Neurotransmitter roles in synaptic modulation, plasticity and learning in the dorsal striatum

“The ratio of responses to paired afferent stimuli delivered at 50 ms intervals is sensitive to the probability of neurotransmitter release (Zucker, 1989), and an increase this paired-pulse ratio generally signals a decrease in release probability.”

“These striatonigral neurons strongly express D1Rs and generally do not express A2A or D2Rs (Augood and Emson, 1994; Gerfen et al., 1990; Gong et al., 2003).”

“The striatum is the major input nucleus of the basal ganglia, and as such it plays a crucial role in action control and action learning (Saint-Cyr et al., 1995; Graybiel,1998; Lalonde and Botez-Marquard, 1997; Yin and Knowlton, 2006).”

“These striatonigral neurons strongly express D1Rs and generally do not express A2A or D2Rs (Augood and Emson, 1994; Gerfen et al., 1990; Gong et al., 2003).”

“…injection of a local anesthetic, which should inactivate the structure, just prior to a retention test did not impair the ability of the animal to perform a cross-maze task, but just altered the strategy used by the animal from a response-based to a place-based approach (Packard and McGaugh, 1996).”

“Excitotoxic lesions of dorsolateral striatum disrupted habit learning in this study, as previously reported in rat (Hilario et al., 2007; Yin et al., 2004).”

“Dopamine can only act via GPCRs, and thus only modulates striatal neuronal function and synaptic transmission (Richfield et al., 1989; Surmeier et al., 2007).”

“The effect of D2 receptors on striatal LTD has been replicated numerous times using a variety of LTD induction paradigms including STDP (Tang et al., 2001; Kreitzer and Malenka, 2005; Wang et al., 2006; Shen et al., 2008).”

“Studies from a number of laboratories over the last 15e20 years have revealed two predominant forms of long-lasting synaptic plasticity at glutamatergic striatal synapses: long-term potentiation (LTP) and long-term depression (LTD) (see Kreitzer and Malenka, 2008; Wickens, 2009 for review) (Fig.”

“The striatum is the major input nucleus of the basal ganglia, and as such it plays a crucial role in action control and action learning (Saint-Cyr et al., 1995; Graybiel,1998; Lalonde and Botez-Marquard, 1997; Yin and Knowlton, 2006).”

“More recent studies using excitotoxic lesions, neurochemical approaches, and direct measurement of striatal neuronal activity in vivo have revealed roles for the dorsal striatum in skill learning, responsebased learning, and instrumental conditioning involving both goaldirected and habitual responding (Yin and Knowlto…”

“There is some experimental evidence for this idea from in vivo studies (Reynolds and Wickens, 2000; Reynolds et al., 2001).”

“Findings from studies in a maze paradigm also revealed striatal neuronal activity related to response learning (Jog et al., 1999).”

“Depotentiation at glutamatergic synapses has been reported (Picconi et al., 2003, 2006; Centonze et al., 2006).”

“Antagonists of the D1 dopamine receptor also disrupt rotarod performance when given within the first day or two of training (Yin et al., 2009).”

“Striatal LTD involves a “retrograde signaling” mechanism in which postsynaptic induction mechanisms give rise to a presynaptic expression mechanism that appears to involve a decrease in probability of glutamate release (Choi and Lovinger, 1997a,b; Gerdeman et al., 2002) (Fig.”

“Deletion of the D2 receptor in mice, and depletion of striatal dopamine likewise prevent LTD induction using the high frequency stimulation paradigm (Calabresi et al., 1992a,b; Kreitzer and Malenka, 2007; Tang et al., 2001).”

“Preventing postsynaptic depolarization above w 60 mV prevents LTD even when strong high frequency stimulation is delivered at afferent fibers (Calabresi et al., 1992b, 1994; Choi and Lovinger, 1997a,b).”

“The CB1 receptor is expressed almost exclusively on presynaptic terminals in striatum and other brain regions (Katona et al., 2001, 2006; Matyas et al., 2006; Uchigashima et al., 2007), and is known to inhibit glutamate release when activated (Gerdeman and Lovinger, 2001; Huang et al., 2001;…”

“In other brain regions, NMDARdependent, postsynaptically-expressed LTP involves insertion of additional AMPA receptors into synapses (see Kerchner and Nicoll, 2008 for review).”

