Distinct Roles of Synaptic Transmission in Direct and Indirect Striatal Pathways to Reward and Aversive Behavior

In the basal ganglia, convergent input and dopaminergic modulation of the direct striatonigral and the indirect striatopallidal pathways are critical in rewarding and aversive learning and drug addiction. To explore how the basal ganglia information is processed and integrated through these two pathways, we developed a reversible neurotransmission blocking technique, in which transmission of each pathway was selectively blocked by specific expression of transmission-blocking tetanus toxin in a doxycycline-dependent manner. The results indicated that the coordinated modulation of these two pathways was necessary for dopamine-mediated acute psychostimulant actions. This modulation, however, shifted to the predominant roles of the direct pathway in reward learning and cocaine sensitization and the indirect pathway in aversive behavior. These two pathways thus have distinct roles: the direct pathway critical for distinguishing associative rewarding stimuli from nonassociative ones and the indirect pathway for rapid memory formation to avoid aversive stimuli.

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title: The basal ganglia.
abstract: That the basal ganglia are related to the control of movement has been known for a long time; diseases affecting primarily the basal ganglia lead to characteristic disturbances of movement and of resting muscle tone. Improved methods for tracing fiber connections have shown, however, that the main efferent connections of the basal ganglia do not descend to motor nuclei in the brain stem and spinal cord but are rather directed 'upstream' to the motor and other areas of the cerebral cortex. Even though the most obvious symptoms of the basal ganglia are related to the motor system, both clinical and experimental evidence indicates that the basal ganglia also play a role in higher mental functions.

title: Neural mechanisms of reward-related motor learning
abstract: The analysis of the neural mechanisms responsible for reward-related learning has benefited from recent studies of the effects of dopamine on synaptic plasticity. Dopamine-dependent synaptic plasticity may lead to strengthening of selected inputs on the basis of an activity-dependent conjunction of sensory afferent activity, motor output activity, and temporally related firing of dopamine cells. Such plasticity may provide a link between the reward-related firing of dopamine cells and the acquisition of changes in striatal cell activity during learning. This learning mechanism may play a special role in the translation of reward signals into context-dependent response probability or directional bias in movement responses.

title: The functional anatomy of basal ganglia disorders
abstract: Basal ganglia disorders are a heterogeneous group of clinical syndromes with a common anatomic locus within the basal ganglia. To account for the variety of clinical manifestations associated with insults to various parts of the basal ganglia we propose a model in which specific types of basal ganglia disorders are associated with changes in the function of subpopulations of striatal projection neurons. This model is based on a synthesis of experimental animal and post-mortem human anatomic and neurochemical data. Hyperkinetic disorders, which are characterized by an excess of abnormal movements, are postulated to result from the selective impairment of striatal neurons projecting to the lateral globus pallidus. Hypokinetic disorders, such as Parkinson's disease, are hypothesized to result from a complex series of changes in the activity of striatal projection neuron subpopulations resulting in an increase in basal ganglia output. This model suggests that the activity of subpopulations of striatal projection neurons is differentially regulated by striatal afferents and that different striatal projection neuron subpopulations may mediate different aspects of motor control.

title: Basal ganglia and movement disorders: an update
abstract: A model of basal ganglia functioning proposed a few years ago suggests that increased and decreased activity in basal ganglia output to the thalamus underlies akinesia, as seen in Parkinson's disease, and dyskinetic movements as seen in Huntington's disease or after treatment with L-dopa and neuroleptics, respectively. Although the basic features of this model have stood the test of time, patterns of electrophysiological activity and changes in indices of GABA-dependent transmission in the external pallidum lead to a reconsideration of the mechanisms responsible for these changes in output activity.

title: Neural mechanisms of addiction: the role of reward-related learning and memory.
abstract: Addiction is a state of compulsive drug use; despite treatment and other attempts to control drug taking, addiction tends to persist. Clinical and laboratory observations have converged on the hypothesis that addiction represents the pathological usurpation of neural processes that normally serve reward-related learning. The major substrates of persistent compulsive drug use are hypothesized to be molecular and cellular mechanisms that underlie long-term associative memories in several forebrain circuits (involving the ventral and dorsal striatum and prefrontal cortex) that receive input from midbrain dopamine neurons. Here we review progress in identifying candidate mechanisms of addiction.

title: Functional architecture of basal ganglia circuits: neural substrates of parallel processing
abstract: Concepts of basal ganglia organization have changed markedly over the past decade, due to significant advances in our understanding of the anatomy, physiology and pharmacology of these structures. Independent evidence from each of these fields has reinforced a growing perception that the functional architecture of the basal ganglia is essentially parallel in nature, regardless of the perspective from which these structures are viewed. This represents a significant departure from earlier concepts of basal ganglia organization, which generally emphasized the serial aspects of their connectivity. Current evidence suggests that the basal ganglia are organized into several structurally and functionally distinct 'circuits' that link cortex, basal ganglia and thalamus, with each circuit focused on a different portion of the frontal lobe. In this review, Garrett Alexander and Michael Crutcher, using the basal ganglia 'motor' circuit as the principal example, discuss recent evidence indicating that a parallel functional architecture may also be characteristic of the organization within each individual circuit.

title: The pars reticulata of the substantia nigra: a window to basal ganglia output.
abstract: Together with the internal segment of the globus pallidus (GP(i)), the pars reticulata of the substantia nigra (SNr) provides a main output nucleus of the basal ganglia (BG) where the final stage of information processing within this system takes place. In the last decade, progress on the anatomical organization and functional properties of BG output neurons have shed some light on the mechanisms of integration taking place in these nuclei and leading to normal and pathological BG outflow. In this review focused on the SNr, after describing how the anatomical arrangement of nigral cells and their afferents determines specific input-output registers, we examine how the basic electrophysiological properties of the cells and their interaction with synaptic inputs contribute to the spatio-temporal shaping of BG output. The reported data show that the intrinsic membrane properties of the neurons subserves a tonic discharge allowing BG to gate the transmission of information to motor and cognitive systems thereby contributing to appropriate selection of behavior.

title: D1 and D2 dopamine-receptor modulation of striatal glutamatergic signaling in striatal medium spiny neurons
abstract: Dopamine shapes a wide variety of psychomotor functions. This is mainly accomplished by modulating cortical and thalamic glutamatergic signals impinging upon principal medium spiny neurons (MSNs) of the striatum. Several lines of evidence suggest that dopamine D1 receptor signaling enhances dendritic excitability and glutamatergic signaling in striatonigral MSNs, whereas D2 receptor signaling exerts the opposite effect in striatopallidal MSNs. The functional antagonism between these two major striatal dopamine receptors extends to the regulation of synaptic plasticity. Recent studies, using transgenic mice in which cells express D1 and D2 receptors, have uncovered unappreciated differences between MSNs that shape glutamatergic signaling and the influence of DA on synaptic plasticity. These studies have also shown that long-term alterations in dopamine signaling produce profound and cell-type-specific reshaping of corticostriatal connectivity and function.

