Dopamine D2/3 Receptor Availabilities and Evoked Dopamine Release in Striatum Differentially Predict Impulsivity and Novelty Preference in Roman High- and Low-Avoidance Rats.

BACKGROUND: Impulsivity and novelty preference are both associated with an increased propensity to develop addiction-like behaviors, but their relationship and respective underlying dopamine (DA) underpinnings are not fully elucidated. METHODS: We evaluated a large cohort (n = 49) of Roman high- and low-avoidance rats using single photon emission computed tomography to concurrently measure in vivo striatal D2/3 receptor (D2/3R) availability and amphetamine (AMPH)-induced DA release in relation to impulsivity and novelty preference using a within-subject design. To further examine the DA-dependent processes related to these traits, midbrain D2/3-autoreceptor levels were measured using ex vivo autoradiography in the same animals. RESULTS: We replicated a robust inverse relationship between impulsivity, as measured with the 5-choice serial reaction time task, and D2/3R availability in ventral striatum and extended this relationship to D2/3R levels measured in dorsal striatum. Novelty preference was positively related to impulsivity and showed inverse associations with D2/3R availability in dorsal striatum and ventral striatum. A high magnitude of AMPH-induced DA release in striatum predicted both impulsivity and novelty preference, perhaps owing to the diminished midbrain D2/3-autoreceptor availability measured in high-impulsive/novelty-preferring Roman high-avoidance animals that may amplify AMPH effect on DA transmission. Mediation analyses revealed that while D2/3R availability and AMPH-induced DA release in striatum are both significant predictors of impulsivity, the effect of striatal D2/3R availability on novelty preference is fully mediated by evoked striatal DA release. CONCLUSIONS: Impulsivity and novelty preference are related but mediated by overlapping, yet dissociable, DA-dependent mechanisms in striatum that may interact to promote the emergence of an addiction-prone phenotype.

Loss of Adult 5-HT1A Autoreceptors Results in a Paradoxical Anxiogenic Response to Antidepressant Treatment.

Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are first-line antidepressants but require several weeks to elicit their actions. Chronic SSRI treatment induces desensitization of 5-HT1A autoreceptors to enhance 5-HT neurotransmission. Mice (both sexes) with gene deletion of 5-HT1A autoreceptors in adult 5-HT neurons (1AcKO) were tested for response to SSRIs. Tamoxifen-induced recombination in adult 1AcKO mice specifically reduced 5-HT1A autoreceptor levels. The 1AcKO mice showed a loss of 5-HT1A autoreceptor-mediated hypothermia and electrophysiological responses, but no changes in anxiety- or depression-like behavior. Subchronic fluoxetine (FLX) treatment induced an unexpected anxiogenic effect in 1AcKO mice in the novelty suppressed feeding and elevated plus maze tests, as did escitalopram in the novelty suppressed feeding test. No effect was seen in wild-type (WT) mice. Subchronic FLX increased 5-HT metabolism in prefrontal cortex, hippocampus, and raphe of 1AcKO but not WT mice, suggesting hyperactivation of 5-HT release. To detect chronic cellular activation, FosB+ cells were quantified. FosB+ cells were reduced in entorhinal cortex and hippocampus (CA2/3) and increased in dorsal raphe 5-HT cells of 1AcKO mice, suggesting increased raphe activation. In WT but not 1AcKO mice, FLX reduced FosB+ cells in the median raphe, hippocampus, entorhinal cortex, and median septum, which receive rich 5-HT projections. Thus, in the absence of 5-HT1A autoreceptors, SSRIs induce a paradoxical anxiogenic response. This may involve imbalance in activation of dorsal and median raphe to regulate septohippocampal or fimbria-fornix pathways. These results suggest that markedly reduced 5-HT1A autoreceptors may provide a marker for aberrant response to SSRI treatment.SIGNIFICANCE STATEMENT Serotonin-selective reuptake inhibitors (SSRIs) are effective in treating anxiety and depression in humans and mouse models. However, in some cases, SSRIs can increase anxiety, but the mechanisms involved are unclear. Here we show that, rather than enhancing SSRI benefits, adulthood knockout (KO) of the 5-HT1A autoreceptor, a critical negative regulator of 5-HT activity, results in an SSRI-induced anxiety effect that appears to involve a hyperactivation of the 5-HT system in certain brain areas. Thus, subjects with very low levels of 5-HT1A autoreceptors, such as during childhood or adolescence, may be at risk for an SSRI-induced anxiety response.