“The striatum can also be subdivided into the “patch” and “matrix” compartments based on the relative expression of different molecular markers and patterns of afferent and efferent connections (Gerfen, 1992; Joel and Weiner, 2000; Canales, 2005).”

“In this context it is interesting to note that some cholinergic neurons show increased activity before conditioned stimulus presentation, and the pause is often followed by an increase in activity (Aosaki et al., 1994).”

“It is well established that presynaptic nAChRs on dopaminergic terminals can stimulate dopamine release in striatum, and these LGICs have been implicated in stimulation-induced release of dopamine (Giorguieff et al., 1976; Kulak et al., 1997; Wonnacott et al., 2000; Zhou et al., 2001).”

“Studies of the ventral striatum/nucleus accumbens indicate roles for this brain region in spatial learning, Pavlovian conditioning, and Pavlovian-instrumental transfer, among other types of learning (Corbit et al., 2001; Ito et al., 2008; Parkinson et al., 2000; Roitman et al., 2005).”

“Early studies implicated the dorsal striatum in response-based learning and instrumental conditioning (Divac et al., 1967; Konorski, 1967).”

“…mechanism to produce a subtle increase in excitation of MSNs. Dopamine produces modulation of neurotransmitter release at both GABAergic and glutamatergic striatal synapses (Bamford et al., 2004a; Centonze et al., 2004; Cepeda et al., 1993; Flores-Hernandez et al., 1997; Yin and Lovinger, 2006).”

“Ideas about striatal-based learning have long included the postulate that LTP would be an important component of the strengthening of stimulus-response associations in this brain region (Mahon et al., 2005; Reynolds and Wickens, 2002).”

“Large cholinergic interneurons receive glutamatergic afferent input from thalamus and neocortex (Wilson et al., 1990).”

“The effect of D2 receptors on striatal LTD has been replicated numerous times using a variety of LTD induction paradigms including STDP (Tang et al., 2001; Kreitzer and Malenka, 2005; Wang et al., 2006; Shen et al., 2008).”

“The CB1 receptor is expressed almost exclusively on presynaptic terminals in striatum and other brain regions (Katona et al., 2001, 2006; Matyas et al., 2006; Uchigashima et al., 2007), and is known to inhibit glutamate release when activated (Gerdeman and Lovinger, 2001; Huang et al., 2001;…”

“Acetylcholine coming from the large aspiny neurons could potentially act via nicotinic ACh receptors, and these LGICs are abundant in striatum (Zhou et al., 2002).”

“Another recent study indicates that CB1 receptor activation is necessary for extinction of response-based learning in the plusmaze paradigm (Rueda-Orozco et al., 2008).”

“However, a well-known response of cholinergic interneurons is a pause in activity in response to reward-predictive stimuli in a Pavlovian conditioning task (Aosaki et al., 1994; Apicella et al., 1996; Matsumoto et al., 2001).”

“Dopamine can only act via GPCRs, and thus only modulates striatal neuronal function and synaptic transmission (Richfield et al., 1989; Surmeier et al., 2007).”

“Using an instrumental conditioning paradigm, Yin et al. (2005) demonstrated that direct injection of an NMDAR antagonist into dorsomedial striatum prevented action-outcome learning.”

“MSNs as well as striatal interneurons (Tepper et al., 2004).”

“…and group II and III metabotropic glutamate receptors has been shown to inhibit glutamatergic synaptic transmission in striatum (Lovinger, 1991; Lovinger and McCool, 1995; Calabresi et al., 1991, 1993; Gerdeman and Lovinger, 2001; Malenka and Kocsis, 1998; Pisani et al., 1997; Sugita et al., 1991).”

“The effect of D2 receptors on striatal LTD has been replicated numerous times using a variety of LTD induction paradigms including STDP (Tang et al., 2001; Kreitzer and Malenka, 2005; Wang et al., 2006; Shen et al., 2008).”

“Preventing postsynaptic depolarization above w 60 mV prevents LTD even when strong high frequency stimulation is delivered at afferent fibers (Calabresi et al., 1992b, 1994; Choi and Lovinger, 1997a,b).”