title: Differential effects of intra-accumbens sulpiride on cocaine-induced locomotion and conditioned place preference.
abstract: The effects of intra-accumbens sulpiride on conditioned place preference and locomotion produced by i.v. cocaine were investigated. Every other day during conditioning, rats received infusions of sulpiride (0-0.4 microgram) into the nucleus accumbens (NAc) or caudate-putamen. Fifteen min later, they were placed into a distinct compartment and injected with saline or cocaine (4.2 mg/kg, i.v.). On the alternate days, rats received sham intracranial injections and were placed into a different compartment. Locomotion and stereotypies were assessed after the first and last injection, and conditioned place preference was assessed 24 hr after the last conditioning day. After behavioral testing, receptors occupied by sulpiride were quantified by injecting rats intracranially with their respective dose of sulpiride, followed by a systemic injection of the irreversible antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). Receptors protected from EEDQ induced inactivation by sulpiride were revealed on autoradiograms of sections labeled with 3H-sulpiride. Sulpiride did not alter cocaine-conditioned place preference or cocaine-induced stereotypies. However, the two lowest doses of intra-accumbens sulpiride attenuated cocaine-induced locomotion and occupied > 42% of the sulpiride binding sites in the NAc, and the highest dose completely reversed cocaine-induced locomotion and occupied > 96% of the sulpiride binding sites in the NAc. Intracaudate sulpiride also attenuated cocaine-induced locomotion without occupying a significant number of binding sites in the NAc. These findings suggest that D2-like receptors in the NAc and anterior medial caudate-putamen are involved in cocaine-induced locomotion, but not cocaine-conditioned place preference.

title: Effects of intraaccumbens administration of SCH‐23390 on cocaine‐induced locomotion and conditioned place preference
abstract: The effects of systemic (0–1.0 mg/kg) or intraaccumbens (0–1.0 μg/side) administration of SCH‐23390 on cocaine‐induced (0 or 4.2 mg/kg, IV) locomotion, sniffing, and conditioned place preference (CPP) were investigated in rats. After behavioral testing was completed, animals were injected with their respective dose of SCH‐23390 into the nucleus accumbens (NAc), followed by a systemic injection of the irreversible antagonist N‐ethoxycarbonyl‐2‐ethoxy‐1,2‐dihydroquinoline (EEDQ). Receptors occupied by intraaccumbens SCH‐23390, and therefore protected from EEDQ‐induced inactivation, were then quantified from autoradiograms of sections labeled with 3H‐SCH‐23390. Systemic administration of 0.5 and 1.0 mg/kg SCH‐23390 reversed cocaine‐induced locomotion, sniffing, and CPP, suggesting that stimulation of D1‐like receptors is necessary for these behavioral changes. Intraaccumbens administration of 1.0 μg/side SCH‐23390 reversed cocaine‐CPP, and this dose occupied D1‐like receptors primarily in the rostral pole of the NAc. Intraaccumbens administration of 0.5 μg/side SCH‐23390 reversed cocaine‐induced locomotion. However, this dose occupied a similar number of D1‐like receptors in the NAc as a lower and behaviorally ineffective dose of 0.1 μg/side, but occupied more receptors in the caudate‐putamen relative to both the 0.1 and 1.0 μg/side doses. These findings suggest that stimulation of D1‐like receptors in the NAc is necessary for cocaine‐CPP, but not for cocaine‐induced locomotion.  1998.

title: Dopamine D2L receptor knockout mice display deficits in positive and negative reinforcing properties of morphine and in avoidance learning
abstract: The dopamine D2 receptor (D2) is implicated in drug addiction, learning and memory. Two isoforms of the D2 receptor, termed D2L (long form) and D2S (short form), have been identified. We previously generated mice lacking D2L (D2L-/-), but expressing functional D2S. In this study, we investigated the role of D2L in the positive and negative reinforcing properties of abused drugs and electrical stimuli, using D2L-/- mice as a model system. Mice were trained in three associative learning tasks: conditioned place preference to morphine and cocaine, conditioned place aversion to naloxone-precipitated morphine withdrawal, and active avoidance. D2L-/- mice, like wild type mice, developed a place preference to cocaine. In contrast to wild type mice, D2L-/- mice did not develop a place preference to morphine, nor did they attain a place aversion to morphine withdrawal. D2L-/- mice also failed to acquire avoidance behavior in response to electrical stimuli. There were no significant differences between D2L-/- and wild type mice in mu-opioid receptor density, morphine-induced locomotor stimulation and morphine withdrawal symptoms. These results suggest that D2L may have a greater impact than D2S on the rewarding aspects of morphine, and the aversive properties of morphine withdrawal and electrical stimulus. These findings also suggest that the presence of D2L is critical in the acquisition (learning) and/or retention (memory) of context-stimulus associations in certain situations. On the other hand, D2L is not essential for the rewarding aspects of cocaine and for the development of morphine dependence. Thus, these studies reveal distinct functional roles of D2L and/or D2S in drug addiction and avoidance learning, which may lead to a better understanding of the neurobiological basis underlying these behaviors.

title: Absence of dopamine D2 receptors unmasks an inhibitory control over the brain circuitries activated by cocaine
abstract: Cocaine is a psychostimulant and a drug widely abused by humans. Cocaine elicits its effects primarily by blocking the activity of the dopamine (DA) transporter, leading to elevated levels of extracellular DA in areas receiving dopaminergic innervation, with the consequent activation of DA receptors. Cocaine, however, also elevates other neurotransmitter levels, leading to a general activation of interconnected brain circuitries. Studies aimed at unraveling the molecular mechanisms underlying the effects of cocaine have shown a leading role of DA D1 receptors in the cascade of cellular events elicited by this drug. In this study, we have analyzed the acute response to cocaine in animals deleted for the expression of DA D2 receptors (D2R), an inhibitor of DA signaling. Importantly, we show that although D1 receptor-mediated functions are preserved and even enhanced in D2R−/− mutants, the behavioral response to acute cocaine administration is severely altered. In addition, c-fos response to acute cocaine administration, in contrast to wild-type mice, is absent in D2R−/− mutants. Our findings show that the absence of D2R, very likely through a presynaptic mechanism, uncovers an inhibitory signaling pathway normally masked by the activity of this receptor on brain circuitries engaged by abused drugs.