Correlation between ethanol behavioral sensitization and midbrain dopamine neuron reactivity to ethanol.

Repeated ethanol injections lead to a sensitization of its stimulant effects in mice. Some recent results argue against a role for ventral tegmental area (VTA) dopamine neurons in ethanol behavioral sensitization. The aim of the present study was to test whether in vivo ethanol locomotor sensitization correlates with changes in either basal- or ethanol-evoked firing rates of dopamine neurons in vitro. Female Swiss mice were daily injected with 2.5 g/kg ethanol (or saline in the control group) for 7 days and their locomotor activity was recorded. At the end of the sensitization procedure, extracellular recordings were made from dopaminergic neurons in midbrain slices from these mice. Significantly higher spontaneous basal firing rates of dopamine neurons were recorded in ethanol-sensitized mice relative to control mice, but without correlations with the behavioral effects. The superfusion of sulpiride, a dopamine D2 antagonist, induced a stronger increase of dopamine neuron firing rates in ethanol-sensitized mice. This shows that the D2 feedback in dopamine neurons is preserved after chronic ethanol administration and argues against a reduced D2 feedback as an explanation for the increased dopamine neuron basal firing rates in ethanol-sensitized mice. Finally, ethanol superfusion (10-100 mM) significantly increased the firing rates of dopamine neurons and this effect was of higher magnitude in ethanol-sensitized mice. Furthermore, there were significant correlations between such a sensitization of dopamine neuron activity and ethanol behavioral sensitization. These results support the hypothesis that changes in brain dopamine neuron activity contribute to the behavioral sensitization of the stimulant effects of ethanol.

Functional status of somatodendritic serotonin 1A autoreceptor after long-term treatment with fluoxetine in a mouse model of anxiety/depression based on repeated corticosterone administration.

Most preclinical studies investigating the effects and the mechanism of action of antidepressants have been performed in naive rodents. This is inappropriate because antidepressants act on specific symptoms of the pathological condition, such as distress and anxiety. We have developed a mouse model of anxiety/depression based on addition of corticosterone to drinking water. This model is highly reproducible and easy to set up compared with unpredictable chronic mild stress. The serotonin 1A (5-HT(1A)) autoreceptor is known to play a role in mood disorders and their treatments. An increase in somatodendritic 5-HT(1A) autoreceptor density in the dorsal raphe (DR) attenuates the therapeutic activity of selective serotonin-reuptake inhibitors (SSRIs), whereas their functional desensitization promotes activation of brain serotonergic transmission, thereby representing an adaptive change relevant to their therapeutic effect. Here we assessed the effects of sustained administration of the SSRI fluoxetine on 5-HT(1A) autoreceptor sensitivity in mice administered with corticosterone. Fluoxetine attenuated hypothermia induced by the 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin, decreased DR 5-HT neuronal activity, and decreased 5-HT release in both vehicle- and corticosterone-pretreated mice. However, such desensitization was more pronounced in corticosterone-pretreated mice. This change had an overall effect on serotonergic tone because we found a greater firing rate of 5-HT neurons associated with an enhancement of 5-HT outflow in the DR of corticosterone-pretreated mice in response to fluoxetine compared with the corresponding group of vehicle-pretreated mice. These results provide cellular explanations for the antidepressant effects produced by SSRIs in subjects with pathological conditions but not in naive animals or healthy volunteers.

Methamphetamine produces bidirectional, concentration-dependent effects on dopamine neuron excitability and dopamine-mediated synaptic currents.

