Comparative distribution of dopamine D-1 and D-2 receptors in the basal ganglia of turtles, pigeons, rats, cats, and monkeys

The distribution and density of dopamine D-1 and D-2 receptors were studied in the basal ganglia of adult turtles, pigeons, rats, cats, and monkeys. Dopamine receptors were measured in vitro by quantitative autoradiography in alternate sections processed for D-1 and D-2 receptor subtypes and compared to adjacent sections stained for acetylcholinesterase (AChE) activity. [ 3 H]-SCH 23390 and [ 3 H]-spiroperidol were used to label the D-1 and D-2 dopamine receptor subtypes, respectively. The anatomic distribution of both D-1 and D-2 receptors in the basal ganglia was remarkably similar across all species examined. Whereas the absolute number of D-1 and D-2 receptors in the basal ganglia varied between species, the percentage of D-1 and D-2 receptors in a region was quite similar among species. The pattern of binding to the D-1 and D-2 receptor varied among the different species. The adult turtles, pigeons, and rats demonstrated non-patchy D-1 and D-2 receptor binding in the striatum and pallidum. The adult cat and monkey caudate nucleus and putamen demonstrated mildly heterogeneous receptor binding in a pattern that differed from that seen with AChE staining, but did occasionally demonstrate similar patterns of the D-1 and D-2 receptor subtypes, The immature cat striatum was characterized by heterogeneous D-1 receptor binding that corresponded to heterogeneous AChE rich patches, whereas D-2 receptor binding was homogeneous. Heterogeneous binding was seen in other basal ganglia structures including the nucleus accumbens, olfactory tubercle, and substantia nigra pars compacta and reticulata. Complementary D-1 and D-2 receptor binding patterns were seen in the pallidum and substantia nigra of the mammals. The results of this study indicate that both D-1 and D-2 dopamine receptors are present in the basal ganglia of five different vertebrates. A common feature of dopamine receptors in the basal ganglia is their heterogeneity in distribution and density. The heterogeneity of dopamine receptors has similarities to and differences from the distribution of presynaptic dopamine and other neurotransmitter markers of the basal ganglia.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/50037/1/902620308_ftp.pd

Dopamine D(2 )receptors mediate two-odor discrimination and reversal learning in C57BL/6 mice

BACKGROUND: Dopamine modulation of neuronal signaling in the frontal cortex, midbrain, and striatum is essential for processing and integrating diverse external sensory stimuli and attaching salience to environmental cues that signal causal relationships, thereby guiding goal-directed, adaptable behaviors. At the cellular level, dopamine signaling is mediated through D(1)-like or D(2)-like receptors. Although a role for D(1)-like receptors in a variety of goal-directed behaviors has been identified, an explicit involvement of D(2 )receptors has not been clearly established. To determine whether dopamine D(2 )receptor-mediated signaling contributes to associative and reversal learning, we compared C57Bl/6J mice that completely lack functional dopamine D(2 )receptors to wild-type mice with respect to their ability to attach appropriate salience to external stimuli (stimulus discrimination) and disengage from inappropriate behavioral strategies when reinforcement contingencies change (e.g. reversal learning). RESULTS: Mildly food-deprived female wild-type and dopamine D(2 )receptor deficient mice rapidly learned to retrieve and consume visible food reinforcers from a small plastic dish. Furthermore, both genotypes readily learned to dig through the same dish filled with sterile sand in order to locate a buried food pellet. However, the dopamine D(2 )receptor deficient mice required significantly more trials than wild-type mice to discriminate between two dishes, each filled with a different scented sand, and to associate one of the two odors with the presence of a reinforcer (food). In addition, the dopamine D(2 )receptor deficient mice repeatedly fail to alter their response patterns during reversal trials where the reinforcement rules were inverted. CONCLUSIONS: Inbred C57Bl/6J mice that develop in the complete absence of functional dopamine D(2 )receptors are capable of olfaction but display an impaired ability to acquire odor-driven reinforcement contingencies. Furthermore, the ability of dopamine D(2 )receptor deficient mice to adjust their responding to a previously reinforced stimulus when unexpected outcomes are encountered is significantly impaired. These findings suggest that signaling mediated by the dopamine D(2 )receptor is important for regulating associative and reversal learning and may have implications for the treatment of human attention disorders

Dibenzazecine compounds with a novel dopamine/5HT(2A )receptor profile and 3D-QSAR analysis