title: Behavioral responses to cocaine and amphetamine administration in mice lacking the dopamine D1 receptor
abstract: Cocaine and amphetamine can induce both short-term and long-term behavioral changes in rodents. The major target for these psychostimulants is thought to be the brain dopamine system. To determine whether the dopamine D1 receptor plays a crucial role in the behavioral effects of psychostimulants, we tested both the locomotor and stereotyped behaviors in D1 receptor mutant and wild-type control mice after cocaine and amphetamine treatments. We found that the overall locomotor responses of D1 receptor mutant mice to repeated cocaine administration were significantly reduced compared to those of the wild-type mice and the responses of the D1 receptor mutant mice to cocaine injections were never significantly higher than their responses to saline injections. D1 receptor mutant mice were less sensitive than the wild-type mice to acute amphetamine stimulation over a dose range even though they exhibited apparently similar behavioral responses as those of the wild-type mice after repeated amphetamine administration at the 5 mg/kg dose. Immunostaining experiments indicated that there was no detectable neurotoxicity in the nucleus accumbens in both D1 receptor mutant and wild-type mice after repeated amphetamine administration. The data suggest that the D1 receptor plays an essential role in mediating cocaine-induced behavioral changes in mice. Moreover, the D1 receptor also participates in behavioral responses induced by amphetamine administration.

title: Retained cocaine conditioned place preference in D1 receptor deficient mice.
abstract: The role of the D1 dopamine receptor subtype in mediating cocaine effects was examined in mice in which the D1 receptor gene had been ablated by homologous recombination. Cocaine reward was assessed by conditioned place preference experiments using mice which had either one allele (+/-) or both alleles (-/-) of the D1 dopamine receptor gene disrupted and in their wild type (+/+) littermates. Cocaine conditioning resulted in similar increases in preference for drug-paired environments in mice of each of the three genotypes. Cocaine did not alter locomotor activity levels in homozygous, D1 knockout mice -/-, whereas increased activity was noted in both +/+ and +/- animals. These results are consistent with the idea that the D1 receptor is involved in the locomotor stimulant effects of cocaine, but has little role in a major test of the rewarding and reinforcing effects of the drug.

title: Conditioned eyeblink learning is formed and stored without cerebellar granule cell transmission
abstract: Classical conditioning of the eyeblink reflex is elicited by paired presentation of a conditioned stimulus and an unconditioned stimulus and represents a basic form of cerebellum-dependent motor learning. Purkinje cells and the deep nuclei receive convergent information of conditioned stimulus and unconditioned stimulus through the mossy fiber and climbing fiber projections, respectively. To explore the relative importance of these neural circuits and the underlying mechanism in associative eyeblink learning, we adopted a novel gene-manipulating technique, termed reversible neurotransmission blocking (RNB). In this technology, cerebellar granule cells specifically expressed neurotransmission-blocking tetanus toxin in a doxycycline (DOX)-dependent manner. Extracellular recording of Purkinje cells in awake RNB mice revealed that DOX treatment and withdrawal reversibly turned off and on simple spikes elicited by granule cell inputs, respectively, without interference with complex spikes evoked by climbing fiber inputs. Blockade of granule cell inputs to Purkinje cells abolished eyeblink conditioned responses (CRs) in a DOX-dependent manner. Importantly, when granule cell inputs recovered by removal of DOX, normal CRs were immediately produced in the DOX-treated, CR-negative RNB mice from the beginning of reconditioning. This learning process in RNB mice during DOX treatment was completely abolished by bilateral lesion of the interpositus nucleus before eyeblink conditioning. These results indicate that the convergent information at the interpositus nucleus is critical for acquisition and storage of learning in intimate association with the Purkinje cell circuit for expression of CRs in eyeblink conditioning.

title: The distribution of substance P immunoreactive fibers in the rat central nervous system
abstract: A detailed account of the distribution of immunoreactive substance P‐containing structures in the rat central nervous system is presented, from results obtained by applying an indirect immunofluorescent technique. High densities of substance P‐containing nerve terminals were present in sensory nuclei and other non‐sensory structures such as thalamus, hypothalamus and extrapyramidal system. Substance P‐reactive neuron cell bodies were present in spinal root ganglia, nucleus habenulae medialis, nucleus interpeduncularis, caudoputamen and globus pallidus. Most of the neocortex and the cerebellar cortices had no substance P‐positive elements. The results support the hypothesis that substance P may be a widespread neurotransmitter in the central nervous system.

title: The distribution and functions of the enkephalins.
abstract: The enkephalins are two pentapeptides with pharmacological properties similar to narcotic drugs. These peptides are widely distributed in the central nervous system. The basal ganglia contain particularly high concentrations of enkaphalins. In the caudate nucleus ultrastructural studies show that enkephalin is contained within synaptic vesicles. Similar observations have been made with respect to enkephalin containing neurons in th A2 nucleus of the medulla and locus ceruleus. In the caudate, lower intensity staining for enkephalin can also be seen in the dendrites of enkephalin positive neurons. Staining for enkephalins is also widely distributed outside the central nervous system. The myenteric plexus in particular contains many enkephalinergic fibers and cell bodies. In addition, enkephalin-containing endocrine cells are found in the gastrointestinal mucosa. These endocrine cells also contain serotonin. Enkephalins have also been detected in several sympathetic ganglia. In some cases postganglionic neurons have been shown to contain enkephalin. SIF (small intensely fluorescent) cells and nerve terminals within sympathetic ganglia also show enkephalin positive staining. Many cells of the adrenal medulla show positive staining for enkephalin.

title: Reversible Silencing of Neuronal Excitability in Behaving Mice by a Genetically Targeted, Ivermectin-Gated Cl− Channel
abstract: Several genetic strategies for inhibiting neuronal function in mice have been described, but no system that directly suppresses membrane excitability and is triggered by a systemically administered drug, has been validated in awake behaving animals. We expressed unilaterally in mouse striatum a modified heteromeric ivermectin (IVM)-gated chloride channel from C. elegans (GluClalphabeta), systemically administered IVM, and then assessed amphetamine-induced rotational behavior. Rotation was observed as early as 4 hr after a single intraperitoneal IVM injection (10 mg/kg), reached maximal levels by 12 hr, and was almost fully reversed by 4 days. Multiple cycles of silencing and recovery could be performed in a single animal. In striatal slice preparations from GluClalphabeta-expressing animals, IVM rapidly suppressed spiking. The two-subunit GluCl/IVM system permits "intersectional" strategies designed to increase the cellular specificity of silencing in transgenic animals.

