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Cognitive impairment in schizophrenia remains a clinically and pharmacologically unsolved challenge. Clinical and preclinical studies have revealed that the concomitant reduction in dysbindin (DYS) and dopamine receptor D3 functionality improves cognitive functions. However, the molecular machinery underlying this epistatic interaction has not yet been fully elucidated. The glutamate NMDA receptors and the neurotrophin BDNF, with their established role in promoting neuroplasticity, may be involved in the complex network regulated by the D3/DYS interaction. Furthermore, as inflammation is involved in the etiopathogenesis of several psychiatric diseases, including schizophrenia, the D3/DYS interaction may affect the expression levels of pro-inflammatory cytokines. Thus, by employing mutant mice bearing selective heterozygosis for D3 and/or DYS, we provide new insights into the functional interactions (single and synergic) between these schizophrenia susceptibility genes and the expression levels of key genes for neuroplasticity and neuroinflammation in three key brain areas for schizophrenia: the prefrontal cortex, striatum, and hippocampus. In the hippocampus, the epistatic interaction between D3 and DYS reversed to the wild-type level the downregulated mRNA levels of GRIN1 and GRIN2A were observed in DYS +/- and D3 +/- mice. In all the areas investigated, double mutant mice had higher BDNF levels compared to their single heterozygote counterparts, whereas D3 hypofunction resulted in higher pro-inflammatory cytokines. These results may help to clarify the genetic mechanisms and functional interactions involved in the etiology and development of schizophrenia.

The dopamine D3 receptor (D3R) plays a prominent role in the modulation of cognition in healthy individuals, as well as in the pathophysiological mechanism underlying the cognitive deficits affecting patients suffering from neuropsychiatric disorders. At a therapeutic level, a growing body of evidence suggests that the D3R blockade enhances cognitive and thus it may be an optimal therapeutic strategy against cognitive dysfunctions. However, this is not always the case because other ligands targeting the D3R, and behaving as partial agonists or biased agonists, may exert their pro-cognitive effect by maintaining adequate level of dopamine in key brain areas tuning cognitive performances. In this chapter, we review and discuss preclinical and clinical findings with the aim to remark the crucial role of the D3R in cognition and to strengthen the message that drugs targeting D3R may be excellent cognitive enhancers for the treatment of several neuropsychiatric and neurological disorders., (© 2022. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Dopamine receptors (DRs) are generally considered as mediators of vasomotor functions. However, when used in pharmacological studies, dopamine and/or DR agonists may not discriminate among different DR subtypes and may even stimulate alpha1 and beta-adrenoceptors. Here, we tested the hypothesis that D2R and/or D3R may specifically induce vasoconstriction in isolated mouse aorta. Aorta, isolated from wild-type (WT) and D3R - / - mice, was mounted in a wire myograph and challenged with cumulative concentrations of phenylephrine (PE), acetylcholine (ACh), and the D3R agonist 7-hydrxy-N,N-dipropyl-2-aminotetralin (7-OH-DPAT), with or without the D2R antagonist L741,626 and the D3R antagonist SB-277011-A. The vasoconstriction to PE and the vasodilatation to ACh were not different in WT and D3R - / - ; in contrast, the contractile responses to 7-OH-DPAT were significantly weaker in D3R - / - , though not abolished. L741,626 did not change the contractile response induced by 7-OH-DPAT in WT or in D3R - / - , whereas SB-277011-A significantly reduced it in WT but did not in D3R - / - . D3R mRNA (assessed by qPCR) was about 5-fold more abundant than D2R mRNA in aorta from WT and undetectable in aorta from D3R - / - . Following transduction with lentivirus (72-h incubation) delivering synthetic microRNAs to specifically inactivate D2R (LV-miR-D2) or D3R (LV-miR-D3), the contractile response to 7-OH-DPAT was unaffected by LV-miR-D2, while it was significantly reduced by LV-miR-D3. These data indicate that, at least in mouse aorta, D3R stimulation induces vasoconstriction, while D2R stimulation does not. This is consistent with the higher expression level of D3R. The residual vasoconstriction elicited by high concentration D3R agonist in D3R - / - and/or in the presence of D3R antagonist is likely to be unrelated to DRs.

