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Abstract: The effects of aripiprazole, (−)-(3-hydroxyphenyl)-N-n-propylpiperidine ((−)-3-PPP) and quinpirole on single and multiple pulse stimulated dopamine release were investigated using the technique of fast cyclic voltammetry (FCV) in isolated rat striatal slices. Aripiprazole and (−)-3-PPP had no significant effect on single pulse dopamine release at concentrations from 10nM to 10μM indicating low agonist activity. The compounds failed to potentiate 5 pulse stimulated release of dopamine although inhibitory effects were seen at 10μM for aripiprazole. Both compounds were tested against the concentration–response curve for quinpirole''s inhibition of stimulated single pulse dopamine release. Aripiprazole and (−)-3-PPP shifted the concentration–response curve for quinpirole to the right. In each case this was greater than a 100-fold shift for the 10μM test compound. Whilst these results indicate that both compounds show little agonist activity on dopamine release and significant antagonism of the inhibitory effect of quinpirole on dopamine release, whether they are functionally selective dopamine D2 ligands remains controversial. [Copyright &y& Elsevier]

Abstract: Striatal dopamine neurotransmission is critical for normal voluntary movement, affect and cognition. Dysfunctions of its regulation are implicated in a broad range of behaviors and disorders including Parkinson’s disease, schizophrenia and drug abuse. Extracellular dopamine levels result from a dynamic equilibrium between release and reuptake by dopaminergic terminals. Both processes are regulated by multiple mechanisms. Here we review data characterizing how dopamine levels are regulated by presynaptic autoreceptors and heteroreceptors, an area intensively investigated due to advances in real time electrochemical detection of extracellular dopamine, i.e., fast-scan cyclic voltammetry and amperometry, and the development of mutant mouse lines with deletions for specific receptors. [Copyright &y& Elsevier]

Abstract: We have recently established the socially monogamous prairie vole (Microtus ochrogaster) as an animal model with which to investigate the involvement of mesocorticolimbic dopamine (DA) in the amphetamine (AMPH)-induced impairment of social behavior. As the majority of our work, to date, has focused on males, and sex differences are commonly reported in the behavioral and neurobiological responses to AMPH, the current study was designed to examine the behavioral and neurobiological effects of AMPH treatment in female prairie voles. We used a conditioned place preference (CPP) paradigm to determine a dose–response curve for the behavioral effects of AMPH in female prairie voles, and found that conditioning with low to intermediate (0.2 and 1.0mg/kg), but not very low (0.1mg/kg), doses of AMPH induced a CPP. We also found that exposure to a behaviorally relevant dose of AMPH (1.0mg/kg) induced an increase in DA concentration in the nucleus accumbens (NAcc) and caudate putamen but not the medial prefrontal cortex or ventral tegmental area (VTA). Finally, repeated AMPH exposure (1.0mg/kg once per day for 3consecutive days; an injection paradigm that has been recently shown to alter DA receptor expression and impair social bonding in male prairie voles) increased D1, but not D2, receptor mRNA in the NAcc, and decreased D2 receptor mRNA and D2-like receptor binding in the VTA. Together, these data indicate that AMPH alters mesocorticolimbic DA neurotransmission in a region- and receptor-specific manner, which, in turn, could have profound consequences on social behavior in female prairie voles. [Copyright &y& Elsevier]

Acute administration of antipsychotic drugs increases dopamine (DA) neuron activity and DA release via D2 receptor blockade. However, it is unclear whether the DA neuron activation produced by antipsychotic drugs is due to feedback from post-synaptic blockade or is due to an action on DA neuron autoreceptors. This was evaluated using two drugs: the first-generation antipsychotic drug haloperidol that has potent D2 blocking properties, and the second-generation drug sertindole, which is unique in that it is reported to fail to reverse the apomorphine-induced decrease in firing rate typically associated with DA neuron autoreceptor stimulation. Using single-unit extracellular recordings from ventral tegmental area (VTA) DA neurons in anaesthetized rats, both drugs were found to significantly increase the number of spontaneously active DA neurons (population activity). Apomorphine administered within 10 min either before or after sertindole reversed the sertindole-induced increase in population activity, but had no effect when administered 1 h after sertindole. Moreover, both sertindole- and haloperidol-induced increase in population activity was prevented when nucleus accumbens feedback was interrupted by local infusion of the GABAA antagonist bicuculline into the ventral pallidum. Taken together, these data suggest that antipsychotics increase DA neuron population activity via a common action on the nucleus accumbens-ventral pallidum-VTA feedback pathway and thus provide further elucidation on the mechanism by which antipsychotic drugs affect DA neuron activity. This provides an important insight into the relationship between altered DA neuron activity and potential antipsychotic efficacy. [ABSTRACT FROM AUTHOR]

In the study of behavioural sensitization induced by dopamine agonists, D1 and D2 receptors have a critical, but a puzzling role. The objective of this study is to examine the effects of the D1 antagonist SCH-23390 and the D2 antagonist sulpiride given repeatedly alone or in combination with apomorphine upon apomorphine conditioning and sensitization. Apomorphine-induced (2.0 mg/kg) conditioning and sensitization were assessed following five paired/unpaired treatments. Sulpiride (10, 30 and 100 mg/kg) and SCH-23390 (0.01, 0.02 and 0.05 mg/kg) were administered alone or in combination with apomorphine. In experiment 1, the effect of 5 days of sulpiride and SCH-23390 treatments given alone were assessed on apomorphine reactivity. In experiment 2, sulpiride and SCH-23390 were co-administered with apomorphine for 5 days and subsequently, conditioning and sensitization tests were performed. In experiment 3, following five apomorphine treatment sessions, sulpiride and SCH-23390 were administered prior to the conditioning and sensitization tests. SCH-23390 and sulpiride induced hyper-reactivity to apomorphine. SCH-23390 when given after the induction of apomorphine sensitization, blocked the expression of apomorphine sensitization. When given in combination with apomorphine, SCH-23390 blocked the apomorphine conditioning and sensitization, whereas low-dose sulpiride permitted conditioning and enhanced apomorphine sensitization and high-dose sulpiride blocked conditioning but permitted apomorphine sensitization. Both sulpiride doses transformed apomorphine sensitization from context-specific to context-independent sensitization. The SCH-23390 findings are supportive of a critical role for D1 receptors in apomorphine effects whereas the sulpiride effects diminish the importance of conditioning and dopamine autoreceptor subsensitivity mechanisms in the mediation of apomorphine sensitization. [ABSTRACT FROM AUTHOR]