title: Cocaine Regulates MEF2 to Control Synaptic and Behavioral Plasticity
abstract: Repeated exposure to cocaine causes sensitized behavioral responses and increased dendritic spines on medium spiny neurons of the nucleus accumbens (NAc). We find that cocaine regulates myocyte enhancer factor 2 (MEF2) transcription factors to control these two processes in vivo. Cocaine suppresses striatal MEF2 activity in part through a mechanism involving cAMP, the regulator of calmodulin signaling (RCS), and calcineurin. We show that reducing MEF2 activity in the NAc in vivo is required for the cocaine-induced increases in dendritic spine density. Surprisingly, we find that increasing MEF2 activity in the NAc, which blocks the cocaine-induced increase in dendritic spine density, enhances sensitized behavioral responses to cocaine. Together, our findings implicate MEF2 as a key regulator of structural synapse plasticity and sensitized responses to cocaine and suggest that reducing MEF2 activity (and increasing spine density) in NAc may be a compensatory mechanism to limit long-lasting maladaptive behavioral responses to cocaine.

title: Synaptic integration mediated by striatal cholinergic interneurons in basal ganglia function.
abstract: The physiological role of striatal cholinergic interneurons was investigated with immunotoxin-mediated cell targeting (IMCT). Unilateral cholinergic cell ablation caused an acute abnormal turning behavior. These mice showed gradual recovery but displayed abnormal turning by both excess stimulation and inhibition of dopamine actions. In the acute phase, basal ganglia function was shifted to a hyperactive state by stimulation and suppression of striatonigral and striatopallidal neurons, respectively. D1 and D2 dopamine receptors were then down-regulated, relieving dopamine-predominant synaptic perturbation but leaving a defect in controlling dopamine responses. The acetylcholine-dopamine interaction is concertedly and adaptively regulated for basal ganglia synaptic integration.

title: Turning behaviour in animals
abstract: Publisher Summary This chapter discusses earlier studies examining brain sites, which elicit turning activity, and more recent detailed pharmacological investigations that give clues of functional neuronal interactions within the brain. Many of these behavioral observations are complementary to biochemical data regarding neurotransmitter interactions within the basal ganglia. The unilateral electrical stimulation of a number of regions within the brain is accompanied by varying degrees of head turning, posturing, or circling behavior. The direction of this asymmetry, whether towards the side of stimulation or away from the side of stimulation, varies not only with the particular brain region being subjected to the stimulus of a particular species but also with the particular location of the electrodes within a specific nucleus.

title: Dopaminergic regulation of immediate early gene expression in the basal ganglia.
abstract: Publisher Summary The dopaminergic influences in neostriatum are thought to be mediated by different dopamine (DA) receptors having distinct locations on the striatonigral and striatopallidal pathways. Yet several attributes of dopaminergic influences on basal ganglia function are not addressed by or seem contradictory to these models as some recent findings concerning dopaminergic influences on basal ganglia cell function are opposite to predictions of such models. These considerations call for a reformulation of the underlying models. Studies—aiming this and presented in this chapter—use the expression of Fos, the protein product of the immediate early gene (IEG) c-fos , to characterize dopaminergic influences on cells of the direct (striato-SNr) and indirect (striato-GP-STN-SNr) pathways. IEGs have been first characterized as a set of genes that are quickly transcribed following growth factor-induced re-entry of cultured cells into the proliferative cycle. Typically, IEGs are expressed at low levels basally, and their induced transcription is short-lived. By phosphorylation of a constitutively expressed transcription factor, cyclic response element binding (CREB), depolarization and adenylate cyclase activation can both induce IEG expression. The ability of DA agonists to induce striatal c-fos has been a key observation in exploring the basal ganglia circuitry on which DA acts. The necessary role of D1 receptors in amphetamine (AMPH)- or cocaine (COC)- induced striatal c-fos has long been recognized, because the D1 antagonist SCH 23390 blocks the striatal IEG induction. The role of the D2 receptors, however, has been less clear.

title: Increased sensitivity to cocaine by cholinergic cell ablation in nucleus accumbens
abstract: Chronic exposure to cocaine causes long-lasting behavioral changes associated with cocaine reinforcement and addiction. An important neural substrate for cocaine addiction is the nucleus accumbens (NAc), which receives dopaminergic input from the ventral tegmental area. Although the neural circuit of the NAc is controlled by several other neurotransmitters, their involvement in cocaine addiction remains elusive. In this investigation, we ablated cholinergic interneurons from the adult NAc with immunotoxin-mediated cell targeting and examined the role of acetylcholine transmitter in adaptive behavioral changes associated with cocaine reinforcement and addiction. Acute exposure to cocaine induced abnormal rotation in unilaterally cholinergic cell-eliminated mice. This abnormal turning was enhanced by repeated exposure of cocaine. In bilaterally cholinergic cell-eliminated mice, chronic cocaine administration induced a prominent and progressive increase in locomotor activity. Moreover, these mice showed robust conditioned place preference with a lower dose of cocaine, compared with wild-type littermates. This investigation demonstrates that acetylcholine in the NAc plays a key role in both acute and chronic actions of cocaine.

title: Acetylcholine enhancement in the nucleus accumbens prevents addictive behaviors of cocaine and morphine
abstract: Drug addiction poses serious social, medical, and economic problems, but effective treatments for drug addiction are still limited. Cocaine and morphine elevate dopamine levels in the nucleus accumbens (NAc), and the overwhelming actions of dopamine are implicated in reinforcement and addiction of abusive drugs. In our previous studies, we reported the regulatory role of acetylcholine (ACh) in the NAc function by selectively ablating the NAc cholinergic neurons with use of immunotoxin-mediated cell targeting. These studies indicated that ACh and dopamine acted convergently but oppositely on the NAc circuit and that cholinergic cell ablation enhanced long-lasting behavioral changes of cocaine addiction. In this investigation, we showed that immunotoxin-mediated ablation of the NAc cholinergic neurons enhanced not only the sensitivity to morphine in conditioned place preference but also negative reinforcement of morphine withdrawal in conditioned place aversion. Remarkably, acetylcholinesterase (AChE) inhibitors that act on the brain AChE suppressed both cocaine- and morphine-induced conditioned place preference and blocked the induction and persistence of cocaine-evoked hyperlocomotion. Importantly, this inhibition was abolished by ablation of the NAc cholinergic neurons. These results demonstrate that centrally active AChE inhibitors prevent long-lasting behavioral abnormalities associated with cocaine and morphine addictions by potentiating the actions of ACh released from the NAc cholinergic neurons. Centrally active AChE inhibitors could thus be approached as novel and potential therapeutic agents for drug addiction.