The dopamine D 3 receptor (D 3 R), in the nucleus accumbens (NAc), plays an important role in alcohol reward mechanisms. The major neuronal type within the NAc is the GABAergic medium spiny neuron (MSN), whose activity is regulated by dopaminergic inputs. We previously reported that genetic deletion or pharmacological blockade of D 3 R increases GABA A α6 subunit in the ventral striatum. Here we tested the hypothesis that D 3 R-dependent changes in GABA A α6 subunit in the NAc affect voluntary alcohol intake, by influencing the inhibitory transmission of MSNs. We performed in vivo and ex vivo experiments in D 3 R knockout (D 3 R -/- ) mice and wild type littermates (D 3 R +/+ ). Ro 15-4513, a high affinity α6-GABA A ligand was used to study α6 activity. At baseline, NAc α6 expression was negligible in D 3 R +/+ , whereas it was robust in D 3 R -/- ; other relevant GABA A subunits were not changed. In situ hybridization and qPCR confirmed α6 subunit mRNA expression especially in the NAc. In the drinking-in-the-dark paradigm, systemic administration of Ro 15-4513 inhibited alcohol intake in D 3 R +/+ , but increased it in D 3 R -/- ; this was confirmed by intra-NAc administration of Ro 15-4513 and furosemide, a selective α6-GABA A antagonist. Whole-cell patch-clamp showed peak amplitudes of miniature inhibitory postsynaptic currents in NAc medium spiny neurons higher in D 3 R -/- compared to D 3 R +/+ ; Ro 15-4513 reduced the peak amplitude in the NAc of D 3 R -/- , but not in D 3 R +/+ . We conclude that D 3 R-dependent enhanced expression of α6 GABA A subunit inhibits voluntary alcohol intake by increasing GABA inhibition in the NAc., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Dopamine receptors (DR) have been extensively studied, but only in recent years they became object of investigation to elucidate the specific role of different subtypes (D1R, D2R, D3R, D4R, D5R) in neural transmission and circuitry. D1-like receptors (D1R and D5R) and D2-like receptors (D2R, D2R and D4R) differ in signal transduction, binding profile, localization in the central nervous system and physiological effects. D3R is involved in a number of pathological conditions, including schizophrenia, Parkinson's disease, addiction, anxiety, depression and glaucoma. Development of selective D3R ligands has been so far challenging, due to the high sequence identity and homology shared by D2R and D3R. As a consequence, despite a rational design of selective DR ligands has been carried out, none of currently available medicines selectively target a given D2-like receptor subtype. The availability of the D3R ligand [(11)C]-(+)-PHNO for positron emission tomography studies in animal models as well as in humans, allows researchers to estimate the expression of D3R in vivo; displacement of [(11)C]-(+)-PHNO binding by concurrent drug treatments is used to estimate the in vivo occupancy of D3R. Here we provide an overview of studies indicating D3R as a target for pharmacological therapy, and a review of market approved drugs endowed with significant affinity at D3R that are used to treat disorders where D3R plays a relevant role., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Increasing evidence indicates that central dopamine (DA) neurotransmission is involved in pathophysiology of anxiety, in particular the DA receptor subtype 3 (D3R). We previously reported that D3R null mice (D3R(-/-)) exhibit low baseline anxiety levels and that acutely administrated diazepam is more effective in D3R(-/-) than in wild type (WT) when tested in the elevated plus maze test (EPM). Here we tested the hypothesis that genetic deletion or pharmacological blockade of D3R affect GABAA subunit expression, which in turn modulates anxiety-like behaviour as well as responsiveness and tolerance to diazepam. D3R(-/-) mice exhibited tolerance to diazepam (0.5mg/kg, i.p.), assessed by EPM, as fast as after 3 day-treatment, performing similarly to untreated D3R(-/-) mice; conversely, WT exhibited tolerance to diazepam after a 14-21 day-treatment. Analysis of GABAA α6 subunit mRNA expression by qPCR in striatum showed that it was about 15-fold higher in D3R(-/-) than in WT. Diazepam treatment did not modify α6 expression in D3R(-/-), but progressively increased α6 expression in WT, to the level of untreated D3R(-/-) after 14-21 