Abstract: Axonal release of serotonin (5-hydroxytryptamine, 5-HT) in the CNS is typically regulated by presynaptic 5-HT autoreceptors. Release of 5-HT in substantia nigra pars reticulata (SNr), a principal output from the basal ganglia, has seemed an interesting exception to this rule. The SNr receives one of the highest densities of 5-HT innervation in mammalian brain and yet negative feedback regulation of axonal 5-HT release by endogenous 5-HT has not been identified here. We explored whether we could identify autoregulation of 5-HT release by 5-HT1B receptors in rat SNr slices using fast-scan cyclic voltammetry at carbon-fiber microelectrodes to detect 5-HT release evoked by discrete stimuli (50 Hz, 20 pulses) paired over short intervals (1–10 s) within which any autoreceptor control should occur. Evoked 5-HT release exhibited short-term depression after an initial stimulus that recovered by 10 s. Antagonists for 5-HT1B receptors, isamoltane (1 μM) or SB 224-289 (1 μM), did not modify release during a stimulus train, but rather, they modestly relieved depression of subsequent release evoked after a short delay (≤2 s). Release was not modified by antagonists for GABA (picrotoxin, 100 μM, saclofen, 50 μM) or histamine-H3 (thioperamide, 10 μM) receptors. These data indicate that 5-HT release can activate a 5-HT1B-receptor autoinhibition of subsequent release, which is mediated directly via 5-HT axons and not via GABAergic or histaminergic inputs. These data reveal that 5-HT release in SNr is not devoid of autoreceptor regulation by endogenous 5-HT, but rather is under modest control which only weakly limits 5-HT signaling. [Copyright &y& Elsevier]

Vilazodone (EMD 68843; 5-{4-[4-(5-cyano-3-indolyl)-butyl]-1-piperazinyl}-benzofuran-2-carboxamide hydrochloride) is a combined serotonin specific reuptake inhibitor (SSRI) and 5-HT1A receptor partial agonist currently under clinical evaluation for the treatment of major depression. This molecule was designed based on the premise that negative feedback circuitry, mediated via 5-HT1 receptors, limits the acute SSRI-induced enhancements in serotonergic neurotransmission. If the hypothesis is correct, combination of SSRI with 5-HT1A partial agonism should temporally enhance the neuroplastic adaptation and subsequently hasten therapeutic efficacy compared to current treatments. Preclinical in vitro evaluation has confirmed vilazodone's primary pharmacological profile both in clonal and native systems, that is, serotonin reuptake blockade and 5-HT1A partial agonism. However, in vivo and in contrast to combination of 8-OH-DPAT and paroxetine, vilazodone selectively enhanced serotonergic output in the prefrontal cortex of rats. Behavioral evaluations, in the ultrasonic vocalization model of anxiety in rats, demonstrated anxiolytic efficacy. In the forced swim test (a putative model of depression), vilazodone also showed efficacy but at a single dose only. In man, vilazodone abolished REM sleep and demonstrated clinical antidepressant efficacy equivalent to an SSRI. Ongoing clinical evaluations will hopefully reveal whether the founding hypothesis was valid and if vilazodone will produce a more rapid onset of antidepressant efficacy. [ABSTRACT FROM AUTHOR]

Abstract: Histamine suppresses feeding behavior via histamine H1 receptors in the hypothalamus. This study was performed to examine whether the acute reduction of histamine release in the hypothalamus caused by immepip, a histamine H3 agonist, modulates the feeding behavior of rats. Rats had a catheter implanted in the third cerebral ventricle (i3v) and were given central injections of phosphate-buffered-saline or immepip (100–300pmol/rat). Following the i3v administration of immepip, the rats developed dose-dependent hypokinesia within 10min of administration. Next to hypokinesia, the rats showed significant dose-dependent feeding behavior. High-performance liquid chromatography (HPLC) confirmed the reduction in histamine release in the hypothalamus of rats following i3v administration of immepip. These results suggest that i3v administration of immepip, an H3 receptor agonist, suppresses hypothalamic histamine release and elicits feeding behavior in rats. [Copyright &y& Elsevier]

Novelty-seeking personality traits are a major risk factor for the development of drug abuse and other unsafe behaviors. Rodent models of temperament indicate that high novelty responding is associated with decreased inhibitory autoreceptor control of midbrain dopamine neurons. It has been speculated that individual differences in dopamine functioning also underlie the personality trait of novelty seeking in humans. However, differences in the dopamine system of rodents and humans, as well as the methods for assessing novelty responding/seeking across species leave unclear to what extent the animal models inform our understanding of human personality. In the present study we examined the correlation between novelty-seeking traits in humans and D[sub2]-like (D[sub2]/D[sub3] ) receptor availability in the substantia nigra/ventral tegmental area. Based on the rodent literature we predicted that novelty seeking would be characterized by lowered levels of D[sub2]-like (auto)receptor availability in the midbrain. Thirty-four healthy adults (18 men, 16 women) completed the Tridimensional Personality Questionnaire-Novelty-Seeking Scale and PET scanning with the D[sub2]/D[sub3] ligand [ [sup18]F]fallypride. Novelty- Seeking personality traits were inversely associated with D[sub2]-like receptor availability in the ventral midbrain, an effect that remained significant after controlling for age. We speculate that the lower midbrain (auto)receptor availability seen in high novelty seekers leads to accentuated dopaminergic responses to novelty and other conditions that induce dopamine release. [ABSTRACT FROM AUTHOR]

In the rodent cerebellum, pharmacological activation of group III pre-synaptic metabotropic glutamate receptors (mGluRs) by the broad spectrum agonistl-2-amino-4-phosphonobutyric acid, acutely depresses excitatory synaptic transmission at parallel fiber (PF)-Purkinje cell (PC) synapses. Among the group III mGluR subtypes, cerebellar granule cells express predominantly mGluR4, but also mGluR7 and mGluR8 mRNA. Taking into account that previous functional and pharmacological studies have used group III mGluR broad spectrum agonists that do not differentiate between these various subtypes, their relative contribution to the modulation of glutamatergic transmission at PF-PC synapses remains to be elucidated. In order to clarify this issue, we applied conventional whole-cell patch-clamp recordings and pre-synaptic calcium influx measurements, combined with pharmacological manipulations to rat and mice cerebellar slices. With the use of (1 S,2 R)-1-amino-2-phosphonomethylcyclopropanecarboxylic acid, a new and selective group III mGluR agonist, N-phenyl-7-(hydroxylimino)cyclopropa[b]-chromen-1a-carboxamide, the specific positive allosteric modulator of mGluR4, ( S)-3,4-dicarboxyphenylglycine, a selective mGluR8 agonist, and mGluR4 knock-out mice, we demonstrate that the inhibitory control of group III mGluRs on excitatory neurotransmission at PF-PC synapses of the rodent cerebellar cortex, is totally because of the activation of pre-synaptic mGluR4 autoreceptors. [ABSTRACT FROM AUTHOR]