title: Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity
abstract: Progress has been made over the last 10 years in determining the neural mechanisms of sensitization induced by amphetamine-like psychostimulants, opioids and stressors. Changes in dopamine transmission in axon terminal fields such as the nucleus accumbens appear to underlie the expression of sensitization, but the actions of drugs and stressors in the somatodendritic regions of the A10/A9 dopamine neurons seem critical for the initiation of sensitization. Manipulations that increase somatodendritic dopamine release and permit the stimulation of D1 dopamine receptors in this region induce changes in the dopamine system that lead to the development of long-term sensitization. However, it is not known exactly how the changes in the A10/A9 region are encoded to permit augmented dopamine transmission in the terminal field. One possibility is that the dopamine neurons of sensitized animals have become increasingly sensitive to excitatory pharmacological and environmental stimuli or desensitized to inhibitory regulation. Alternatively, changes in cellular activity or protein synthesis may result in a change in the presynaptic regulation of axon terminal dopamine release.

title: Neuroadaptation: Incubation of cocaine craving after withdrawal
abstract: Relapse to cocaine addiction is frequently associated with subjective reports of craving, a poorly understood state that precedes and accompanies cocaine-seeking behaviours. It has been suggested that over the first few weeks of withdrawal from cocaine, human addicts become sensitized to drug-associated environmental cues that act as external stimuli for craving, although the evidence for this is inconsistent. Here we provide behavioural evidence from laboratory animals suggesting that the onset of craving is delayed and that craving does not decay, but rather increases progressively, over a two-month withdrawal period.

title: REVIEW ON CPP: Measuring reward with the conditioned place preference (CPP) paradigm: update of the last decade
abstract: Conditioned place preference (CPP) continues to be one of the most popular models to study the motivational effects of drugs and non‐drug treatments in experimental animals. This is obvious from a steady year‐to‐year increase in the number of publications reporting the use this model. Since the compilation of the preceding review in 1998, more than 1000 new studies using place conditioning have been published, and the aim of the present review is to provide an overview of these recent publications. There are a number of trends and developments that are obvious in the literature of the last decade. First, as more and more knockout and transgenic animals become available, place conditioning is increasingly used to assess the motivational effects of drugs or non‐drug rewards in genetically modified animals. Second, there is a still small but growing literature on the use of place conditioning to study the motivational aspects of pain, a field of pre‐clinical research that has so far received little attention, because of the lack of appropriate animal models. Third, place conditioning continues to be widely used to study tolerance and sensitization to the rewarding effects of drugs induced by pre‐treatment regimens. Fourth, extinction/reinstatement procedures in place conditioning are becoming increasingly popular. This interesting approach is thought to model certain aspects of relapse to addictive behavior and has previously almost exclusively been studied in drug self‐administration paradigms. It has now also become established in the place conditioning literature and provides an additional and technically easy approach to this important phenomenon. The enormous number of studies to be covered in this review prevented in‐depth discussion of many methodological, pharmacological or neurobiological aspects; to a large extent, the presentation of data had to be limited to a short and condensed summary of the most relevant findings.

title: Regulation of firing of dopaminergic neurons and control of goal-directed behaviors
abstract: There are several brain regions that have been implicated in the control of motivated behavior and whose disruption leads to the pathophysiology observed in major psychiatric disorders. These systems include the ventral hippocampus, which is involved in context and focus on tasks, the amygdala, which mediates emotional behavior, and the prefrontal cortex, which modulates activity throughout the limbic system to enable behavioral flexibility. Each of these systems has overlapping projections to the nucleus accumbens, where these inputs are integrated under the modulatory influence of dopamine. Here, we provide a systems-oriented approach to interpreting the function of the dopamine system, its modulation of limbic-cortical interactions and how disruptions within this system might underlie the pathophysiology of schizophrenia and drug abuse.

title: Behavioral dopamine signals
abstract: Lesioning and psychopharmacological studies suggest a wide range of behavioral functions for ascending midbrain dopaminergic systems. However, electrophysiological and neurochemical studies during specific behavioral tasks demonstrate a more restricted spectrum of dopamine-mediated changes. Substantial increases in dopamine-mediated activity, as measured by electrophysiology or voltammetry, are related to rewards and reward-predicting stimuli. A somewhat slower, distinct electrophysiological response encodes the uncertainty associated with rewards. Aversive events produce different, mostly slower, electrophysiological dopamine responses that consist predominantly of depressions. Additionally, more modest dopamine concentration fluctuations, related to punishment and movement, are seen at 200-18,000 times longer time courses using voltammetry and microdialysis in vivo. Using these responses, dopamine neurotransmission provides differential and heterogeneous information to subcortical and cortical brain structures about essential outcome components for approach behavior, learning and economic decision-making.

title: Importance of unpredictability for reward responses in primate dopamine neurons.
abstract: 1. We used single neuron recording techniques in two behaving monkeys to investigate the conditions in which dopamine neurons respond to primary rewarding or potentially rewarding stimuli. Animals received drops of liquid either outside behavioral tasks or as rewards during learning or established performance of an auditory reaction time task. 2. Three quarters of dopamine neurons showed a short-latency, phasic response to liquid that was delivered outside the task without being predicted by phasic stimuli. The same neurons responded to liquid reward during learning but not when task performance was established, at which time the neuronal response occurred to the conditioned, reward-predicting, movement-triggering stimulus. 3. These data suggest that the responses of dopamine neurons to rewarding or potentially rewarding liquid are due to the temporally unpredicted stimulus occurrence. A known, reward-predicting, tonic context does not prevent dopamine neurons from responding to the rewarding liquid. The responses during learning apparently occur because reward is not yet reliably predicted by a conditioned phasic stimulus. Because the unpredicted occurrence of reward is of central importance for learning, these responses allow dopamine neurons to play an important role in reward-driven learning.

title: Preferential activation of midbrain dopamine neurons by appetitive rather than aversive stimuli
abstract: MIDBRAIN dopamine systems are crucially involved in motivational processes underlying the learning and execution of goal-directed behaviour1–5. Dopamine neurons in monkeys are uniformly activated by unpredicted appetitive stimuli such as food and liquid rewards and conditioned, reward-predicting stimuli. By contrast, fully predicted stimuli are ineffective6–8, and the omission of predicted reward depresses their activity9. These characteristics follow associative-learning rules10,11, suggesting that dopamine responses report an error in reward prediction12. Accordingly, neural network models are efficiently trained using a dopamine-like reinforcement signal13,14. However, it is unknown whether the responses to environmental stimuli concern specific motivational attributes or reflect more general stimulus salience4,15. To resolve this, we have compared dopamine impulse responses to motivationally opposing appetitive and aversive stimuli. In contrast to appetitive events, primary and conditioned non-noxious aversive stimuli either failed to activate dopamine neurons or, in cases of close resemblance with appetitive stimuli, induced weaker responses than appetitive stimuli. Thus, dopamine neurons preferentially report environmental stimuli with appetitive rather than aversive motivational value.