BACKGROUND: Antipsychotics are divided into typical and atypical compounds based on clinical efficacy and side effects. The purpose of this study was to characterize in vitro a series of novel azecine-type compounds at human dopamine D(1)-D(5 )and 5HT(2A )receptors and to assign them to different classes according to their dopamine/5HT(2A )receptor profile. RESULTS: Regardless of using affinity data (pK(i )values at D(1)-D(5 )and 5HT(2A)) or selectivity data (15 log (K(i )ratios)), principal component analysis with azecine-type compounds, haloperidol, and clozapine revealed three groups of dopamine/5HT(2A )ligands: 1) haloperidol; 2) clozapine plus four azecine-type compounds; 3) two hydroxylated dibenzazecines. Reducing the number of K(i )ratios used for principal component analysis from 15 to two (the D(1)/D(2 )and D(2)/5HT(2A )K(i )ratios) obtained the same three groups of compounds. The most potent dibenzazecine clustering in the same group as clozapine was the non-hydroxylated LE410 which shows a slightly different D(2)-like receptor profile (D(2L )> D(3 )> D(4.4)) than clozapine (D(4.4 )> D(2L )> D(3)). The monohydroxylated dibenzacezine LE404 clusters in a separate group from clozapine/LE410 and from haloperidol and shows increased D(1 )selectivity. CONCLUSION: In conclusion, two compounds with a novel dopamine/5HT(2A )receptor profile, LE404 and LE410, with some differences in their respective D(1)/D(2 )receptor affinities including a validated pharmacophore-based 3D-QSAR model for D(1 )antagonists are presented

Development of behavioral preferences for the optimal choice following unexpected reward omission is mediated by a reduction of D 2‐like receptor tone in the nucleus accumbens

To survive in a dynamic environment, animals must identify changes in resource availability and rapidly apply adaptive strategies to obtain resources that promote survival. We have utilised a behavioral paradigm to assess differences in foraging strategy when resource (reward) availability unexpectedly changes. When reward magnitude was reduced by 50% (receive one reward pellet instead of two), male and female rats developed a preference for the optimal choice by the second session. However, when an expected reward was omitted (receive no reward pellets instead of one), subjects displayed a robust preference for the optimal choice during the very first session. Previous research shows that, when an expected reward is omitted, dopamine neurons phasically decrease their firing rate, which is hypothesised to decrease dopamine release preferentially affecting D 2‐like receptors. As robust changes in behavioral preference were specific to reward omission, we tested this hypothesis and the functional role of D 1‐ and D 2‐like receptors in the nucleus accumbens in mediating the rapid development of a behavioral preference for the rewarded option during reward omission in male rats. Blockade of both receptor types had no effect on this behavior; however, holding D 2‐like, but not D 1‐like, receptor tone via infusion of dopamine receptor agonists prevented the development of the preference for the rewarded option during reward omission. These results demonstrate that avoiding an outcome that has been tagged with aversive motivational properties is facilitated through decreased dopamine transmission and subsequent functional disruption of D 2‐like, but not D 1‐like, receptor tone in the nucleus accumbens. This study investigates the role of dopamine receptors in the nucleus accumbens in altering behavior in response to the omission of an expected reward. Similarly to controls, multiple doses of a D 1‐like receptor agonist, D 1‐like receptor antagonist, and D 2‐like receptor antagonist do not prevent subjects from developing a robust behavioral preference for the rewarded lever and avoiding the omitted‐reward lever during the first session of reward omission. However, the D 2‐like agonist quinpirole dose‐dependently blocks a behavioral preference for the rewarded lever, suggesting that reductions in D 2‐like receptor tone are necessary for altering behavior away from an aversive option and toward the optimal choice.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/99645/1/ejn12253.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/99645/2/ejn12253-sup-0001-Supplement.pd

Mesolimbic dopamine D_{2} receptor plasticity contributes to stress resilience in rats subjected to chronic mild stress