Abstract: Dopamine (DA) neurons comprising the A11 diencephalospinal system represent the major source of DA innervation to the spinal cord. These neurons project axons throughout the rostrocaudal extent of the spinal cord, terminating predominantly in the dorsal horn. Loss of DA-mediated sensorimotor function in the lumbar segment of spinal cord is implicated in the etiology of Restless Legs Syndrome (RLS), which is more prevalent in females as compared with males. The purpose of the present study was to compare the density (DA concentrations) and catabolic activity (3,4-dihydroxyphenylacetic acid; DOPAC) of A11 DA neurons innervating the lumbar spinal cord of male and female C57/BL6 mice, and to determine if there is a sexual difference in the regulation of these neurons by D2 autoreceptor-mediated mechanisms. DA concentrations in the lumbar spinal cord were higher in males, suggesting a greater A11 DA innervation as compared with females, whereas there was no sexual difference in the activity (DOPAC/DA ratio) of these DA neurons under basal conditions. Blockade of D2 receptors with raclopride caused a significant increase in the DOPAC/DA ratio in the striatum and nucleus accumbens in both males and females, but had no effect in the spinal cord. Blockade of neuronal impulse flow and DA release with γ-butyrolactone (GBL) increased DA concentrations in the spinal cord, but this increase was not prevented by pretreatment with the D2 agonist quinelorane. These results are consistent with the conclusion that A11 diencephalospinal DA neurons in both males and females lack presynaptic synthesis modulating D2 autoreceptors. [Copyright &y& Elsevier]

Serotonin is a conspicuous neuromodulator in the nervous system of many vertebrates and invertebrates. In previous experiments performed in the leech nervous system, we compared the effect of the amine released from endogenous sources [using selective serotonin reuptake inhibitors (SSRIs), e.g. fluoxetine] with that of bath-applied serotonin. The results suggested that the amine does not reach all its targets in a uniform way, but produces the activation of an interneuronal pathway that generated specific synaptic responses on different neurons. Taking into account that the release of the amine is often regulated at the presynaptic level, we have investigated whether autoreceptor antagonists mimic the SSRIs effect. We found that methiothepin (100 μM) produced similar effects than fluoxetine. To further test the hypothesis that endogenous serotonin produce its effect by acting locally at specific sites, we analyzed the effect of iontophoretic applications of serotonin. We found a site in the neuropil of the leech ganglia where serotonin application mimicked the effect of the SSRIs and the 5-HT antagonist. The results further support the view that the effect of serotonin exhibits a spatial specificity that can be relevant to understand its modulatory actions. [ABSTRACT FROM AUTHOR]

An increase in brain serotonin (5-HT) levels is thought to be a key mechanism of action responsible for generating antidepressant efficacy. It has been proven that selective serotonin reuptake inhibitors are effective antidepressants, but the delay to therapeutic onset of these agents is thought to be due to the time required for 5-HT1A, and possibly 5-HT1B, autoreceptors to desensitize. Therefore, an agent incorporating 5-HT reuptake inhibition coupled with 5-HT1A and/or 5-HT1B autoreceptor antagonism may provide a fast-acting clinical agent. The current studies review the profile of SB-649915 (6-[(1-{2-[(2-methylquinolin-5-yl)oxy]ethyl}piperidin-4-yl)methyl]-2 H-1,4-benzoxazin-3(4 H)-one), a novel compound with high affinity for human (h) 5-HT1A and 5-HT1B receptors (pKi values of 8.6 and 8.0, respectively) as well as the (h) 5-HT transporter (SERT) (pKi value of 9.3). SB-649915 behaved as an antagonist at both 5-HT1A and 5-HT1B receptors in vitro and in vivo, reversing 5-HT, (+)8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and SKF99101-induced functional/behavioral responses. Furthermore, it inhibited [3H]5-HT reuptake in rat cortical synaptosomes, in vitro and ex vivo. In electrophysiological studies SB-649915 had no effect on rat dorsal raphe neuronal cell firing per se, but reversed 8-OH-DPAT–induced inhibition of firing both in vitro and in vivo. In addition, in a microdialysis study, it produced an acute increase in extracellular 5-HT in forebrain structures of the rat. Finally, SB-649915 demonstrated acute anxiolytic activity in both rodent and non-human primate and reduced the latency to onset of anxiolytic behavior, compared to paroxetine, in the rat social interaction paradigm. In summary, SB-649915 is a novel, potent 5-HT1A/1B autoreceptor antagonist, and 5-HT reuptake inhibitor. This particular pharmacological profile provides a novel mechanism that could offer fast-acting antidepressant activity. [ABSTRACT FROM AUTHOR]

Altered synaptic dopamine levels have been implicated in several neurological/neuropsychiatric disorders, including drug addiction and schizophrenia. However, it is unclear what precipitates these changes in synaptic dopamine levels. One of the key presynaptic components involved in regulating dopaminergic tone is the dopamine transporter (DAT). Here, we report that the DAT is also regulated by the dopamine D2 receptor through a direct protein–protein interaction involving the DAT amino-terminus and the third intracellular loop of the D2 receptor. This physical coupling facilitates the recruitment of intracellular DAT to the plasma membrane and leads to enhanced dopamine reuptake. Moreover, mice injected with peptides that disrupt D2–DAT interaction exhibit decreased synaptosomal dopamine uptake and significantly increased locomotor activity, reminiscent of DAT knockout mice. Our data highlight a novel mechanism through which neurotransmitter receptors can functionally modulate neurotransmitter transporters, an interaction that can affect the synaptic neurotransmitter levels in the brain. [ABSTRACT FROM AUTHOR]

Abstract: Somatostatin (SRIF), as a neuroactive peptide in the CNS, exerts its actions via five subtypes of specific receptors (ssts). In this work, the localization of sst5 was studied immunocytochemically in rat retinal amacrine cells (ACs). Labeling for sst5 was diffusely distributed throughout the full thickness of the inner plexiform layer (IPL) and formed two distinct fluorescence bands in the distal part of the IPL. Double labeling experiments showed that sst5 was expressed in GABAergic ACs. It was further shown that labeling for sst5 was observed in both dopaminergic and cholinergic ACs, stained by tyrosine hydroxylase (TH) and choline acetyltransferase (ChAT), respectively. The immunostaining appeared mainly on the cell membranes and somatodendritic compartments of these ACs. For the cholinergic ACs, weak sst5-immunoreactivity was also observed in the processes terminating in the IPL. In contrast, no sst5-immunoreactivity was found in glycinergic AII ACs, stained by parvalbumin (PV). Furthermore, labeling for SRIF was co-localized with sst5 in both dopaminergic and cholinergic ACs. These results suggest that sst5 may serve as an autoreceptor or conventional receptor in retinal ACs. [Copyright &y& Elsevier]