title: Uniform Inhibition of Dopamine Neurons in the Ventral Tegmental Area by Aversive Stimuli
abstract: Dopamine neurons play a key role in reward-related behaviors. Reward coding theories predict that dopamine neurons will be inhibited by or will not respond to aversive stimuli. Paradoxically, between 3 and 49% of presumed dopamine neurons are excited by aversive stimuli. We found that, in the ventral tegmental area of anesthetized rats, the population of presumed dopamine neurons that are excited by aversive stimuli is actually not dopaminergic. The identified dopamine neurons were inhibited by the aversive stimulus. These findings suggest that dopamine neurons are specifically excited by reward and that a population of nondopamine neurons is excited by aversive stimuli.

title: Dopamine-Dependent Interactions between Limbic and Prefrontal Cortical Plasticity in the Nucleus Accumbens: Disruption by Cocaine Sensitization
abstract: The prefrontal cortex and the hippocampus exhibit converging projections to the nucleus accumbens and have functional reciprocal connections via indirect pathways. As a result, information processing between these structures is likely to be bidirectional. Using evoked potential measures, we examined the interactions of these inputs on synaptic plasticity within the accumbens. Our results show that the direction of information flow between the prefrontal cortex and limbic structures determines the synaptic plasticity that these inputs exhibit within the accumbens. Moreover, this synaptic plasticity at hippocampal and prefrontal inputs selectively involves dopamine D1 and D2 activation or inactivation, respectively. Repeated cocaine administration disrupted this synaptic plasticity at hippocampal and prefrontal cortical inputs and goal-directed behavior in the spatial maze task. Thus, interactions of limbic-prefrontal cortical synaptic plasticity and its dysfunction within the accumbens could underlie complex information processing deficits observed in individuals following psychostimulant administration.

title: Dynamic Dopamine Modulation in the Basal Ganglia: A Neurocomputational Account of Cognitive Deficits in Medicated and Nonmedicated Parkinsonism
abstract: Dopamine (DA) depletion in the basal ganglia (BG) of Parkinson's patients gives rise to both frontal-like and implicit learning impairments. Dopaminergic medication alleviates some cognitive deficits but impairs those that depend on intact areas of the BG, apparently due to DA overdose. These findings are difficult to accommodate with verbal theories of BG/DA function, owing to complexity of system dynamics: DA dynamically modulates function in the BG, which is itself a modulatory system. This article presents a neural network model that instantiates key biological properties and provides insight into the underlying role of DA in the BG during learning and execution of cognitive tasks. Specifically, the BG modulates the execution of actions (e.g., motor responses and working memory updating) being considered in different parts of the frontal cortex. Phasic changes in DA, which occur during error feedback, dynamically modulate the BG threshold for facilitating/suppressing a cortical command in response to particular stimuli. Reduced dynamic range of DA explains Parkinson and DA overdose deficits with a single underlying dysfunction, despite overall differences in raw DA levels. Simulated Parkinsonism and medication effects provide a theoretical basis for behavioral data in probabilistic classification and reversal tasks. The model also provides novel testable predictions for neuropsychological and pharmacological studies, and motivates further investigation of BG/DA interactions with the prefrontal cortex in working memory.

title: The Role of an Amygdalo-Nigrostriatal Pathway in Associative Learning
abstract: The present study examined the role of an amygdalo-nigrostriatal pathway in associative learning. An asymmetrical lesion model was used to test whether a circuit from the amygdala central nucleus to the dorsolateral striatum, via the substantia nigra, is critical for mediating conditioned orienting responses. Rats with an asymmetrical lesion, consisting of neurotoxic removal of central nucleus neurons in one hemisphere and depletion of the dopamine innervation of the dorsolateral striatum in the contralateral hemisphere, failed to acquire conditioned orienting responses. In contrast, the asymmetrical lesion had no effect on spontaneous orienting or learning another response directed to the source of the food unconditioned stimulus in the same task. A second experiment tested the effect of reversible inactivation of the dorsolateral striatum contralateral to a neurotoxic central nucleus lesion on acquisition of the conditioned orienting response. Although inactivation did not affect spontaneous orienting, rats failed to acquire the conditioned orienting response during sessions in which inactivation occurred. Immediately after the inactivation procedure was terminated, however, a significant increase in orienting to the conditioned stimulus was evident. These data support the interpretation that the dorsolateral striatum provides a route for the expression of the conditioned orienting response but is not essential for acquisition of this learned behavior.

title: Dopamine receptors in canine caudate nucleus
abstract: SummaryPhysiological, pharmacological, histochemical and biochemical studies indicate that dopamine receptors are heterogenous in the, central nervous system with each individual functions. This review describes pharmacological and biochemical characteristics of dopamine receptors, particularly in canine caudate nucleus, which have been studied in our laboratory with a brief comparison to the current studies by other workers in similar research fields.Two distinct dopamine receptors have been characterized by means of [3H]dopamine binding to the synaptic membranes from canine caudate nucleus. One of the receptors with a Kd of about 3 μM for dopamine may be associated with adenylate cyclase and referred to as D, receptor. The other receptor with a Kd of about 10 nM for dopamine is independent of adenylate cyclase and referred to as D2. A photochemical irreversible association of [3H]dopamine with the membraneous receptors makes it possible to separate D1 and D2 receptors from one another by gel filtration on a Sephadex G-200 column after solubilization with Lubrol PX. On the basis of selective inhibition of [3H]dopamine binding to D1 and D2 receptors, dopamine antagonists can be classified into three classes: D1-selective (YM-09151-2), D2-selective (sulpiride) and nonselective (haloperidol, chlorpromazine). Effects of these typical antagonists on the metabolism of rat brain dopamine suggest that D1 receptor is more closely associated with the neuroleptic-induced increase in dopamine turnover. Studies with 28 benzamide derivatives and some classical neuroleptics reveal that apomorphine-induced stereotypy displays a greater association with D1 than with D2 receptors.Dopamine-sensitive adenylate cyclase in canine caudate nucleus can be solubilized with Lubrol PX in a sensitive form to either dopamine, Gpp(NH)p or fluoride. Sephadex G-200 gel filtration separates adenylate cyclase from D1 receptors with a concomitant loss of dopamine sensitivity. Addition of the D1 receptor fraction to the adenylate cyclase restores the responsiveness to dopamine. The solubilized dopamine-unresponsive adenylate cyclase can be further separated into two distinct fractions by a batch-wise treatment with GTP-sepharose: a catalytic unit which does not respond to fluoride, and a guanine nucleotide regulatory protein. The regulatory protein confers distinct responsiveness to Gpp(NH)p and fluoride upon adenylate cyclase. These results indicate that dopamine-sensitive adenylate cyclase is composed of at least three distinct units; D1 receptor, guanine nucleotide regulatory protein and adenylate cyclase.