“Posttraining injection of a D2 agonist improved performance in this task, but not in a Win-Shift task that has a stronger spatial/hippocampal contribution (Packard and White, 1991).”

“The striatum is the major input nucleus of the basal ganglia, and as such it plays a crucial role in action control and action learning (Saint-Cyr et al., 1995; Graybiel,1998; Lalonde and Botez-Marquard, 1997; Yin and Knowlton, 2006).”

“For example, lesioning nigrostriatal dopaminergic inputs prevents habit learning while preserving goal-directed learned actions (Faure et al., 2005).”

“In relatively simple brain slice experiments involving sharp electrode or whole-cell patch-clamp recording, LTP was not readily observed (Calabresi et al., 1992a,b; Lovinger et al., 1993; Partridge et al., 2000; Kerr and Wickens, 2001).”

“Glutamatergic synapses act mainly through AMPA-type receptors to produce fast synaptic excitation, and NMDA-type receptors can also contribute to transmission and plasticity (Calabresi et al., 1992c, 2000a).”

“In addition, activation of delta opiate, adenosine A1, GABAB and muscarinic ACh receptors reduces GABAergic transmission via an apparent presynaptic action (Centonze et al., 2001; Jiang and North, 1991; Seabrook et al., 1991; Sugita et al., 1991; Waldmeier et al., 1988).”

“…is expressed almost exclusively on presynaptic terminals in striatum and other brain regions (Katona et al., 2001, 2006; Matyas et al., 2006; Uchigashima et al., 2007), and is known to inhibit glutamate release when activated (Gerdeman and Lovinger, 2001; Huang et al., 2001; Kofalvi et al.,…”

“Costa et al. (2004) observed that striatal neurons, presumably mostly MSNs, develop task-related firing patterns during the acquisition and retention of improved performance on the rotarod rotating-dowel task.”

“The effect of D2 receptors on striatal LTD has been replicated numerous times using a variety of LTD induction paradigms including STDP (Tang et al., 2001; Kreitzer and Malenka, 2005; Wang et al., 2006; Shen et al., 2008).”

“Cholinergic neurons are tonically active in brain slices, and can also be activated by glutamatergic inputs during afferent stimulation (Bennett and Wilson, 1999; Partridge et al., 2002; Pisani et al., 2002).”

“Studies of the ventral striatum/nucleus accumbens indicate roles for this brain region in spatial learning, Pavlovian conditioning, and Pavlovian-instrumental transfer, among other types of learning (Corbit et al., 2001; Ito et al., 2008; Parkinson et al., 2000; Roitman et al., 2005).”

“, 2005), where they may reside on dendrites (Cooper et al., 2001).”

“neurons, with the exception of excitatory actions on fast-spiking interneurons (Koos and Tepper, 2002).”

“Infusion of glutamate itself increased response-based performance on a crossmaze task, another learning paradigm involving striatum (Packard, 1999).”

“For example, dopamine acting via the D1 class of receptors and the downstream DARPP-32 protein acts to maintain normal levels of function of AMPA-type glutamate receptors (Yan et al., 1999).”

“Glutamatergic synapses act mainly through AMPA-type receptors to produce fast synaptic excitation, and NMDA-type receptors can also contribute to transmission and plasticity (Calabresi et al., 1992c, 2000a).”

“More recent studies using excitotoxic lesions, neurochemical approaches, and direct measurement of striatal neuronal activity in vivo have revealed roles for the dorsal striatum in skill learning, responsebased learning, and instrumental conditioning involving both goaldirected and habitual responding (Yin and Knowlto…”

“This enzyme has also been implicated in D1-mediated potentiation of NMDAR function (Flores-Hernandez et al., 2002).”

“…with presynaptic activity (Singla et al., 2007), then postbefore-pre-pairing would favor this form of plasticity (as in Pawlak and Kerr, 2008; Shen et al., 2008) as the retrograde signal would presumably be arriving during periods of consistent presynaptic activation (but see Fino et al., 2005).”