RATIONALE: Few studies have investigated neurobiological and biochemical differences between stress-resilient and stress-vulnerable experimental animals. OBJECTIVES: We investigated alterations in mesolimbic dopamine D(2) receptor density and mRNA expression level in stressed rats at two time points, i.e. after 2 and 5 weeks of chronic mild stress (CMS). METHODS: We used the chronic mild stress paradigm because it is a well-established animal model of depression. Two groups of stressed rats were distinguished during CMS experiments: (1) stress reactive (70 %), which displayed a decrease in the drinking of a palatable sucrose solution during the stress regimen, and (2) stress resilient (30 %), which exhibited an unaltered drinking profile when compared with the unchallenged control group. [(3)H]Domperidone was used as a ligand to label dopamine D(2) receptors, and a mixture of three specific oligonucleotides was used to evaluate dopamine D(2) receptor mRNA changes in various regions of the rat brain. RESULTS: CMS strongly affected the mesolimbic dopamine circuit in stress-resilient group after 2 weeks and stress-reactive group of rats after 5 weeks which exhibited a decrease in the level of dopamine D(2) receptor protein without alterations in D(2) mRNA expression. Stress-resilient animals, but not stress-reactive animals, effectively adapted to the extended stress and coped with it. The increase in D(2) mRNA expression returned the dopamine D(2) receptor density to control levels in stress-resilient rats after 5 weeks of CMS, but not in stress-reactive animals. CONCLUSIONS: These results clearly demonstrate that, despite earlier blunting, the activation of dopamine receptor biosynthesis in the dopamine mesoaccumbens system in stress-resilient rats is involved in active coping with stressful experiences, and it exhibits a delay in time

Repeated apomorphine administration alters dopamine D1 and D2 receptor densities in pigeon basal telencephalon

When pigeons are repeatedly administered a dose of apomorphine they show an increasing behavioral response, much as rodents do. In birds this expresses itself in an augmented pecking response. This sensitization is assumed to be largely due to a conditioning process. Here we present evidence that sensitization is accompanied by an alteration of the D 1 to D 2 dopamine receptor densities. An experimental group of pigeons was repeatedly injected with apomorphine, and a control group with saline. The basal forebrain tissue, known to be rich in dopamine receptors, was subjected to binding assays using tritiated specific D 1 and D 2 dopamine receptor antagonists. There was a trend towards an increase in D 1 and a significant decrease in D 2 receptor densities in apomorphine-treated birds compared to the saline-treated controls. We conclude that extended apomorphine treatment modifies the D 1 dopamine receptor density in the opposite manner to the D 2 dopamine receptor density.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46541/1/221_2004_Article_2158.pd

Gut-brain axis: Central impact of gut peptides and metabolic drug on monoamine neurotransmission

Gastrointestinal peptides like insulin and glucagon-like peptide are not only essential metabolic hormones but can also modulate important brain function, unrelated to feeding behaviour and glucose homeostasis. Different evidence suggests that these peptides, as well as synthetic insulin secretagogue such as tolbutamide, can affect cognition, motivation, addiction as well as neuronal survival. In this thesis, we have investigated in rats whether insulin, or the insulin-releasing agent tolbutamide, and the stable glucagon-like-peptide-1 (GLP-1) receptor agonist exendin-4 as well as putative GLP-1 congener geniposide, can affect the electrical activity of dopamine neurons in the ventral tegmental area (VTA) and of pyramidal neurons in the prefrontal cortex (PFC), using single-unit activity recording techniques. We have also investigated, whether these peptides can alter some dopamine-dependent behaviours such as, D-Amphetamine (a dopamine-releasing agent) -induced motor activity, quinpirole (a dopamine D2/D3 receptor agonist) and pramipexole (a dopamine D3 preferred receptor agonist) -induced yawning, pica eating and pelvic grooming activities, as well as phencyclidine ( an N-Methyl-D-aspartate receptor antagonist)-induced cognitive deficit. We also examined the pharmacological mechanism of these drugs on radiometric in vitro [DA] release and uptake assays and investigated whether GLP-1 can modulate the effect of diet modification in form of chronic sucrose intake on behavioural and electrophysiological parameters. Interestingly, in uptake assay, exendin-4 and insulin weakened dopamine D2/D3 agonist (pramipexole and quinpirole)-induced [DA] uptake which suggests a potential interaction with D2/D3 receptor signalling. In addition, insulin and tolbutamide similarly reduced basal [DA] in striatal synaptosomes. Our electrophysiological data shows that GLP-1 receptor activation can change the excitability of prefrontal cortex neurons, an effect that can be associated with the putative pro-cognitive action of some GLP-1 analogues. Interestingly, on VTA dopamine neurons, GLP-1 receptor activation potentiated a moderate inhibitory action of insulin on firing activity. However, a slight progressive decrease in the firing activity of ventral tegmental area dopamine neurons was observed, when insulin was administered through an electrode to allow for local diffusion into the brain region. The insulin secretagogue agent tolbutamide exerts biphasic or excitatory effects on VTA dopamine and PFC neurons, probably via K+ATP channels blockage through sulphonylurea receptors activation, indicating that most dopamine neurons and PFC neurons can be metabolic-sensitive. On sucrose treated rats, we noticed that sucrose treatment induced a partial but significant decrease in the sensitivity of dopamine autoreceptors which was surprisingly exacerbated by exendin-4 co-administration, indicating that exendin-4 may interact negatively with both pre- and post-synaptic dopamine receptors. Our behavioural data shows that exendin-4 and insulin alter dopamine-dependent behaviour with a remarkable inhibitory effect on D-amphetamine-induced motor activity and pramipexole and quinpirole-induced yawning, pica eating, and pelvic grooming activities. As this behaviour is mainly mediated by dopamine D3 receptors our data suggest the existence of an interaction between GLP-1 and dopamine D3 receptors. This may implicate GLP-1 mediated neuronal processes as a particularly interesting therapeutic target for disorders involving dopamine D2/D3 receptors and dopamine transporter malfunction. GLP-1 also exhibited a pro-cognitive effect on PCP-induced cognitive impairment, through the enhanced glutamatergic transmission. Finally, data on sucrose revealed that prolonged ad libitum access to sucrose by adolescent rats may alter brain circuits related to dopamine neurotransmission. It increases the behavioural responses of dopamine agonists and is possibly associated with hypersensitivity of some postsynaptic dopamine receptors. These effects were partially prevented by exendin-4, which may elicit some protective effects on dopamine receptor function. In succinct, gut peptides impact on neurotransmission as well as behavioural activities and potentially modulate psychostimulant effects