title: Anatomical and affinity state comparisons between dopamine D1 and D2 receptors in the rat central nervous system
abstract: The anatomical distributions and affinity states of dopamine D1 and D2 receptors were compared in the rat central nervous system using quantitative autoradiography. [3H]SCH23390 and [3H]spiperone (in the presence of 100 nM mianserin) were used to label the D1 and D2 receptors, respectively. The densities of D1 and D2 receptors displayed a positive correlation among 21 brain regions (Pearson correlation coefficient, r = 0.80, P less than 0.001). The affinity states for the D1 and D2 receptors were found to be quite different from each other, and different from the results obtained by others using homogenate preparations. Both the D1 and D2 receptors were best modeled using a two-state model. In the absence of exogenous guanine nucleotides and using the nonselective agonist dopamine as the competitor, the D1 receptor was primarily in a low affinity agonist state (RH = 21 +/- 6%), whereas the D2 receptor was primarily in the high affinity agonist state (RH = 77 +/- 3%). In the presence of 10 microM guanylyl-imidodiphosphate or guanosine-5'-O-(2-thiophosphate) both the D1 and the D2 receptor were completely in a low affinity agonist state (RL = 100%). These affinity states were found both in the nucleus accumbens and olfactory tubercle using dopamine as the competitor and in the striatum using selective D1 or D2 agonists as competitors. Receptor occupancy of the D2 receptor with either an agonist or antagonist did not alter the affinity states of the D1 receptor, and conversely, receptor occupancy of the D1 receptor did not alter the affinity states of the D2 receptor. The correlation between densities of D1 and D2 receptors provides an anatomical framework for evaluating behavioral and electrophysiological evidence of an interaction between the two dopamine receptor subtypes. This interaction does not appear to be due to a sharing or coupling of G-proteins in such a way that binding to one dopamine receptor subtype alters the affinity state of the other receptor subtype. The differences between dopamine receptor distributions described by labeled agonists and antagonists may be due in part to differences in their affinity states. The low proportion of high affinity state D1 receptors may explain some of the difficulties in assigning specific behavioral roles to the D1 receptor.

title: Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats.
abstract: The effect of various drugs on the extracellular concentration of dopamine in two terminal dopaminergic areas, the nucleus accumbens septi (a limbic area) and the dorsal caudate nucleus (a subcortical motor area), was studied in freely moving rats by using brain dialysis. Drugs abused by humans (e.g., opiates, ethanol, nicotine, amphetamine, and cocaine) increased extracellular dopamine concentrations in both areas, but especially in the accumbens, and elicited hypermotility at low doses. On the other hand, drugs with aversive properties (e.g., agonists of kappa opioid receptors, U-50,488, tifluadom, and bremazocine) reduced dopamine release in the accumbens and in the caudate and elicited hypomotility. Haloperidol, a neuroleptic drug, increased extracellular dopamine concentrations, but this effect was not preferential for the accumbens and was associated with hypomotility and sedation. Drugs not abused by humans [e.g., imipramine (an antidepressant), atropine (an antimuscarinic drug), and diphenhydramine (an antihistamine)] failed to modify synaptic dopamine concentrations. These results provide biochemical evidence for the hypothesis that stimulation of dopamine transmission in the limbic system might be a fundamental property of drugs that are abused.

title: Dopaminergic modulation of limbic and cortical drive of nucleus accumbens in goal-directed behavior
abstract: Goal-directed behavior is believed to involve interactions of prefrontal cortical and limbic inputs in the nucleus accumbens (NAcc), and their modulation by mesolimbic dopamine (DA) seems to be of primary importance in NAcc function. Using in vivo electrophysiological recordings simultaneously with DA system manipulation in rats, we show that tonic and phasic DA release selectively modulates hippocampal and prefrontal cortical inputs through D1 and D2 receptors, respectively. In addition, we also found that D1 activation and D2 inactivation in the NAcc produced behaviorally selective effects (learning versus set shifting of response strategy) that correspond to specific afferents. These results suggest that the dynamics of DA release regulate the balance between limbic and cortical drive through activation and inactivation of DA receptor subtypes in the accumbens, and this regulates goal-directed behavior.

title: Phasic Firing in Dopaminergic Neurons Is Sufficient for Behavioral Conditioning
abstract: Rewarding Bursts of Dopamine Dopaminergic neurons are thought to be involved in the cognitive and hedonic underpinnings of motivated behaviors. However, it is still unclear whether dopaminergic neuron activation is sufficient to elicit reward-related behavior and which type of neuronal activity pattern serves this purpose. Tsai et al. (p. 1080;  directly compared tonic versus phasic firing of dopaminergic cells in the ventral tegmental area, and the effects on both behavior and dopamine release. Using a transgenic system and virus injection in mice, they targeted the dopaminergic cells with rhodopsin. Light stimulation was then used to drive dopaminergic cells either with a tonic low level of pulses or bursts of high-frequency pulses, with the number of pulses being equal across conditions. Only the high-frequency phasic firing induced a conditioned place preference and dopamine release. High-frequency pulses in deep brain cells release dopamine and cause reward-related behavior in mice. Natural rewards and drugs of abuse can alter dopamine signaling, and ventral tegmental area (VTA) dopaminergic neurons are known to fire action potentials tonically or phasically under different behavioral conditions. However, without technology to control specific neurons with appropriate temporal precision in freely behaving mammals, the causal role of these action potential patterns in driving behavioral changes has been unclear. We used optogenetic tools to selectively stimulate VTA dopaminergic neuron action potential firing in freely behaving mammals. We found that phasic activation of these neurons was sufficient to drive behavioral conditioning and elicited dopamine transients with magnitudes not achieved by longer, lower-frequency spiking. These results demonstrate that phasic dopaminergic activity is sufficient to mediate mammalian behavioral conditioning.