Amphetamine-like compounds are commonly used to enhance cognition and to treat attention deficit/hyperactivity disorder, but they also function as positive reinforcers and are self-administered at doses far exceeding clinical relevance. Many of these compounds (including methamphetamine) are substrates for dopamine reuptake transporters, elevating extracellular dopamine by inhibiting uptake and promoting reverse transport. This produces an increase in extracellular dopamine that inhibits dopamine neuron firing through autoreceptor activation and consequently blunts phasic dopamine neurotransmission, an important learning signal. However, these mechanisms do not explain the beneficial behavioral effects observed at clinically useful concentrations. In the present study, we have used patch-clamp electrophysiology in slices of mouse midbrain to show that, surprisingly, low concentrations of methamphetamine actually enhance dopamine neurotransmission and increase dopamine neuron firing through a dopamine transporter-mediated excitatory conductance. Both of these effects are reversed by higher concentrations of methamphetamine, which inhibit firing through dopamine D2 autoreceptor activation and decrease the peak amplitude of dopamine-mediated synaptic currents. These competing, concentration-dependent effects of methamphetamine suggest a mechanistic interplay by which lower concentrations of methamphetamine can overcome autoreceptor-mediated inhibition at the soma to increase phasic dopamine transmission.

Escitalopram enhances the association of serotonin-1A autoreceptors to heteroreceptors in anxiety disorders.

Selective serotonin reuptake inhibitors (SSRIs) represent one of the most common treatment options in major depression and anxiety disorders. By blocking the serotonin transporter, SSRIs modulate serotonergic neurotransmission as well as the function of autoreceptors and heteroreceptors. However, treatment-induced changes on a network level primarily remain unknown. Thus, we evaluated the association between serotonin-1A (5-HT1A) autoreceptors and heteroreceptors before and after SSRIs. Twenty-one patients with anxiety disorders underwent positron emission tomography using [carbonyl-11C]WAY-100635 before and after 12 weeks of escitalopram treatment; 15 of them completed the study protocol. Additionally, 36 drug-naive healthy controls were measured once. The 5-HT1A receptor binding potential (BPND) was quantified for the dorsal raphe nucleus (DRN) using a region-of-interest approach and for the entire brain by calculating parametric maps. Voxel-wise linear regression was applied between DRN autoreceptor and whole-brain heteroreceptor 5-HT1A BPND. Consistent with previous observations, healthy subjects showed widespread positive correlations of 5-HT1A BPND between autoreceptors and heteroreceptors. Comparing patients before versus after escitalopram treatment revealed enhanced associations of autoreceptor-to-heteroreceptor 5-HT1A BPND within the amygdala and hippocampus (R2=0.21-0.28 vs 0.49-0.81; p<0.05-0.001). In contrast, no significant SSRI-induced changes were found for correlations of heteroreceptor-to-heteroreceptor 5-HT1A BPND between several limbic regions. This interregional approach suggests a treatment-induced reinforcement of the association of 5-HT1A binding between autoreceptors and heteroreceptors specifically in areas involved in anxiety disorders. These findings provide complementary information about treatment effects on a network level and confirm the central role of the DRN as a prime regulatory area.

Effects of repeated and acute aripiprazole or haloperidol treatment on dopamine synthesis in the dorsal striatum of young rats: comparison to adult rats.

The purpose of the present study was to determine whether repeated treatment with the D2 partial agonist aripiprazole or the D2 antagonist haloperidol alters dopamine (DA) synthesis characteristics in the dorsal striatum of young rats. To this end, rats received a daily pretreatment regimen of aripiprazole or haloperidol on postnatal days (PD) 10-20 and were tested 24 or 72 h later after an acute injection of vehicle, aripiprazole, haloperidol, or quinpirole (a D2 agonist). For comparison purposes, adult rats were pretreated with an 11-day regimen of saline or haloperidol on PD 70-80 and DA synthesis was measured after acute drug treatment on PD 83. Dorsal striatal DA synthesis was determined by measuring L-dihydroxyphenylalanine accumulation after NSD-1015 treatment. In a separate experiment, the ability of repeated drug treatment to up-regulate dorsal striatal D2 receptors was assessed in young and adult rats 72 h after drug discontinuation. The major findings of this study were that: (a) acute treatment with haloperidol and aripiprazole increased DA synthesis while quinpirole reduced it; (b) pretreatment with haloperidol and aripiprazole blunted the synthesis-modulating effects of acutely administered dopaminergic drugs; and (c) DA synthesis of young and adult rats was affected in a qualitatively similar manner by DA agonist, antagonist, and partial agonist drugs. In conclusion, results from the present study suggest that synthesis-modulating autoreceptors in the dorsal striatum are functionally mature by the end of the preweanling period and DA synthesis declines to near basal levels during the course of repeated aripiprazole treatment.