In the striatum, dopamine and acetylcholine (ACh) modulate dopamine release by acting, respectively, on dopamine D2 autoreceptors and nicotinic ACh (nACh) heteroreceptors localized on dopaminergic nerve terminals. The possibility that functional interactions exist between striatal D2 autoreceptors and nACh receptors was studied with in vivo microdialysis in freely moving rats. Local perfusion of nicotine in the ventral striatum (shell of the nucleus accumbens) produced a marked increase in the extracellular levels of dopamine, which was completely counteracted by co-perfusion with either the non-α7 nACh receptor antagonist dihydro-β-erythroidine or the D2−3 receptor agonist quinpirole. Local perfusion of the D2−3 receptor antagonist raclopride produced an increase in the extracellular levels of dopamine, which was partially, but significantly, counteracted by coperfusion with dihydro-β-erythroidine. These findings demonstrate a potent crosstalk between G protein-coupled receptors and ligand-gated ion channels in dopaminergic nerve terminals, with the D2 autoreceptor modulating the efficacy of non-α7 nACh receptor-mediated modulation of dopamine release. We further demonstrate physical interactions between β2 subunits of non-α7 nicotinic acetylcholine receptors and D2 autoreceptors in co-immunoprecipitation experiments with membrane preparations from co-transfected mammalian cells and rat striatum. These results reveal that striatal non-α7 nicotinic acetylcholine receptors form part of heteromeric dopamine autoreceptor complexes that modulate dopamine release.Neuropsychopharmacology (2007) 32, 35–42. doi:10.1038/sj.npp.1301103; published online 17 May 2006 [ABSTRACT FROM AUTHOR]

Histamine H3 receptors (H3R5) are located on the presynaptic membranes and cell soma of histamine neurons, where they negatively regulate the synthesis and release of histamine. In addition, H3Rs are also located on nonhistaminergic neurons, acting as heteroreceptors to regulate the releases of other amines such as dopamine, serotonin, and norepinephrine. The present study investigated the effects of H3R ligands on appetite and body-weight regulation by using WT and H3R-deficient mice (H3RKO), because brain histamine plays a pivotal role in energy homeostasis. The results showed that thioperamide, an H3R inverse agonist, increases, whereas imetit, an H3R agonist, decreases appetite and body weight in diet-induced obese (DiO) WT mice. Moreover, in DiO WT mice, but not in DiO H3RKO mice, imetit reduced fat mass, plasma concentrations of leptin and insulin, and hepatic triglyceride content. The anorexigenic effects of imetit were associated with a reduction in histamine release, but a comparable reduction in histamine release with α-fluoromethyl- histidine, an inhibitor of histamine synthesis, increased appetite. Moreover, the anorexigenic effects of imetit were independent of the melanocortin system, because imetit comparably reduced appetite in melanocortin 3 and 4 receptor-deficient mice. The results provide roles of H3Rs in energy homeostasis and suggest a therapeutic potential for H3R agonists in the treatment of obesity and diabetes mellitus. [ABSTRACT FROM AUTHOR]

Abstract: This study utilised the selective 5-ht5A receptor antagonist, SB-699551-A (3-cyclopentyl-N-[2-(dimethylamino)ethyl]-N-[(4′-{[(2-phenylethyl)amino]methyl}-4-biphenylyl)methyl]propanamide dihydrochloride), to investigate 5-ht5A receptor function in guinea pig brain. SB-699551-A competitively antagonised 5-HT-stimulated [35S]GTPγS binding to membranes from human embryonic kidney (HEK293) cells transiently expressing the guinea pig 5-ht5A receptor (pA 2 8.1±0.1) and displayed 100-fold selectivity versus the serotonin transporter and those 5-HT receptor subtypes (5-HT1A/B/D, 5-HT2A/C and 5-HT7) reported to modulate central 5-HT neurotransmission in the guinea pig. In guinea pig dorsal raphe slices, SB-699551-A (1μM) did not alter neuronal firing per se but attenuated the 5-CT-induced depression in serotonergic neuronal firing in a subpopulation of cells insensitive to the 5-HT1A receptor-selective antagonist WAY-100635 (100nM). In contrast, SB-699551-A (100 or 300nM) failed to affect both electrically-evoked 5-HT release and 5-CT-induced inhibition of evoked release measured using fast cyclic voltammetry in vitro. SB-699551-A (0.3, 1 and 3mg/kg s.c.) did not modulate extracellular levels of 5-HT in the guinea pig frontal cortex in vivo. However, when administered in combination with WAY-100635 (0.3mg/kg s.c.), SB-699551-A (0.3, 1 or 3mg/kg s.c.) produced a significant increase in extracellular 5-HT levels. These studies provide evidence for an autoreceptor role for the 5-ht5A receptor in guinea pig brain. [Copyright &y& Elsevier]

Abstract: An increase in brain 5-HT levels is thought to be the key mechanism of action which results in an antidepressant response. It has been proven that selective serotonin re-uptake inhibitors are effective antidepressants but the delay to therapeutic onset of these agents is thought to be due to the time required for 5-HT1A, and possibly 5-HT1B, autoreceptor desensitisation. Therefore an agent incorporating 5-HT re-uptake inhibition coupled with 5-HT1A and/or 5-HT1B autoreceptor antagonism may provide a fast acting clinical agent. The current studies describe the in vitro profile of SB-649915 (6-[(1-{2-[(2-methylquinolin-5-yl)oxy]ethyl}piperidin-4-yl)methyl]-2H-1,4-benzoxazin-3(4H)-one), a novel compound which has high affinity for human recombinant 5-HT1A, 5-HT1B and 5-HT1D receptors (pK i values of 8.6, 8.0, 8.8, respectively) and the human recombinant 5-HT transporter (pK i value of 9.3). SB-649915 also displays high affinity for rat, guinea pig, mouse and marmoset native tissue 5-HT1A, 5-HT1B and 5-HT1D receptors and rat native tissue 5-HT transporters (pK i values≥7.5). In functional [35S]GTPγS binding studies, SB-649915 (up to 1 μM) does not display intrinsic activity in HEK293 cells expressing human recombinant 5-HT1A receptors but acts as a partial agonist at human recombinant 5-HT1B and 5-HT1D receptors with intrinsic activity values of 0.3 and 0.7, respectively, as compared to the full agonist 5-HT. From Schild analysis, SB-649915 caused a concentration-dependent, rightward shift of 5-HT-induced stimulation of basal [35S]GTPγS binding in cells expressing human recombinant 5-HT1A or 5-HT1B receptors to yield pA 2 values of 9.0 and 7.9, respectively. In electrophysiological studies in rat dorsal raphe nucleus, SB-649915 did not affect the cell firing rate up to 1 μM but attenuated (+)8-hydroxy-2-(di-n-propylamino) tetralin-induced inhibition of cell firing with an apparent pK b value of 9.5. SB-649915 (1 μM) significantly attenuated exogenous 5-HT-induced inhibition of electrically-stimulated [3H]5-HT release from guinea pig cortex. In studies designed to enhance endogenous 5-HT levels, and therefore increase tone at 5-HT1B autoreceptors, SB-649915 significantly potentiated [3H]5-HT release at 100 and 1000 nM. In LLCPK cells expressing human recombinant 5-HT transporters and in rat cortical synaptosomes, SB-649915 inhibited [3H]5-HT re-uptake with pIC50 values of 7.9 and 9.7, respectively. In summary, SB-649915 is a novel, potent 5-HT1A/1B autoreceptor antagonist and 5-HT re-uptake inhibitor in native tissue systems and represents a novel mechanism that could offer fast acting antidepressant action. [Copyright &y& Elsevier]

Reports on a study which examined the effectiveness of pharmacological magnetic resonance imaging in mapping dopamine (DA) autoreceptors. Limitations with the tools available for determining DA autoreceptor (DAR) location or function; Effects of D2 antagonism; Association between amphetamine-induced increase in relative cerebral blood volume in the accumbens in animals pre-treated with eticlopride and a similar percentage increase in DA release.