day-treatment. BDNF mRNA expression in striatum was remarkably (>10-fold) increased after 3 days of diazepam-treatment in both WT and D3R(-/-); such expression level, however, slowly declined below control levels, by 14-21 days. Following a 7 day-treatment with the selective D3R antagonist SB277011A, WT exhibited a fast tolerance to diazepam accompanied by a robust increase in α6 subunit expression. In conclusion, genetic deletion or pharmacological blockade of D3R accelerate the development of tolerance to repeated administrations of diazepam and increase α6 subunit expression, a GABAA subunit that has been linked to diazepam insensitivity. Modulation of GABAA receptor by DA transmission may be involved in the mechanisms of anxiety and, if occurring in humans, may have therapeutic relevance following repeated use of drugs targeting D3R., (Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.)

Mesolimbic dopamine (DA) controls drug- and alcohol-seeking behavior, but the role of specific DA receptor subtypes is unclear. We tested the hypothesis that D3R gene deletion or the D3R pharmacological blockade inhibits ethanol preference in mice. D3R-deficient mice (D3R(-/-)) and their wild-type (WT) littermates, treated or not with the D3R antagonists SB277011A and U99194A, were tested in a long-term free choice ethanol-drinking (two-bottle choice) and in a binge-like ethanol-drinking paradigm (drinking in the dark, DID). The selectivity of the D3R antagonists was further assessed by molecular modeling. Ethanol intake was negligible in D3R(-/-) and robust in WT both in the two-bottle choice and DID paradigms. Treatment with D3R antagonists inhibited ethanol intake in WT but was ineffective in D3R(-/-) mice. Ethanol intake increased the expression of RACK1 and brain-derived neurotrophic factor (BDNF) in both WT and D3R(-/-); in WT there was also a robust overexpression of D3R. Thus, increased expression of D3R associated with activation of RACK1/BDNF seems to operate as a reinforcing mechanism in voluntary ethanol intake. Indeed, blockade of the BDNF pathway by the TrkB selective antagonist ANA-12 reversed chronic stable ethanol intake and strongly decreased the striatal expression of D3R. Finally, we evaluated buspirone, an approved drug for anxiety disorders endowed with D3R antagonist activity (confirmed by molecular modeling analysis), that resulted effective in inhibiting ethanol intake. Thus, DA signaling via D3R is essential for ethanol-related reward and consumption and may represent a novel therapeutic target for weaning.

Dopamine D3 receptors (D3Rs) are implicated in synaptic plasticity and memory processes. Previously we have shown that D3Rs mediate inhibitory effects on learning, since D3R knockout (D 3 (-/-) ) mice display enhanced performance in the passive avoidance task (PA). Formation of new memories is known to require de novo synthesis of proteins related to synaptic function through the activation of signaling pathways including the mitogen-activated protein kinases (MAPKs) and activation of the nuclear transcription factor cAMP response element binding protein (CREB). However, there are no clear indications regarding the specific involvement of D3Rs in the activation of these signaling cascades after acquisition of PA. Therefore, in this study we assessed whether phosphorylation levels of several MAPKs, Akt and CREB were differentially affected by PA in both wild-type (WT) and D 3 (-/-) mice hippocampi. Animals were divided in Naïve, unconditioned stimulus trained, conditioned stimulus trained and conditioned animals. Phosphorylation of extracellular signal-regulated kinase 1/2 (ERK 1/2), c-Jun-N-terminal kinase (JNK) and p38, as well as of Akt and CREB were determined. Acquisition of PA significantly increased pCREB levels both in WT and D 3 (-/-) mice. The extent of PA-driven increase in pCREB levels was significantly higher in mice lacking D3Rs. Similarly, pERK 1/2 was further augmented in trained D 3 (-/-) mice as compared to trained WTs, whereas JNK and p38 phosphorylation was not affected neither by PA nor by genetic background. Finally, Akt activation was observed in D 3 (-/-) mice, but not in response to PA. In conclusion, these data supports the notion that D3Rs might modulate CREB phosphorylation after acquisition of PA, probably via activation of ERK signaling.