“…is expressed almost exclusively on presynaptic terminals in striatum and other brain regions (Katona et al., 2001, 2006; Matyas et al., 2006; Uchigashima et al., 2007), and is known to inhibit glutamate release when activated (Gerdeman and Lovinger, 2001; Huang et al., 2001; Kofalvi et al., 2005).”

“…mechanism to produce a subtle increase in excitation of MSNs. Dopamine produces modulation of neurotransmitter release at both GABAergic and glutamatergic striatal synapses (Bamford et al., 2004a; Centonze et al., 2004; Cepeda et al., 1993; Flores-Hernandez et al., 1997; Yin and Lovinger, 2006).”

“Preventing postsynaptic depolarization above w 60 mV prevents LTD even when strong high frequency stimulation is delivered at afferent fibers (Calabresi et al., 1992b, 1994; Choi and Lovinger, 1997a,b).”

“…is expressed almost exclusively on presynaptic terminals in striatum and other brain regions (Katona et al., 2001, 2006; Matyas et al., 2006; Uchigashima et al., 2007), and is known to inhibit glutamate release when activated (Gerdeman and Lovinger, 2001; Huang et al., 2001; Kofalvi et al., 2005).”

“As with most forms of LTP observed in the CNS, striatal LTP requires activation of NMDA-type glutamate receptors (Calabresi et al., 1992b; Dang et al., 2006; Kerr and Wickens, 2001; Popescu et al., 2007; Shen et al., 2008) (Fig.”

“The KCNQ2 and 3 subtypes are expressed MSNs (Shen et al., 2005), where they may reside on dendrites (Cooper et al.”

“…ACh and group II and III metabotropic glutamate receptors has been shown to inhibit glutamatergic synaptic transmission in striatum (Lovinger, 1991; Lovinger and McCool, 1995; Calabresi et al., 1991, 1993; Gerdeman and Lovinger, 2001; Malenka and Kocsis, 1998; Pisani et al., 1997; Sugita et al.,…”

“It is well established that presynaptic nAChRs on dopaminergic terminals can stimulate dopamine release in striatum, and these LGICs have been implicated in stimulation-induced release of dopamine (Giorguieff et al., 1976; Kulak et al., 1997; Wonnacott et al., 2000; Zhou et al., 2001).”

“The striatum can also be subdivided into the “patch” and “matrix” compartments based on the relative expression of different molecular markers and patterns of afferent and efferent connections (Gerfen, 1992; Joel and Weiner, 2000; Canales, 2005).”

“aptic expression of LTD involves endocannabinoid signaling (Gerdeman et al., 2002; Ronesi et al., 2004; Kreitzer andMalenka, 2005)”

“However, it is clear that CB1 cannabinoid receptors have such an action (Narushima et al., 2006, 2007; Szabo et al., 1998; Adermark et al., 2009; Adermark and Lovinger, 2009).”

“In a recent study, the Surmeier laboratory reported that these antagonists could rescue LTD in the presence of a D2R antagonist (Wang et al., 2006), and they may also rescue LTD that is lost in a mouse model of dystonia (Martella et al., 2009).”

“investigators to focus on areas where LTP was more easily induced (Partridge et al., 2000; Spencer and Murphy, 2000).”

“In relatively simple brain slice experiments involving sharp electrode or whole-cell patch-clamp recording, LTP was not readily observed (Calabresi et al., 1992a,b; Lovinger et al., 1993; Partridge et al., 2000; Kerr and Wickens, 2001).”

“Preventing postsynaptic depolarization above w 60 mV prevents LTD even when strong high frequency stimulation is delivered at afferent fibers (Calabresi et al., 1992b, 1994; Choi and Lovinger, 1997a,b).”

“It is well established that presynaptic nAChRs on dopaminergic terminals can stimulate dopamine release in striatum, and these LGICs have been implicated in stimulation-induced release of dopamine (Giorguieff et al., 1976; Kulak et al., 1997; Wonnacott et al., 2000; Zhou et al., 2001).”

“The CB1 receptor is expressed almost exclusively on presynaptic terminals in striatum and other brain regions (Katona et al., 2001, 2006; Matyas et al., 2006; Uchigashima et al., 2007), and is known to inhibit glutamate release when activated (Gerdeman and Lovinger, 2001; Huang et al., 2001;…”

“Dopamine also alters the function of GABAA receptors (Yan and Surmeier, 1997).”