Nanomolar concentrations of cocaine enhance D2-like agonist-induced inhibition of the K+-evoked [3H]-dopamine efflux from rat striatal synaptosomes: a novel action of cocaine.

Previous studies have indicated that cocaine binding sites contain both high- and low-affinity binding components and have actions not related to dopamine uptake inhibition. Therefore, it has been studied if concentrations of cocaine in the range of 0.1-100 nM can affect not only dopamine uptake but also the quinpirole-induced inhibition of the K(+)-evoked [(3)H]-dopamine efflux from rat striatal synaptosomes. It was found that quinpirole-induced inhibition of K(+)-evoked [(3)H]-dopamine efflux was significantly enhanced by cocaine at 1 and 10 nM but not at 0.1 nM with cocaine alone being inactive and 1 nM cocaine lacking effects on [(3)H]-dopamine uptake in rat striatal synaptosomes. The results indicate the existence of a novel allosteric agonist action of cocaine in low concentrations, not affecting dopamine uptake, at striatal D(2) autoreceptors modulating striatal dopamine transmission.

5-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-2(1H)-quinolinones and 3,4-dihydro-2(1H)-quinolinones: dual-acting 5-HT1 receptor antagonists and serotonin reuptake inhibitors. Part 3.

5-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}-2(1H)-quinolinones and 3,4-dihydro-2(1H)-quinolinones have been identified with different combinations of 5-HT(1) autoreceptor antagonist and hSerT potencies and excellent rat PK profiles. The availability of tool compounds with a range of profiles at targets known to play a key role in the control of synaptic 5-HT levels will allow exploration of different pharmacological profiles in a range of animal behavioral and disease models.

RGS4-dependent attenuation of M4 autoreceptor function in striatal cholinergic interneurons following dopamine depletion.

Parkinson disease is a neurodegenerative disorder whose symptoms are caused by the loss of dopaminergic neurons innervating the striatum. As striatal dopamine levels fall, striatal acetylcholine release rises, exacerbating motor symptoms. This adaptation is commonly attributed to the loss of interneuronal regulation by inhibitory D(2) dopamine receptors. Our results point to a completely different, new mechanism. After striatal dopamine depletion, D(2) dopamine receptor modulation of calcium (Ca(2+)) channels controlling vesicular acetylcholine release in interneurons was unchanged, but M(4) muscarinic autoreceptor coupling to these same channels was markedly attenuated. This adaptation was attributable to the upregulation of RGS4-an autoreceptor-associated, GTPase-accelerating protein. This specific signaling adaptation extended to a broader loss of autoreceptor control of interneuron spiking. These observations suggest that RGS4-dependent attenuation of interneuronal autoreceptor signaling is a major factor in the elevation of striatal acetylcholine release in Parkinson disease.

The D(3) dopamine receptor inhibits dopamine release in PC-12/hD3 cells by autoreceptor signaling via PP-2B, CK1, and Cdk-5.

The function of the D(3) dopamine (DA) receptor remains ambiguous largely because of the lack of selective D(3) receptor ligands. To investigate the function and intracellular signaling of D(3) receptors, we established a PC-12/hD3 clone, which expresses the human D(3) DA receptor in a DA producing cell line. In this model, we find that the D(3) receptor functions as an autoreceptor controlling neurotransmitter secretion. Pre-treatment with 3,6a,11, 14-tetrahydro-9-methoxy-2 methyl-(12H)-isoquino[1,2-b] pyrrolo[3,2-f][1,3] benzoxanzine-1-carboxylic acid, a D(3) receptor preferring agonist, dose-dependently suppressed K+-evoked [3H]DA release in PC-12/hD3 cells but not in the control cell line. This effect was prevented by D(3) receptor preferring antagonists GR103691 and SB277011-A. Furthermore, activation of D(3) receptors significantly inhibits forskolin-induced cAMP accumulation and leads to transient increases in phosphorylation of cyclin-dependent kinase 5 (Cdk5), dopamine and cAMP-regulated phosphoprotein of M(r) 32 000 and Akt. Because we observed differences in Cdk5 phosphorylation as well as Akt phosphorylation after DA stimulation, we probed the ability of Cdk5 and phosphatidylinositol-3 kinase (PI3K) to influence DA release. Cdk5 inhibitors, roscovitine, or olomoucine, but not the PI3K inhibitor wortmannin, blocked the D(3) receptor inhibition of DA release. In a complimentary experiment, over-expression of Cdk5 potentiated D(3) receptor suppression of DA release. Pertussis toxin, 3-[(2,4,6-trimethoxyphenyl)methylidenyl]-indolin-2-one and cyclosporine A also attenuated D(3) receptor-mediated inhibition of DA release indicating that this phenomenon acts through Gi/oalpha and casein kinase 1, and phosphatase protein phosphatase 2B (calcineurin), respectively. In support of previous data that D(3) DA receptors reduce transmitter release from nerve terminals, the current results demonstrate that D(3) DA receptors function as autoreceptors to inhibit DA release and that a signaling pathway involving Cdk5 is essential to this regulation.