title: Phasic excitation of dopamine neurons in ventral VTA by noxious stimuli
abstract: Midbrain dopamine neurons play central roles in reward processing. It is widely assumed that all dopamine neurons encode the same information. Some evidence, however, suggests functional differences between subgroups of dopamine neurons, particularly with respect to processing nonrewarding, aversive stimuli. To directly test this possibility, we recorded from and juxtacellularly labeled individual ventral tegmental area (VTA) dopamine neurons in anesthetized rats so that we could link precise anatomical position and neurochemical identity with coding for noxious stimuli. Here, we show that dopamine neurons in the dorsal VTA are inhibited by noxious footshocks, consistent with their role in reward processing. In contrast, we find that dopamine neurons in the ventral VTA are phasically excited by footshocks. This observation can explain a number of previously confusing findings that suggested a role for dopamine in processing both rewarding and aversive events. Taken together, our results indicate that there are 2 functionally and anatomically distinct VTA dopamine systems.

title: Nociceptive responses of midbrain dopaminergic neurones are modulated by the superior colliculus in the rat
abstract: Midbrain dopaminergic neurones exhibit a short-latency phasic response to unexpected, biologically salient stimuli. In the rat, the superior colliculus is critical for relaying short-latency visual information to dopaminergic neurones. Since both collicular and dopaminergic neurones are also responsive to noxious stimuli, we examined whether the superior colliculus plays a more general role in the transmission of short-latency sensory information to the ventral midbrain. We therefore tested whether the superior colliculus is a critical relay for nociceptive input to midbrain dopaminergic neurones. Simultaneous recordings were made from collicular and dopaminergic neurones in the anesthetized rat, during the application of noxious stimuli (footshock). Most collicular neurones exhibited a short-latency, short duration excitation to footshock. The majority of dopaminergic neurones (92/110; 84%) also showed a short-latency phasic response to the stimulus. Of these, 79/92 (86%) responded with an initial inhibition and the remaining 14/92 (14%) responded with an excitation. Response latencies of dopaminergic neurones were reliably longer than those of collicular neurones. Tonic suppression of collicular activity by an intracollicular injection of the local anesthetic lidocaine reduced the latency, increased the duration but reduced the magnitude of the phasic inhibitory dopaminergic response. These changes were accompanied by a decrease in the baseline firing rate of dopaminergic neurones. Activation of the superior colliculus by the local injections of the GABA(A) antagonist bicuculline also reduced the latency of inhibitory nociceptive responses of dopaminergic neurones, which was accompanied by an increased in baseline dopaminergic firing. Aspiration of the ipsilateral superior colliculus failed to alter the nociceptive response characteristics of dopaminergic neurones although fewer nociceptive neurones were encountered after the lesions. Together these results suggest that the superior colliculus can modulate both the baseline activity of dopaminergic neurones and their phasic responses to noxious events. However, the superior colliculus is unlikely to be the primary source of nociceptive sensory input to the ventral midbrain.

title: Dual Role of Medial A10 Dopamine Neurons in Affective Encoding
abstract: Increasing evidence suggests that the activation of medial A10 neurons mediates positive affective encoding. However, little is known about the functions of the inhibition of midbrain dopamine neurons. Here we show evidence suggesting that the inhibition of medial A10 neurons mediates a negative affective state, leading to negative affective encoding, whereas blunting the activation of medial A10 neurons disrupts positive affective encoding involving food reward. We used a microinjection procedure, in which the D2 dopamine receptor agonist quinpirole was administered into the cell body region of the dopamine neurons, a procedure that reduces dopamine cell firing. Microinjections of quinpirole into the posteromedial ventral tegmental area, but not its more lateral counterparts, led to conditioned place aversion. Quinpirole administration to this site also decreased food intake and basal dopamine concentration in the ventromedial striatum, a major projection area of medial A10 neurons. In addition, moderate quinpirole doses that did not lead to conditioned place aversion or disrupt food intake abolished food-conditioned place preference, suggesting that blunting dopamine impulse activity in response to food reward disrupts positive affective encoding in associated external stimuli. Our data support the hypothesis that activation of medial A10 dopamine neurons mediates a positive affective state, leading to positive affective encoding, while their inhibition mediates a negative affective state, leading to negative affective encoding. Together with previous findings, we propose that medial A10 neurons are an important component of the mechanism via which animals learn to avoid negative incentive stimuli.

title: Dichotomous Dopaminergic Control of Striatal Synaptic Plasticity
abstract: At synapses between cortical pyramidal neurons and principal striatal medium spiny neurons (MSNs), postsynaptic D1 and D2 dopamine (DA) receptors are postulated to be necessary for the induction of long-term potentiation and depression, respectively—forms of plasticity thought to underlie associative learning. Because these receptors are restricted to two distinct MSN populations, this postulate demands that synaptic plasticity be unidirectional in each cell type. Using brain slices from DA receptor transgenic mice, we show that this is not the case. Rather, DA plays complementary roles in these two types of MSN to ensure that synaptic plasticity is bidirectional and Hebbian. In models of Parkinson's disease, this system is thrown out of balance, leading to unidirectional changes in plasticity that could underlie network pathology and symptoms.

title: Metabotropic Glutamate Receptor Subtype 7 Ablation Causes Deficit in Fear Response and Conditioned Taste Aversion
abstract: Metabotropic glutamate receptors (mGluRs) consist of eight different subtypes and exert their effects on second messengers and ion channels via G-proteins. The function of individual mGluR subtypes in the CNS, however, largely remains to be clarified. We examined the fear response of freezing after electric shock in wild-type and mGluR7−/− knockout littermates. Wild-type mice displayed freezing immediately after and 1 d after footshock. In comparison, mGluR7−/− knockout mice showed significantly reduced levels in both immediate postshock and delayed freezing responses. However, the knockout mice exhibited no abnormalities in pain sensitivity and locomotor activity. To further examine amygdala-dependent behavior, we performed conditioned taste aversion (CTA) experiments. In wild-type mice, the administration of saccharin followed by intraperitoneal injection of the malaise-inducing agent LiCl resulted in an association between saccharin and LiCl. This association caused strong CTA toward saccharin. In contrast, mGluR7−/− knockout mice failed to associate between the taste and the negative reinforcer in CTA experiments. Again, the knockout mice showed no abnormalities in taste preference and in the sensitivity to LiCl toxicity. These results indicate that mGluR7 deficiency causes an impairment of two distinct amygdala-dependent behavioral paradigms. Immunohistochemical and immunoelectron-microscopic analyses showed that mGluR7 is highly expressed in amygdala and preferentially localized at the presynaptic axon terminals of glutamatergic neurons. Together, these findings strongly suggest that mGluR7 is involved in neural processes subserving amygdala-dependent averse responses.