“Preventing postsynaptic depolarization above w 60 mV prevents LTD even when strong high frequency stimulation is delivered at afferent fibers (Calabresi et al., 1992b, 1994; Choi and Lovinger, 1997a,b).”

“A rich interplay of the actions of numerous neurotransmitters is involved in the input, processing and output functions of the striatum (see Lovinger et al., 2003; Schmidt, 1995; Tepper et al., 2007 for review).”

“Coherent local field potential activity occurs in BLA and ventral striatal MSNs, and increases during learning of the Pavlovian task, and this activity may drive the plasticity needed for this type of learning (Popescu et al., 2009).”

“It is well established that presynaptic nAChRs on dopaminergic terminals can stimulate dopamine release in striatum, and these LGICs have been implicated in stimulation-induced release of dopamine (Giorguieff et al., 1976; Kulak et al., 1997; Wonnacott et al., 2000; Zhou et al., 2001).”

“The effect of D2 receptors on striatal LTD has been replicated numerous times using a variety of LTD induction paradigms including STDP (Tang et al., 2001; Kreitzer and Malenka, 2005; Wang et al., 2006; Shen et al., 2008).”

“In addition, activation of delta opiate, adenosine A1, GABAB and muscarinic ACh receptors reduces GABAergic transmission via an apparent presynaptic action (Centonze et al., 2001; Jiang and North, 1991; Seabrook et al., 1991; Sugita et al., 1991; Waldmeier et al., 1988).”

“…mechanism to produce a subtle increase in excitation of MSNs. Dopamine produces modulation of neurotransmitter release at both GABAergic and glutamatergic striatal synapses (Bamford et al., 2004a; Centonze et al., 2004; Cepeda et al., 1993; Flores-Hernandez et al., 1997; Yin and Lovinger, 2006).”

“When mice are treated with CB1 antagonist during training but not testing, they also show impaired habit learning and intact action-outcome learning (Hilario et al., 2007).”

“Blockade of group I mGluRs also prevents LTD induction (Gubellini et al., 2001; Sung et al., 2001), and LTD can be induced by combined activation of group I mGluRs and mild postsynaptic depolarization (Fig.”

“Packard and Teather (1997) used posttraining injection of antagonists into the dorsal striatum to show that activation of NMDA receptors is crucial for memory in a cued version of the Morris Water Maze task.”

“Using these approaches it has been possible to determine the roles of different neurotransmitters in striatal LTP (Di Filippo et al., 2009; Lovinger et al., 2003; Wickens, 2009).”

“Activation of D2 receptors has also been reported to inhibit GABA release at synapses onto striatal MSNs (Centonze et al., 2004).”

“There is some experimental evidence for this idea from in vivo studies (Reynolds and Wickens, 2000; Reynolds et al., 2001).”

“…and group II and III metabotropic glutamate receptors has been shown to inhibit glutamatergic synaptic transmission in striatum (Lovinger, 1991; Lovinger and McCool, 1995; Calabresi et al., 1991, 1993; Gerdeman and Lovinger, 2001; Malenka and Kocsis, 1998; Pisani et al., 1997; Sugita et al., 1991).”

“Glutamate, GABA and ACh can also act through GPCRs to influence the function of striatal neurons (Lovinger, 1991; Calabresi et al., 1991; Seabrook et al., 1991; Sugita et al., 1991).”

“In contrast to the mACh antagonist effects, blockade of nicotinic ACh receptors (nAChRs) prevents LTD induction (Partridge et al., 2002).”

“The role of the A2A receptor in striatal-based instrumental conditioning has also been examined using a gene-targeted mouse in which expression of A2A is eliminated in striatum (Yu et al., 2009).”

“However, it is clear that CB1 cannabinoid receptors have such an action (Narushima et al., 2006, 2007; Szabo et al., 1998; Adermark et al., 2009; Adermark and Lovinger, 2009).”

“Acetylcholinealsoappears toplaya role instriatal LTP. Inductionof LTP is prevented in the presence ofmuscarinic acetylcholine receptor (mAChR) antagonists (Calabresi et al., 1999; Lovinger et al., 2003) (Fig.”