A substantial proportion of depressed patients do not respond to current antidepressant drug therapies. So far, antidepressant drugs have been developed based on the "monoaminergic hypothesis" of depression, which considers a synaptic deficiency in 5-hydroxytryptamine (5-HT; serotonin) or noradrenaline as main cause. More recently, the dopaminergic system has been implicated in the efficacy of some antidepressants, such as desipramine, amineptine, nomifensine. Dysfunction of dopaminergic neurotransmission within the mesolimbic system may contribute to anhedonia, loss of motivation and psychomotor retardation in severe depressive disorders. Dopamine D3 receptor subtype is located both pre- and postsynaptically in brain areas regulating motivation and reward-related behavior and has been implicated in depression-like behaviors. Activity of mesolimbic dopamine neurons in the reward circuit is a key determinant of behavioral susceptibility/resilience to chronic stress, which plays a central role in the pathogenesis of depression. Dopamine D3 receptor expression and function are both down-regulated in stress and depression, and these changes are reversed by antidepressant treatments, suggesting that enhanced dopaminergic neurotransmission mediated by dopamine D3 receptor participates in adaptive changes related to antidepressant activity. Of note, brain derived neurotrophic factor (BDNF) controls the expression of the dopamine D3 receptor in some brain areas and BDNF induction by antidepressant treatments is related to their behavioral activity. A number of experimental drugs in pre-clinical or clinical development, including aripiprazole and cariprazine, may act as antidepressants because of their partial agonist activity at dopamine D3 receptors. These preclinical and clinical data are discussed in the present review., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Passive avoidance (PA) conditioning is a fear motivated task able to initiate a cascade of altered gene expression within the hippocampus, a structure critical to learning and memory. We have previously shown that neurofibromin (NF1) and amyloid precursor protein (APP), two genes implicated in cognitive function, are differentially expressed in brain of dopamine D3 receptor knock-out mice (D(3)R(-/-)), suggesting that the receptor might have a role in their trascriptional regulation. Here in this study, we hypothesized that during acquisition of PA conditioning the expression of NF1 and APP genes could be influenced by D(3)Rs. To address this issue, we analyzed the expression of NF1 and APP in the hippocampus of both wild-type (WT) and D(3)R(-/-) mice subjected to the single trial step-through PA paradigm. Our finding demonstrated that (1) D(3)R(-/-) mice exhibit increased cognitive performance as compared to WT mice in the step-through PA trial; (2) acquisition of PA increased D(3)R and NF1, but not APP expression in WT mice hippocampus; (3) PA-driven NF1 induction in WT was abrogated in D(3)R(-/-) mice and finally that (4) the heightened basal APP expression observed in naive D(3)R(-/-) mice was totally reversed by acquisition of PA. In conclusion, the present finding show for the first time that both D(3)R and NF1 genes are upregulated following PA conditioning and suggest that hippocampal D(3)Rs might be relevant to NF1 transcriptional regulation in the hippocampus.