Cocaine conditioning: reversal by autoreceptor dose levels of 8-OHDPAT.

In order to investigate the contribution of serotonergic effects of cocaine to Pavlovian conditioning of cocaine locomotor stimulant effects, two experiments were conducted in which groups of rats (N=10) received cocaine treatments (10 mg/kg) paired or unpaired to placement in an open-field environment. Initially, a cocaine conditioned locomotion stimulant effect was established. Next, additional Coc-P and Coc-UP pairings were carried out in conjunction with pretreatment injections of the 5-HT1A agonist, 8-OHDPAT (0.01, 0.025 and 0.05 mg/kg) or saline. In experiment 1, the Coc-P group which received the saline pretreatment again exhibited conditioning but in the 8-OHDPAT pretreatment Coc-P group conditioning was eliminated. In the second experiment, the protocol of the first experiment was repeated but expanded in the post-conditioning phase to include an 8-OHDPAT plus the 5-HT1A antagonist pretreatment Coc-P group. As in the first experiment, the 8-OHDPAT pretreatment Coc-P group did not exhibit a cocaine conditioned locomotion stimulant effect; whereas, the saline pretreatment Coc-P and the 8-OHDPAT plus WAY-100635 pretreatment Coc-P groups did exhibit the cocaine conditioned locomotion stimulant effect. These findings are consistent with an important role for serotonin in the maintenance of cocaine Pavlovian conditioned effects.

Serotonin and psychostimulant addiction: focus on 5-HT1A-receptors.

Serotonin(1A)-receptors (5-HT(1A)-Rs) are important components of the 5-HT system in the brain. As somatodendritic autoreceptors they control the activity of 5-HT neurons, and, as postsynaptic receptors, the activity in terminal areas. Cocaine (COC), amphetamine (AMPH), methamphetamine (METH) and 3,4-methylenedioxymethamphetamine ("Ecstasy", MDMA) are psychostimulant drugs that can lead to addiction-related behavior in humans and in animals. At the neurochemical level, these psychostimulant drugs interact with monoamine transporters and increase extracellular 5-HT, dopamine and noradrenalin activity in the brain. The increase in 5-HT, which, in addition to dopamine, is a core mechanism of action for drug addiction, hyperactivates 5-HT(1A)-Rs. Here, we first review the role of the various 5-HT(1A)-R populations in spontaneous behavior to provide a background to elucidate the contribution of the 5-HT(1A)-Rs to the organization of psychostimulant-induced addiction behavior. The progress achieved in this field shows the fundamental contribution of brain 5-HT(1A)-Rs to virtually all behaviors associated with psychostimulant addiction. Importantly, the contribution of pre- and postsynaptic 5-HT(1A)-Rs can be dissociated and frequently act in opposite directions. We conclude that 5-HT(1A)-autoreceptors mainly facilitate psychostimulant addiction-related behaviors by a limitation of the 5-HT response in terminal areas. Postsynaptic 5-HT(1A)-Rs, in contrast, predominantly inhibit the expression of various addiction-related behaviors directly. In addition, they may also influence the local 5-HT response by feedback mechanisms. The reviewed findings do not only show a crucial role of 5-HT(1A)-Rs in the control of brain 5-HT activity and spontaneous behavior, but also their complex role in the regulation of the psychostimulant-induced 5-HT response and subsequent addiction-related behaviors.