Abstract: By using immunohistochemical approaches at the light and electron microscopic levels, we have shown that aging modifies the subcellular distribution of the m2 muscarinic autoreceptor (m2R) differentially at somato-dendritic postsynaptic sites and at axonal presynaptic sites in cholinergic basalocortical neurons, in vivo. In cholinergic perikarya and dendrites of the nucleus basalis magnocellularis (NBM), aging is associated with a decrease of the density of m2R at the plasma membrane and in the cytoplasm, suggesting a decrease of the total number of m2R in the somato-dendritic field. In contrast, the number of substance P receptors per somato-dendritic surface was not affected. In the frontal cortex (FC), we have shown a decrease of cytoplasmic m2R density also leading to a decrease of the number of m2R per surface of varicosities but with no change of the density of m2R at the membrane. Our results suggest that the decrease of m2R in the somato-dendritic field of the NBM, but not a modification of the number of presynaptic m2 autoreceptors at the plasma membrane in the FC, could contribute to the decrease of the efficacy of cholinergic transmission observed with aging in the rat. [Copyright &y& Elsevier]

Abstract: The dopamine D3 receptor (D3R) has been implicated in schizophrenia, drug addiction, depression and Parkinson''s disease. The D3R is localized post-synaptically on nucleus accumbens neurons, but is also an autoreceptor on dopaminergic neurons in the mesencephalon. Its functional role as autoreceptor is highly debated, but supported by the elevated basal extracellular dopamine levels found in D3R-deficient mice. To investigate the functional role of the D3R in vivo, we used mice with a targeted disruption of the D3R gene. We found a higher basal level of grooming in D3R-deficient mice, compared to their wild-type littermates. This behavior, which is under the control of D1R stimulation, may be related to an increased dopaminergic tone, since no changes in the gene expression of dopamine D1 and D2 receptors were noticed in the striatum of these mice. D3R-deficient mice displayed other neuroadaptive changes, including decreased tyrosine hydroxylase, increased dopamine transporter mRNAs and increased dopamine reuptake in striatum. The level of tyrosine hydroxylase protein was unchanged in the striatum, as preprodynorphin and preproenkephalin gene expressions. All the changes identified in D3R-deficient mice cannot explain hyperdopaminergia, but, on the contrary, tend to attenuate this phenotype. These results support a distinct role for D2R and D3R as autoreceptors: the D2R is the release-regulating and firing rate-regulating autoreceptor, whereas the D3R may control basal dopamine levels in the striatum, by an unknown mechanism, which does not involve regulation of dopamine transporters or tyrosine hydroxylase. This hyperdopaminergia phenotype of D3R-deficient mice may explain their hyperactivity to drug-paired environmental cues. [Copyright &y& Elsevier]

Abstract: Substantial pharmacological evidence is consistent with an inhibitory effect of D3 receptor activation on dopamine (DA) release. Although receptor selectivity of the ligands employed in initial studies has been questioned, studies employing new, more selective, compounds continue to support an involvement of this receptor subtype in regulating extracellular dopamine levels in the dorsal striatum and nucleus accumbens. Consistent with this hypothesis, microdialysis studies have shown that the dose–effect curve for (+)-PD 128907, a moderately selective D3 agonist, is shifted to the right in D3 knock out mice. The present microdialysis studies sought to further examine the role of D2 vs. D3 receptors in mediating (+)-PD 128907-evoked alterations in basal and depolarization-evoked DA levels. Dialysate DA levels were determined in D2 knock out mice and wild type littermate controls following both systemic and local administration of (+)-PD 128907. In view of regional differences in D3 receptor localization, studies were conducted in the nucleus accumbens, a D3 receptor rich area, and in the dorsal striatum, a region with low D3 receptor abundance. Systemic or reverse dialysis of (+)-PD 128907 into the nucleus accumbens significantly decreased basal and depolarization-evoked DA levels in wild type mice. A similar effect was observed in the dorsal striatum. Regardless of the route of administration, (+)-PD 128907 was ineffective in modulating DA levels in either brain region of D2 knock out mice. These data contrast with previous results in D3 knock out mice and indicate that the D2 receptor is necessary for the inhibition of presynaptic DA neurotransmission produced by a preferential D3 agonist. Based on the documented physical interaction of D2 and D3 receptors in heterologous expression systems, we put forth a hypothesis that reconciles the seemingly paradoxical results of this and previous microdialysis studies. [Copyright &y& Elsevier]

Abstract: Information concerning striatal levels of noradrenaline (NA) remains inconsistent. Here we have addressed this issue using a sensitive method of HPLC coupled to amperometric detection. The NA reuptake-inhibitor, reboxetine, selectively elevated levels of NA versus dopamine (DA), and NA levels were also selectively elevated by the α2-adrenoceptor (AR) antagonist, atipamezole. The actions of atipamezole were mimicked by the preferential α2A-AR antagonist, BRL44408, while JO-1 and prazosin, preferential antagonists at α2C-ARs, caused less marked elevations in NA levels. In contrast to antagonists, the α2-AR agonist, S18616, decreased NA levels and likewise suppressed those of DA. Unilateral lesions of the substantia nigra with 6-hydroxydopamine depleted DA levels without affecting those of NA. Further, the D3/D2 receptor agonist, quinelorane, decreased levels of DA without modifying those of NA. However, the D3/D2 receptor antagonists, haloperidol and raclopride, and the DA reuptake-inhibitor, GBR12935, elevated levels of both DA and NA. Levels of 5-HT (but not of NA or DA) were increased only by the 5-HT reuptake-inhibitor, citalopram. They were decreased by S18616 and prazosin, reflecting the inhibitory and excitatory influence of α2- and α1-ARs, respectively, upon serotonergic pathways. In conclusion, NA in the striatum is derived from adrenergic terminals. Its release is subject to tonic, inhibitory control by α2-ARs, possibly involving both α2A- and α2C-AR subtypes, though their respective contribution requires clarification. A role of dopaminergic terminals in the reuptake of NA likely explains the elevation in its levels elicited by DA reuptake-inhibitors and D3/D2 receptor antagonists. [Copyright &y& Elsevier]