“Preventing postsynaptic depolarization above w 60 mV prevents LTD even when strong high frequency stimulation is delivered at afferent fibers (Calabresi et al., 1992b, 1994; Choi and Lovinger, 1997a,b).”

“Glutamate, GABA and ACh can also act through GPCRs to influence the function of striatal neurons (Lovinger, 1991; Calabresi et al., 1991; Seabrook et al., 1991; Sugita et al., 1991).”

“Endocannabinoid-dependent striatal LTD is not restricted to glutamatergic synapses, but also appears to be readily inducible at GABAergic synapses (Adermark et al., 2009; Adermark and Lovinger, 2009).”

“Studies from a number of laboratories over the last 15e20 years have revealed two predominant forms of long-lasting synaptic plasticity at glutamatergic striatal synapses: long-term potentiation (LTP) and long-term depression (LTD) (see Kreitzer and Malenka, 2008; Wickens, 2009 for review) (Fig.”

“Blockade of group I mGluRs also prevents LTD induction (Gubellini et al., 2001; Sung et al., 2001), and LTD can be induced by combined activation of group I mGluRs and mild postsynaptic depolarization (Fig.”

“…and group II and III metabotropic glutamate receptors has been shown to inhibit glutamatergic synaptic transmission in striatum (Lovinger, 1991; Lovinger and McCool, 1995; Calabresi et al., 1991, 1993; Gerdeman and Lovinger, 2001; Malenka and Kocsis, 1998; Pisani et al., 1997; Sugita et al., 1991).”

“Glutamatergic synapses in striatum also exhibit long-term decreases in synaptic efficacy, known as long-term depression (LTD) (Calabresi et al., 1992a,b; Lovinger et al., 1993; Walsh, 1993).”

“These striatonigral neurons strongly express D1Rs and generally do not express A2A or D2Rs (Augood and Emson, 1994; Gerfen et al., 1990; Gong et al., 2003).”

“3 L-type calcium channels (Kreitzer and Malenka, 2005; Wang et al., 2006; Adermark and Lovinger, 2007a).”

“Alternatively, evidence from two recent studies suggests that D2-mediated inhibition of glutamatergic transmission results from production of an endocannabinoid retrograde signal leading to activation of presynaptic CB1 receptors and reduced glutamate release (Kreitzer and Malenka, 2005; Yin et al., 2006).”

“The striatum can also be subdivided into the “patch” and “matrix” compartments based on the relative expression of different molecular markers and patterns of afferent and efferent connections (Gerfen, 1992; Joel and Weiner, 2000; Canales, 2005).”

“In addition, the AC5 knockout mice learned an instrumental task and appeared to be using a goal-directed strategy in this learning tasks (Kheirbek et al., 2008).”

“3 L-type calcium channels (Kreitzer and Malenka, 2005; Wang et al., 2006; Adermark and Lovinger, 2007a).”

“Calabresi et al. (1992b) found that mAChR antagonists enhance the magnitude of LTD at glutamatergic striatal synapses (Bonsi et al., 2008).”

“Ideas about striatal-based learning have long included the postulate that LTP would be an important component of the strengthening of stimulus-response associations in this brain region (Mahon et al., 2005; Reynolds and Wickens, 2002).”

“However, it is clear that CB1 cannabinoid receptors have such an action (Narushima et al., 2006, 2007; Szabo et al., 1998; Adermark et al., 2009; Adermark and Lovinger, 2009).”

“Pharmacological studies indicate involvement of muscarinic ACh receptors in the induction of depotentiation (Picconi et al., 2006).”

“If LTD requires that CB1 activation occurs coincidentally with presynaptic activity (Singla et al., 2007), then postbefore-pre-pairing would favor this form of plasticity (as in Pawlak and Kerr, 2008; Shen et al., 2008) as the retrograde signal would presumably be arriving during periods of…”

“In addition, activation of delta opiate, adenosine A1, GABAB and muscarinic ACh receptors reduces GABAergic transmission via an apparent presynaptic action (Centonze et al., 2001; Jiang and North, 1991; Seabrook et al., 1991; Sugita et al., 1991; Waldmeier et al., 1988).”