Biphasic effects of 5-HT1A agonism on impulsive responding are dissociable from effects on anxiety in the variable consecutive number task.

The serotonergic 5-HT1A receptor is known to be involved in both impulsivity and anxiety-related behavior. Although anxiety and impulsivity are different constructs, it has been shown that anxiogenesis can result in impulsiveness. It is therefore important to determine if the 5-HT1A receptor is involved in the commission of impulsive actions independent of its effects on anxiety. The 5-HT1A agonist 8-OH-DPAT (0.0125-0.1 mg/kg subcutaneous) increased impulsive action at low doses, but decreased it at higher doses, on the novel paced variable consecutive number with discriminative stimulus task (VCN). Neither the 5-HT1A antagonist WAY 100,635 (0.2-1.2 mg/kg subcutaneous), nor the noradrenergic antagonist and pharmacological stressor yohimbine (1-2 mg/kg intraperitoneal) altered measures of impulsivity. Stress induced by yohimbine was sufficient to produce anxiety-like behavior in the elevated zero maze, confirming that the VCN task is a selective assay of impulsive action that is not affected by anxiety. We hypothesize that the biphasic effect of 8-OH-DPAT is due to actions on presynaptic raphe 5-HT1A autoreceptors, and also postsynaptic 5-HT1A receptors. These results suggest that this receptor mediates impulsive action and that this is not secondary to its role in anxiety.

AMP-activated protein kinase slows D2 dopamine autoreceptor desensitization in substantia nigra neurons.

Dopamine neurons in the substantia nigra zona compacta (SNC) are well known to express D2 receptors. When dopamine is released from somatodendritic sites, activation of D2 autoreceptors suppresses dopamine neuronal activity through activation of G protein-coupled K+ channels. AMP-activated protein kinase (AMPK) is a master enzyme that acts in somatic tissues to suppress energy expenditure and encourage energy production. We hypothesize that AMPK may also conserve energy in central neurons by reducing desensitization of D2 autoreceptors. We used whole-cell patch-clamp recordings to study the effects of AMPK activators and inhibitors on D2 autoreceptor-mediated current in SNC neurons in midbrain slices from rat pups (11-23 days post-natal). Slices were superfused with 100 µM dopamine or 30 µM quinpirole for 25 min, which evoked outward currents that decayed slowly over time. Although the AMPK activators A769662 and ZLN024 significantly slowed rundown of dopamine-evoked current, slowing of quinpirole-evoked current required the presence of a D1-like agonist (SKF38393). Moreover, the D1-like agonist also slowed the rundown of quinpirole-induced current even in the absence of an AMPK activator. Pharmacological antagonist experiments showed that the D1-like agonist effect required activation of either protein kinase A (PKA) or exchange protein directly activated by cAMP 2 (Epac2) pathways. In contrast, the effect of AMPK on rundown of current evoked by quinpirole plus SKF38393 required PKA but not Epac2. We conclude that AMPK slows D2 autoreceptor desensitization by augmenting the effect of D1-like receptors.

A presynaptic kainate receptor is involved in regulating the dynamic properties of thalamocortical synapses during development.

Previous studies have shown that pharmacological activation of presynaptic kainate receptors at glutamatergic synapses facilitates or depresses transmission in a dose-dependent manner. However, the only synaptically activated kainate autoreceptor described to date is facilitatory. Here, we describe a kainate autoreceptor that depresses synaptic transmission. This autoreceptor is present at developing thalamocortical synapses in the barrel cortex, specifically regulates transmission at frequencies corresponding to those observed in vivo during whisker activation, and is developmentally down regulated during the first postnatal week. This receptor may, therefore, limit the transfer of high-frequency activity to the developing cortex, the loss of which mechanism may be important for the maturation of sensory processing.

Chronic activation of the D2 dopamine autoreceptor inhibits synaptogenesis in mesencephalic dopaminergic neurons in vitro.