The neostriatum is known to receive glutamatergic projections from the cerebral cortex and thalamic nuclei. Vesicular glutamate transporters 1 and 2 (VGluT1 and VGluT2) are located on axon terminals of corticostriatal and thalamostriatal afferents, respectively, whereas VGluT3 is found in axon terminals of cholinergic interneurons in the neostriatum. In the present study, the postsynaptic localization of ionotropic glutamate receptors was examined in rat neostriatum by the postembedding immunogold method for double labelling of VGluT and glutamate receptors. Immunoreactive gold particles for AMPA receptor subunits GluR1 and GluR2/3 were frequently found not only on postsynaptic but also on presynaptic profiles immunopositive for VGluT1 and VGluT2 in the neostriatum, and GluR4-immunoreactive particles were observed on postsynaptic and presynapticprofiles positive for VGluT1. Quantitative analysis revealed that 27–45% of GluR1-, GluR2-, GluR2/3- and GluR4-immunopositive particles found in VGluT1- or VGluT2-positive synaptic structures in the neostriatum were associated with the presynaptic profiles of VGluT-positive axons. In contrast, VGluT-positive presynaptic profiles in the neostriatum showed almost no immunoreactivity for NMDA receptor subunits NR1 or NR2A/B. Furthermore, almost no GluR2/3-immunopositive particles were observed in presynaptic profiles of VGluT3-positive (cholinergic) terminals that made asymmetric synapses in the neostriatum, or in those of VGluT1- or VGluT2-positive terminals in the neocortex. The present results indicate that AMPA receptor subunits but not NMDA receptor subunits are located on axon terminals of corticostriatal and thalamostriatal afferents, and suggest that glutamate released from these axon terminals controls the activity of the terminals through the presynaptic AMPA autoreceptors. [ABSTRACT FROM AUTHOR]

Rationale. Sigma1 receptors (Sig-1R) are implicated in behavioral sensitization, conditioned place preference, and cellular restructuring induced by psychostimulants. We previously reported that rats which actively self-administered methamphetamine for 5 weeks and were then withdrawn from methamphetamine for 24 h showed downregulation of dopamine D2 autoreceptors (approximately 30%) in the midbrain and this was not seen in rats that passively received injections of methamphetamine or saline at the same time (yoked controls). Involvement of Sig-1R in the self-administration of psychostimulants, however, has never been reported. Objectives. This study examined neuroadaptive changes in Sig-1R in the brains of rats self-administering methamphetamine. Methods. Three groups of rats were tested simultaneously 5 days per week, for 5 weeks (25 daily sessions). Two groups served as yoked controls and passively received an injection of either 0.1 mg/kg methamphetamine or saline (not contingent on responding) each time a response-contingent injection of 0.1 mg/kg methamphetamine was actively self-administered by the first group of rats. Protein and mRNA levels of Sig-1R were then measured by Western and Northern blottings, respectively. Results. There was a marked upregulation of Sig-1R proteins (50%) in the midbrain and altered levels of Sig-1R mRNA in the frontal cortex and hippocampus of rats that learned to actively self-administer methamphetamine, but not in yoked methamphetamine- or saline-control rats. Conclusions. Neuroadaptive increases in Sig-1R seen in this study may contribute to the reinforcing effects of methamphetamine. This upregulation of Sig-1R may be mediated by increased protein kinase A activity due to downregulation of dopamine D2 autoreceptors. [ABSTRACT FROM AUTHOR]

The present study provides further evidence for transient D1 autoreceptor-like synthesis modulation in prefrontal cortex, but not striatum, of developing rats. DOPA accumulation was attenuated in a concentration-dependent manner in slices from the prefrontal cortex and striatum at 15 days of age by the partial D1 agonist SKF 38393 (0.01–10 μM) and the full D1 agonist SKF-81297 (0.01–10 μM) following NSD-1015; the response was no longer apparent by 40 days. Both agonists had greater potency in prefrontal cortex than striatum, and SKF-81297 exerted greater maximal inhibitory effects than SKF-38393. The inhibitory effects of both agonists were antagonized by pre-incubation with the D1 antagonist SCH-23390 in cortex, but not in striatum. [Copyright &y& Elsevier]

Cataplexy, an emotion-triggered sudden loss of muscle tone specific to narcolepsy, is tightly associated with hypocretin deficiency. Using hypocretin receptor 2 gene (hcrtr 2)-mutated narcoleptic Dobermans, we have previously demonstrated that altered dopamine (DA) D2/3 receptor mechanisms in mesencephalic DA nuclei are important for the induction of cataplexy. In the current study, we also found that the administration of D2/3 agonists into diencephalic dopaminergic cell groups, including the area dorsal to the ventral tegmental area (DRVTA) and the periventricular gray (PVG) matter of the caudal thalamus (corresponding to area A11), significantly aggravated cataplexy in hcrtr 2-mutated narcoleptic Dobermans. A D1 agonist and antagonist and a DA uptake inhibitor perfused into the DRVTA had no effect on cataplexy, suggesting an involvement of D2/3 receptors located on DA cell bodies (i.e., autoreceptors) for the regulation of cataplexy. Because the A11 cell group projects to the spinal ventral horn, the A11 D2/3 receptive mechanisms may directly modulate the activity of spinal motoneurons and modulate cataplexy. [Copyright &y& Elsevier]

The aim of this study was to examine the ability of somatostatin receptor (sst1) to regulate the release of somatostatin in rat retina. Immunohistochemistry studies were performed to locate the somatostatin neurons, and radioligand binding to ascertain the presence of sst1. The neuronal release of somatostatin was examined ex vivo in rat retinal explants in the presence of KCl (50 and 100 mM), and absence of Ca++ (EGTA; 10 mM). Somatostatin levels, quantified by radioimmunoassay, were increased in the presence of KCl (100 mM, 151%) and attenuated in the absence of Ca++ (31%). CH275 (sst1 agonist) reduced the somatostatin levels in a concentration-dependent manner (10−5–10−7 M), and this effect was reversed by NVP-SRA 880 (sst1 antagonist;10−5 M). MK678 (sst2 agonist; 10−5 M) had no effect. These data suggest an autoreceptor role for sst1 in retina. [Copyright &y& Elsevier]

The concept that NK1 receptors are located pre-junctionally on substance P (SP)-containing nerves, acting as autoreceptors to inhibit SP release, has been suggested, but remains a controversial issue. To further investigate the existence of this receptor on central and peripheral terminals of primary afferent fibres, NK1 receptor knockout mice and an NK1 receptor antagonist were used in nerve-attached tissue preparations. These were the isolated dorsal horn of the spinal cord with dorsal roots attached, and the hairy skin of the hind paw with attached saphenous nerve. The results reveal that in the dorsal horn preparation, basal release of SP is significantly higher in NK1−/− mice than NK1+/+ mice (P<0.05, n=7 mice/strain). However, a difference in SP release evoked in the dorsal horn by electrical stimulation of the dorsal roots or capsaicin application was not observed. In contrast, antidromic electrical stimulation of the saphenous nerve caused a substantially greater release of SP in the skin of NK1−/− mice than in NK1+/+ mice (P<0.05, n=5 to 6 mice/strain). These results provide evidence for the existence of NK1 autoreceptors on sensory nerves in skin, which may be relevant to the modulation of their peripheral pathophysiological effector functions. [Copyright &y& Elsevier]

