4. Basolateral Amygdala

The BLA contributes to the activity of the motive circuit by sending glutamatergic projections to both the accumbens and the PFC. Stimulation of the BLA produces a brief increase in the frequency of cells in the up state in the accumbens (44). In turn, the activity of the BLA is modulated by excitatory afferents from the PFC, sensory cortex, and thalamus, as well as dopaminergic afferents from the VTA (60,61). Specifically, extracellular dopamine in the BLA acts to inhibit PFC afferents while enhancing afferents originating in sensory cortical regions (62). Within the BLA, there are two types of neurons: inhibitory interneurons and pyramidal like projection neurons. Stimulation of dopamine receptors in the BLA decreases the firing rate of projection neurons while increasing the firing rate of interneurons (62). Thus, similar to putative functions in the VTA and PFC, dopamine in the BLA acts to modulate or gate the activity of cortical glutamatergic afferents.

2.4. Neurotransmitter Release in the Motive Circuit

The electrophysiological studies outlined above demonstrate that activation of medium spiny neurons is the result of to cortical glutamatergic afferents to the accumbens, but spiny cells in the nucleus accumbens are also highly regulated by meso-accumbens dopaminergic projections. Thus, extracellular dopamine and glutamate levels in the accumbens are key players in determining output from the nucleus accumbens and of the motive circuit in general. The following sections will examine how extracellular levels of dopamine and glutamate are coregulated by stimulation of dopamine and glutamate receptors in the accumbens, VTA, and PFC.

2.4.1. Nucleus Accumbens

The extracellular levels of dopamine and glutamate in the accumbens are modulated by stimulation of dopamine receptors. Stimulating D2-like receptors in the accumbens decreases extracellular levels of glutamate (63,64) and dopamine (65,66), indicating that these receptors serve as presynaptic receptors on glutamate terminals, in addition to a well-established inhibitory effect on dopamine terminals (67). Conversely, D1-like receptor stimulation fails to alter extracellular glutamate levels in the NAc (63,64), although electrophysiological studies indicate potential direct or indirect modulation of glutamate release by D1 receptor stimulation (68-70).

Extracellular levels of dopamine and glutamate are modulated by stimulation of glutamate receptors in the accumbens. Stimulation of ionotropic glutamate receptors produces a decrease in extracellular dopamine levels in the nucleus accumbens, unless high doses of AMPA and NMDA agonists are used (71). Regardless, stimulation of ionotropic receptors in the accumbens likely regulates dopamine levels via feedback to dopamine cell bodies in the VTA. In support, excitatory stimulation of spiny cells produces a decrease in activity of cells in the VTA (72). Although the effect of ionotropic receptors is not fully clarified, stimulation of group 2 or 3 mGluRs produces a decrease in extracellular levels of dopamine in the accumbens (73). Interestingly, reverse dialysis of the group 2/3 antagonist, a-methyl-4-phosponophenylglycine (MPPG), increased extracellular dopamine levels, indicating that stimulation of these receptors exerts a tonic inhibition of dopamine release in accumbens (73). Stimulation of group 2 or 3 mGluRs also decreases the extracellular levels of glutamate, whereas blockade of these receptors increases glutamate (74). Collectively, these studies indicate that dopamine and glutamate in the accumbens can regulate transmitter release from respective synaptic terminals via presy-naptic heteroreceptors.

2.4.2. Ventral Tegmental Area

Stimulation of dopamine and glutamate receptors in the VTA differentially regulate extracellular dopamine and glutamate levels in the PFC and accumbens. Dopamine receptor stimulation in the VTA reduces the release of mesoaccumbens dopamine neurons because of the stimulation of D2-like somatodendritic autoreceptors (75,76). Interestingly, recent reports indicate that meso-prefrontal dopamine neurons have relatively fewer somatodendritic autoreceptors (76). In support, the blockade of D2-like dopamine receptors in the PFC failed to alter extracellular levels in the PFC at a concentration that potently increased dopamine levels in the accumbens (76). The effect of D1-like dopamine receptor stimulation on dopamine neurons is unclear because these receptors regulate the release of glutamate and GABA in the VTA (77-79).

Glutamate neurotransmission differentially regulates meso-accumbens and meso-prefrontal neurons via ionotropic receptor stimulation. Stimulation of NMDA receptors in VTA exerts tonic excitation on both meso-accumbens and meso-prefrontal neurons, and intra-VTA administration of an NMDA antagonist decreases dopamine levels in the accumbens and PFC (80-82), although see refs. (83 and 84). These findings are partly supported by reports of decreased levels of dopamine in the accumbens following simultaneous blockade of NMDA and AMPA receptors in VTA (80,85). Interestingly, AMPA receptor stimulation in the VTA exerts a greater effect on meso-accumbens versus meso-cortical neurons. In support, AMPA receptor blockade in the VTA produced an increase in extracellular dopamine levels in the accumbens, but a decrease in the PFC (82,86), whereas AMPA receptor stimulation more effectively elevated dopamine transmission in the accumbens versus PFC (87).

2.4.3. Prefrontal Cortex

Stimulation of dopamine and glutamate receptors in the PFC differentially regulate local and nucleus accumbens extracellular dopamine and glutamate levels. Specifically, stimulation of NMDA receptors produces tonic inhibition of dopamine release in the PFC, whereas AMPA receptor stimulation produces tonic increases in dopamine release in the PFC (82,88-90). The mechanism underlying NMDA receptor modulation of extracellular cortical levels of dopamine may involve activation of GABAergic interneurons (91). However, the mechanism underlying AMPA receptor modulation of cortical dopamine levels is unclear, but it likely involves regulation of dopamine neurons within the VTA. Consistent with this interpretation, corticofugal glutamatergic projections to the VTA synapse directly onto meso-prefrontal neurons (41). D1-like dopamine receptors in the PFC have been shown to exert tonic inhibition on PFC pyramidal neurons. In support, stimulation of D1-like receptors in the PFC via reverse dialysis of SKF 38393 produced a decrease in extracellular concentrations of glutamate (92).

2.4.4. Basolateral Amygdala

The BLA sends excitatory projections to the accumbens and contributes to regulation of biphasic states in medium spiny neurons (see above). Electrophysiological studies also indicate that stimulation of dopamine in BLA inhibits firing of efferent pyramidal cells. However, microdialysis studies characterizing the effect of dopamine and glutamate receptor stimulation on extracellular neurotransmitter levels are currently lacking.

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