“Inductionof LTP is prevented in the presence ofmuscarinic acetylcholine receptor (mAChR) antagonists (Calabresi et al., 1999; Lovinger et al., 2003)”

“investigators to focus on areas where LTP was more easily induced (Partridge et al., 2000; Spencer and Murphy, 2000).”

“Cholinergic neurons are tonically active in brain slices, and can also be activated by glutamatergic inputs during afferent stimulation (Bennett and Wilson, 1999; Partridge et al., 2002; Pisani et al., 2002).”

“However, it is clear that CB1 cannabinoid receptors have such an action (Narushima et al., 2006, 2007; Szabo et al., 1998; Adermark et al., 2009; Adermark and Lovinger, 2009).”

“there is not strong consensus as to when and where this occurs within the striatum (Bracci and Panzeri, 2006).”

“The striatum is the major input nucleus of the basal ganglia, and as such it plays a crucial role in action control and action learning (Saint-Cyr et al., 1995; Graybiel,1998; Lalonde and Botez-Marquard, 1997; Yin and Knowlton, 2006).”

“…and group II and III metabotropic glutamate receptors has been shown to inhibit glutamatergic synaptic transmission in striatum (Lovinger, 1991; Lovinger and McCool, 1995; Calabresi et al., 1991, 1993; Gerdeman and Lovinger, 2001; Malenka and Kocsis, 1998; Pisani et al., 1997; Sugita et al., 1991).”

“As with most forms of LTP observed in the CNS, striatal LTP requires activation of NMDA-type glutamate receptors (Calabresi et al., 1992b; Dang et al., 2006; Kerr and Wickens, 2001; Popescu et al., 2007; Shen et al., 2008) (Fig.”

“…known about the roles of other striatal neurotransmitters and receptors in the induction and modulation of LTP and LTD. Activation of presynaptic group II mGluRs has been shown to induce a form of LTD that may share presynaptic expression mechanisms with the LTD discussed above (Kahn et al., 2001).”

“necessary for extinction of response-based learning in the plusmaze paradigm (Rueda-Orozco et al., 2008).”

“Depotentiation at glutamatergic synapses has been reported (Picconi et al., 2003, 2006; Centonze et al., 2006).”

“GABAergic connections among interneurons are likely to occur, but characterization of these connections is just beginning (Partridge et al., 2009).”

“In addition, activation of delta opiate, adenosine A1, GABAB and muscarinic ACh receptors reduces GABAergic transmission via an apparent presynaptic action (Centonze et al., 2001; Jiang and North, 1991; Seabrook et al., 1991; Sugita et al., 1991; Waldmeier et al., 1988).”

“Blockade of adenosine receptors does not alter LTD induction or expression (Lovinger and Choi, 1995), suggesting that this transmitter may only participate in LTP.”

“In addition, activation of delta opiate, adenosine A1, GABAB and muscarinic ACh receptors reduces GABAergic transmission via an apparent presynaptic action (Centonze et al., 2001; Jiang and North, 1991; Seabrook et al., 1991; Sugita et al., 1991; Waldmeier et al., 1988).”

“These mice show deficiencies in several striatal-based skill, response-based, appetitive Pavlovian and Pavlovian-intrumental transfer learning (Kheirbek et al., 2008, 2009).”

“However, a well-known response of cholinergic interneurons is a pause in activity in response to reward-predictive stimuli in a Pavlovian conditioning task (Aosaki et al., 1994; Apicella et al., 1996; Matsumoto et al., 2001).”

“Endocannabinoids, lipid metabolites that activate the CB1 GPCR, are an intriguing subclass of small molecules that modulate synaptic transmission in striatum (Lovinger et al., 2010), and more will be said about their emerging role in striatal function later in this review.”

“underlying habit memory and motor learning (reviewed by Gubellini et al., 2004; Bonsi et al., 2008; Lovinger, 2010).”

“The phasic dopaminergic activation that drives incentive salience is hypothesized to also engage habit formation and compulsive-like responding for addictive agents via activation of cortical-striatal-pallidal-thalamic loops (90,91).”