1 Group I metabotropic glutamate receptors (mGluRs) are thought to be important modulators of neuronal function in the superior colliculus (SC). Here, we investigated the pharmacology and signalling mechanisms underlying group I mGluR-mediated inhibition of neuronal excitability and synaptic transmission in the rat SC slice. 2 The group I agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) potently depressed synaptically evoked excitatory postsynaptic potentials ( EPSPs). currents (EPSCs), and action potentials in a dose-dependent manner( lC[sub50] 6.3.μM). This was strongly reduced by the broad-spectrum antagonist (+)-alpha-methyl-4-carboxyphenylglycine (MCPG. I mM. ∼95‰ reduction), by the mGluR antagonist LY 367385 (100μM. ∼80% reduction) but not by the mGluR5 antagonist 6-methyl-2-(phenylethynyl)-pyridine (MPEP. 1- 100μM). 3 The putative mGluR5-specific agonist (RS)-2-chloro-5-hydroxyphenylgycine (CHPG. 500μM) also inhibited EPSPs. Interestingly, CHPG's actions were not blocked by MPEP, but LY367385 (100μM) reduced the effect of CHPG by 50%. 4 Inhibition induced by DHPG was independent of phospholipase C (PLC)/ protein kinase C pathways, and did not require intact intracellular Ca[sup2+] stores. It was not abolished but enhanced by the GABA[subA] antagonist bicuculline (5μM), suggesting that DHPG's action was not due to facilitated inhibition or changes in neuronal network activity. 5 The K[sup+] channel antagonist 4-aminopyridine (4-.AP. 50- 100μM) converted the inhibitory effect of DHPG into facilitation. Paired-pulse depression was strongly reduced by DHPG, an effect that was also prevented by 4-AP. 6 Our data indicate that group 1 agonists regulate transmitter release, presumably via an autoreceptor in the SC. This receptor may be involved in adaptation to repetitive stimulation via a non-PLC mediated pathway. [ABSTRACT FROM AUTHOR]

Although the localization and role of kainate receptors in the CNS remain poorly known, complex, and rather unusual, pre-synaptic auto- and heteroreceptor functions have been disclosed in various brain regions. Basal ganglia nuclei, including the globus pallidus, are enriched in GluR6/7 immunoreactivity. Using electron microscopic immunocytochemistry for GluR6/7 combined with post-embedding immunogold labeling for GABA, we demonstrate that GluR6/7 immunoreactivity is enriched in a large subpopulation of small unmyelinated, presumably pre-terminal, axons as well as GABAergic and putative glutamatergic axon terminals in the internal and external segments of the globus pallidus in monkey. Our findings suggest that kainate receptors are located to subserve pre-synaptic modulation of inhibitory and excitatory transmission in the primate globus pallidus. [Copyright &y& Elsevier]

To test the hypothesis that 5-HT1B receptors modulate serotonin (5-hydroxytryptamine, 5-HT) and dopamine release in the striatum, we used in vivo microdialysis in mice lacking 5-HT1B receptors. Local administration by reversed microdialysis of the selective 5-HT reuptake inhibitor, fluvoxamine (0.1–10 μM), concentration dependently increased 5-HT to the same extent in wildtype and in 5-HT1B knockout (KO) mice. Fluvoxamine (10 μM) increased dopamine levels similarly in both genotypes. The 5-HT releaser, fenfluramine (50 μM), increased both 5-HT and dopamine levels, but no difference was found between the genotypes. The 5-HT1B receptor agonist, 1,4-dihydro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-5H-pyrrolo[3,2-b]pyridin-5-one (CP-93,129), reduced 5-HT levels in the wildtype, but not in 5-HT1B KO mice. CP-93,129 at a concentration of 0.5 μM did not affect striatal dopamine outflow in either genotype, whereas dopamine outflow was increased 5-fold by 50 μM CP-93,129 in both genotypes. The CP-93,129-induced dopamine increase was not attenuated by ritanserin, a 5-HT2A/2C receptor antagonist, but was completely blocked by tetrodotoxin, demonstrating that the dopamine release was of neuronal origin. In conclusion, 5-HT1B autoreceptors are functionally present in the mouse striatum, but do not appear to play a significant role in the effects of a selective 5-HT reuptake inhibitor on extracellular 5-HT. In addition, the results in 5-HT1B knockout mice do not support a role of 5-HT1B heteroreceptors in the striatum on dopamine outflow in this brain area of mice. [Copyright &y& Elsevier]

Serotonergic neurons in the dorsal raphe nucleus, the major source of forebrain serotonin projections, synthesize a terminal autoreceptor that inhibits serotonin release—the 5-HT1B autoreceptor. Overexpression of this autoreceptor is hypothesized to contribute to anxiety. Antidepressants decrease (while learned helplessness increases) 5-HT1B mRNA in dorsal raphe neurons, and viral-mediated overexpression of 5-HT1B here increases anxiety behavior after stress. However, 5-HT1B mRNA levels in dorsal raphe are substantially elevated in unstressed rats in two models of stress resistance. Thus, the role of dorsal raphe 5-HT1B autoreceptors in anxiety is complex. Therefore, we tested whether different stressors differentially affect dorsal raphe 5-HT1B mRNA [via in situ hybridization histochemistry] and anxiety behavior (using the elevated plus maze). Rats were assigned to a stressor (either forced swim, water restraint, dry restraint, or electric tail shock) or a control condition, then were tested and sacrificed 24 h later. Overall, controls exhibited less anxiety than stressed rats as indicated by a higher ratio of open arm to total arm entries (OTR). The stressors did not differentially affect the OTR, nor did any alter dorsal raphe 5-HT1B mRNA levels. There was, however, a significant positive correlation between the OTR and 5HT1B mRNA intensity in controls (r=.64; P=.006), but not in stressed rats (r=.16, P=.36), providing further evidence that elevated dorsal raphe 5-HT1B levels are associated with reduced anxiety in animals that have not been exposed to stress. [Copyright &y& Elsevier]

We investigated by means of behavioral and neurochemical studies the effects of either D1 or D2 agonist on excessive dopamine release and hyperactivity induced by the microinjection of Bay K 8644, and an L-type Ca2+ channel stimulant, into the rat caudate putamen under a novel environmental condition. Hyperactivity (locomotor activity and rearing counts) and significant increases in extracellular dopamine levels induced by Bay K 8644 were concomitantly observed. D1 agonist, SKF81297, administered into the caudate putamen did not block Bay K 8644-induced hyperactivity measured by monitoring both animal activity and increases in extracellular dopamine levels detected by microdialysis. Pretreatment with the D2 agonists, bromocriptine, talipexole and pramipexole, into the caudate putamen significantly blocked Bay K 8644-induced hyperactivity for 45 min after Bay K 8644 administration, although the single administration of these agonists significantly potentiated locomotor activity and rearing behavior. Furthermore, these agonists significantly suppressed Bay K 8644-induced extracellular dopamine levels. Our results indicate that these D2 agonists (1) act on postsynaptic neuronal D2 receptors under conditions of normal or low dopamine release in the caudate putamen, and (2) act on presynaptic D2 receptors (autoreceptors) when excessive levels of dopamine are released or hyperdopamine neuronal activity is induced. Consequently, the effect of D2 agonists in the clinical treatment of Parkinson’s disease may be due to stimulation of postsynaptic D2 receptors rather than presynaptic autoreceptors. [Copyright &y& Elsevier]