Chronic blockade or activation of dopamine receptors is critical for the pharmacological treatment of diseases like schizophrenia, Parkinson's or attention deficit and hyperactivity disorder. However, the long-term impact of such treatments on dopamine neurons is unclear. Chronic blockade of the dopamine D2 receptor in vivo triggers an increase in the axonal arborization of dopamine neurons [European Journal of Neuroscience, 2002, 16, 787-794]. However, the specific involvement of presynaptic (autoreceptors) vs. postsynaptic D2 receptors as well as the molecular mechanisms involved have not been determined. Here, we examined the role of D2 autoreceptors in regulating the ability of mouse dopamine neurons to establish axon terminals. Chronic activation of this receptor with quinpirole, a specific agonist, decreased the number of axon terminals established by isolated dopamine neurons. This effect was accompanied by a decrease in dopamine release and was mediated through inhibition of protein kinase A. The decrease in axon terminal number induced by D2 receptor activation was also occluded when the mammalian Target of Rapamycin pathway of mRNA translation was blocked. Our results suggest that chronic activation of the D2 autoreceptor inhibits synaptogenesis by mesencephalic dopamine neurons through translational regulation of the synthesis of proteins required for synapse formation. This study provides a better understanding of the impact of long-term pharmacological interventions acting through the D2 receptor.

Effect of chronic lithium treatment on D2/3 autoreceptor regulation of dopaminergic function in the rat.

Dysregulation of mesolimbic dopamine (DA) neurotransmission has been implicated in bipolar disorder. DA release in the nucleus accumbens is reduced in rats treated chronically with the mood stabiliser lithium, and this effect is maintained for 3 days after withdrawal from the lithium treatment. We tested whether this decrease in DA release is due to an increase in D(2/3) autoreceptor sensitivity. In vivo microdialysis studies showed that in the shell of the nucleus accumbens, dialysate DA was decreased following chronic lithium treatment and 3 days after withdrawal from lithium treatment. The elevation of dialysate DA induced by local blockade of the terminal D(2/3) receptor was reduced in both lithium treated and lithium withdrawn groups. In vitro electrophysiology studies showed that chronic lithium treatment (and lithium withdrawal) did not alter either basal firing rate of DA neurones in the ventral tegmental area, or somatodendritic D(2/3) autoreceptor-mediated inhibition of firing. D(2) mRNA expression in the ventral tegmental area was unchanged by lithium treatment and lithium withdrawal. Our data suggest that the decrease in dopamine release in the nucleus accumbens induced by chronic lithium treatment is not the result of increased terminal or somatodendritic autoreceptor sensitivity or decreased firing rate of DA neurones.

Presynaptic metabotropic glutamate and GABAB receptors.

Glutamate and GABA, the two most abundant neurotransmitters in the mammalian central nervous system, can act on metabotropic receptors that are structurally quite dissimilar from those targeted by most other neurotransmitters/modulators. Accordingly, metabotropic glutamate receptors (mGluRs) and GABA(B) receptors (GABA(B)Rs) are classified as members of family 3 (or family C) of G protein-coupled receptors. On the other hand, mGluRs and GABA(B)Rs exhibit pronounced and partly unresolved differences between each other. The most intriguing difference is that mGluRs exist as multiple pharmacologically as well as structurally distinct subtypes, whereas, in the case of GABA(B)Rs, molecular biologists have so far identified only one structurally distinct heterodimeric complex whose few variants seem unable to explain the pharmacological heterogeneity of GABA(B)Rs observed in many functional studies. Both mGluRs and GABA(B)Rs can be localized on axon terminals of different neuronal systems as presynaptic autoreceptors and heteroreceptors modulating the exocytosis of various transmitters.

Therapeutic use of release-modifying drugs.

Presynaptic inhibitory or facilitatory autoreceptors are targets for the endogenous neurotransmitter of the respective neuron, and also for exogenous agonists, partial agonists and antagonists which can produce pharmacological actions through changes in transmitter release. In addition, presynaptic inhibitory or facilitatory heteroreceptors can also be acted upon by exogenous agonists, partial agonists or antagonists to induce changes in transmitter release with useful therapeutic effects. This article summarizes drugs that are known or likely to produce their therapeutic effects through presynaptic modulation of neurotransmitter release. Included are drugs acting on alpha and beta adrenoceptors, dopamine receptors, angiotensin, opioid, cannabinoid, and nicotinic acetylcholine receptors. Also discussed are changes in presynaptic receptor mechanisms produced by drugs that inhibit transmitter re-uptake.