Changes in Striatal N-methyl-D-aspartate (NMDA) Stimulation of Dopamine Release and Receptor Subunit Expression During Expression of and Recovery from MPTP-Induced Parkinsonism

Normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-treated cats were used to examine changes in N-methyl-D-aspartate (NMDA) receptor function. In vivo microdialysis studies showed that NMDA-stimulated dopamine (DA) release was similar in the normal dorso-lateral and ventro-medial caudate nucleus. In symptomatic animals, NMDA-stimulated DA release was significantly decreased in both striatal regions. In symptomatic animals, NMDA-stimulated dopamine release was significantly decreased in both striatal regions. In recovered animals, the dorsal striatum and ventral striatum demonstrated an upregulation in NMDA-stimulated dopamine release compared to symptomatic animals. Receptor autoradiography showed no significant differences in NMDA receptor binding between normal, symptomatic, and recovered animals in the dorso-lateral caudate. NMDA receptor binding was, however, upregulated in the ventro-medial caudate of recovered animals. With Western analysis, NR1 and NR2A subunit levels in the dorso-lateral caudate were shown to decrease significantly in symptomatic animals compared to normal and then increase in recovered animals compared to symptomatic animals. In the ventro-medial caudate, NR1 and NR2A levels in the symptomatic group were significantly increased compared to normal and recovered groups. These data suggest that there may be recovery-induced changes in the functional regulation of the NMDA receptors in the striatum contributing to the behavioral recovery seen in this model

SCH-23390 antagonism of a D-2 dopamine agonist depends upon catecholaminergic neurons

SCH-23390, a selective D-1 dopamine antagonist, was found to antagonize the locomotor stimulation induced by LY-171555, an action similar to that for haloperidol in control animals. However, this action of SCH-23390 was prevented in rats treated with 6-hydroxydopamine (6-OHDA) or with reserpine plus α-methyl-tyrosine pretreatment. These results indicate that the action of SCH-23390 to antagonize D-2 dopamine receptor actions is dependent upon functional catecholamine-containing neurons. In contrast to the lack of action of SCH-23390 to antagonize LY-171555 in 6-OHDA-treated rats, SCH-23390 blocked the locomotor stimulation induced by SKF-39393, a D-1 dopamine agonist, after this treatment. Thus, D-1 dopamine receptors are distinct from D-2 receptor sites and can exhibit a behavior similar to that observed when D-2 receptors are stimulated. These data suggest that D-1 receptor sites modulate D-2 dopamine receptor function through a mechanism dependent upon functionally intact catecholamine-containing neurons