Psychomotor stimulants and neuroleptics exert multiple effects on dopaminergic signaling and produce the dopamine (DA)-related behaviors of motor activation and catalepsy, respectively. However, a clear relationship between dopaminergic activity and behavior has been very difficult to demonstrate in the awake animal, thus challenging existing notions about the mechanism of these drugs. The present study examined whether the drug-induced behaviors are linked to a presynaptic site of action, the DA transporter (DAT) for psychomotor stimulants and the DA autoreceptor for neuroleptics. Doses of nomifensine (7 mg/kg i.p.), a DA uptake inhibitor, and haloperidol (0.5 mg/kg i.p.), a dopaminergic antagonist, were selected to examine characteristic behavioral patterns for each drug: stimulant-induced motor activation in the case of nomifensine and neuroleptic-induced catalepsy in the case of haloperidol. Presynaptic mechanisms were quantified in situ from extracellular DA dynamics evoked by electrical stimulation and recorded by voltammetry in the freely moving animal. In the first experiment, the maximal concentration of electrically evoked DA ([DA]max) measured in the caudate-putamen was found to reflect the local, instantaneous change in presynaptic DAT or DA autoreceptor activity according to the ascribed action of the drug injected. A positive temporal association was found between [DA]max and motor activation following nomifensine (r=0.99) and a negative correlation was found between [DA]max and catalepsy following haloperidol (r=−0.96) in the second experiment.Taken together, the results suggest that a dopaminergic presynaptic site is a target of systemically applied psychomotor stimulants and regulates the postsynaptic action of neuroleptics during behavior. This finding was made possible by a voltammetric microprobe with millisecond temporal resolution and its use in the awake animal to assess release and uptake, two key mechanisms of dopaminergic neurotransmission. Moreover, the results indicate that presynaptic mechanisms may play a more important role in DA-behavior relationships than is currently thought. [Copyright &y& Elsevier]

Neuropeptide Y (NPY) is an abundant brain peptide with endogenous antiepileptic activity. Here we examined the role played by Y1 receptors (Y1R) in the mouse hippocampus. Using whole-cell patch-clamp recordings, we show that hilar neurons in acute mouse hippocampal slices exhibit a G-protein coupled inwardly rectifying potassium (GIRK) current that is significantly enhanced during exogenous NPY application. NPY-mediated enhancement of GIRK current was observed on 47% of putative interneurons and was mimicked by application of Y1R specific agonist (Leu31Pro34 NPY). Immunostaining revealed the presence of Y1R on cell somas of hilar NPY-containing interneurons. Thus, our results suggest that Y1R on hilar interneurons may act as a peptide autoreceptor. [Copyright &y& Elsevier]

To elucidate the relationship between glutamatergic and dopaminergic transmissions, the effects of antisense oligodeoxynucleotide (aODN) to mRNA of NR1 subunit of N-methyl-D-aspartate (NMDA) receptors on the expression of dopamine D2 receptors (DRD2) were examined. Rats received continuous intracerebroventricular administration (20 nmol /day, for 7 days) of aODN or sense ODN (sODN), or of the same amount of saline. In vitro receptor autoradiography revealed that NR1 aODN induced a significant decrease in specific [3H]YM-09151-2 binding in the substantia nigra as compared to sODN and saline. Non-significant decreases were also seen in the ventral tegmental area. Northern blot analysis demonstrated a significant increase in DRD2 mRNA expression in the striata of aODN-treated animals. These results suggest that specific inhibition of NMDA receptor expression modulates pre- and post-synaptic expression of DRD2, possibly via reduced nigrostriatal dopaminergic activity. [Copyright &y& Elsevier]

The contribution of metabotropic glutamate 8 (mGlu8) receptors to modulation of medial and lateral perforant path (MPP and LPP) inputs to the dentate gyrus was investigated using electrophysiological recording of field excitatory postsynaptic potentials (fEPSPs) from hippocampal slices taken from wild-type and mGlu8 receptor knockout animals. Application of the selective group III mGlu receptor agonist, L-AP4 (1–100 μM), reduced fEPSPs evoked by LPP, but not MPP stimulation in wild-type slices in a concentration-dependent manner (EC50=4.7 μM). The selective mGlu8 receptor agonist, DCPG (1–30 μM) also suppressed LPP fEPSPs with an EC50 value of 3.1 μM. The L-AP4-induced reduction in LPP fEPSPs could be blocked by the group III antagonist, MSOP (100 μM) in wild-type slices and was eliminated in mGlu8 receptor-deficient slices. Additional experiments showed that MPP fEPSPs were suppressed by the group II agonist, LY379268 (0.01–3 μM) in control slices (EC50=153.1 nM); an effect that was not altered in mGlu8 receptor knockout slices (EC50=153.8 nM) . In addition, LY379268 had little effect on fEPSPs evoked by LPP stimulation in mGlu8 receptor-deficient slices. In conjunction with recent receptor localization studies, these results suggest that the mGlu8 receptors serve as autoreceptors on LPP afferents to the dentate gyrus. [Copyright &y& Elsevier]

Group II metabotropic glutamate (mGlu) receptors can act as presynaptic autoinhibitory receptors at perforant path inputs to the hippocampus under conditions of high frequency synaptic activation. We have used mGlu2 -/- mice to examine the relative roles of mGlu2 and mGlu3 in the regulation of perforant path synaptic transmission mediated by both the selective group II receptor agonist, DCG-IV, and by synaptically released glutamate. Field excitatory postsynaptic potentials evoked by stimulation of either the perforant path inputs to the dentate gyrus mid-moleculare or the CA1 stratum lacunosum moleculare were inhibited by DCG-IV with IC50 values and maximum percentage inhibition of: 169 nM (60%) and 41 nM (72%) in wild-type mice and 273 nM (19%) and 116 nM (49%) in mGlu2 -/- mice, respectively. Activation of presynaptic group II mGlu autoreceptors by synaptically released glutamate, as revealed by a LY341495-mediated increase in the relative amplitude of a test fEPSP evoked after a conditioning burst, was observed in both the dentate gyrus and the stratum lacunosum of wild-type, but not mGlu2 -/- mice. These observations demonstrate that activation of mGlu3 receptors can regulate synaptic transmission at perforant path synapses but suggest that mGlu2 is the major presynaptic group II autoreceptor activated by synaptically released glutamate. [Copyright &y& Elsevier]