The aim of the present study was to investigate the role of D₃ receptor on intraocular pressure regulation using WT and KO D₃R⁻/⁻ mice. Both mice were used with normal eye pressure or steroid-induced ocular hypertension. As measured by tonometry, the topical application of 7-OH-DPAT, a dopamine D₃-preferring receptor agonist, significantly decreased, in a dose-dependent manner, the intraocular pressure in WT mice both in an ocular normotensive group and an ocular hypertensive group. Pretreatment with U-99194A, a D₃ receptor antagonist, reverted 7-OH-DPAT induced ocular hypotension in WT mice. No change of intraocular pressure was observed after topical application of 7-OH-DPAT in KO D₃R⁻/⁻ mice. PCR analysis demonstrated the presence of all dopamine receptor genes in eye tissues obtained from WT mice, and the lack of D₃R mRNAs in KO mice. The present study identified the D₃R subtype as the most important receptor of the dopaminergic system to modulate intraocular pressure with relevant implications for glaucoma that represents one of the most crippling optic neuropathies., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Dopamine (DA) receptors, a class of G-protein coupled receptors (GPCRs), have been targeted for drug development for the treatment of neurological, psychiatric and ocular disorders. The lack of structural information about GPCRs and their ligand complexes has prompted the development of homology models of these proteins aimed at structure-based drug design. Crystal structure of human dopamine D(3) (hD(3)) receptor has been recently solved. Based on the hD(3) receptor crystal structure we generated dopamine D(2) and D(3) receptor models and refined them with molecular dynamics (MD) protocol. Refined structures, obtained from the MD simulations in membrane environment, were subsequently used in molecular docking studies in order to investigate potential sites of interaction. The structure of hD(3) and hD(2L) receptors was differentiated by means of MD simulations and D(3) selective ligands were discriminated, in terms of binding energy, by docking calculation. Robust correlation of computed and experimental K(i) was obtained for hD(3) and hD(2L) receptor ligands. In conclusion, the present computational approach seems suitable to build and refine structure models of homologous dopamine receptors that may be of value for structure-based drug discovery of selective dopaminergic ligands.

Dopamine D(3) receptors (DRsD3) seem to have a pivotal role in mood disorders. Using the elevated plus maze (EPM) and the novelty-induced grooming test (NGT), we assessed the responses of DRD3-deficient (D(3)(-/-)) mice to the acute treatment (different testing time) with the anxiolytic drug, diazepam. D(3)(-/-) mice treated with diazepam (0.1 or 0.5mg/kg) exhibited a better behavioral response in the EPM than their wild type (WT). Furthermore, in D(3)(-/-) mice, but not in WT, 1mg/kg diazepam induced anxiolytic effects at all testing times. The contribution of DRsD3 in the anxiolytic effects of diazepam was confirmed by similar results obtained in EPM by using the selective DRD3 antagonist U99194A (10mg/kg) in combination with diazepam, in WT animals. D(3)(-/-) mice treated with diazepam (all doses), also showed a decrease in grooming behavior. However, the [(3)H]flunitrazepam autoradiographic analysis revealed no significant changes in D(3)(-/-) mice compared to WT, suggesting that if γ-aminobutyric acid receptor GABA(A) changes are involved, they do not occur at the level of binding to benzodiazepine site. These data suggest that D(3)(-/-) mice exhibit low baseline anxiety levels and provide the evidence that the DRD3 is involved in the modulation of benzodiazepine anxiolytic effects., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Recently, it has been proposed that neurofibromin (NF1) forms a binding complex with amyloid precursor protein (APP) that interacts with the dopamine D(3) receptor (D(3)R). In the present study we investigated whether the absence of the D(3)R is correlated to modifications in the expression of both NF1 and APP. Quantitative real-time PCR analyses of both transcripts showed that NF1 mRNA levels were significantly reduced whereas APP levels were strikingly increased in D(3)R knock-out (D(3)R KO) as compared to wild type (WT) mice brains. Western blot analyses using mice whole brains produced comparable results with those obtained by mRNA measurements. Moreover, immunohistochemical analyses revealed a similar brain regional distribution of APP protein in the hippocampus, in the cerebral and cerebellar cortex of D(3)R KO mice. Conversely, hippocampal NF1 immunoreactivity did not seem to be affected by the absence of D(3)Rs. Further analyses confirmed that regional NF1 protein expression in the hippocampus was not affected by the absence of the D(3)R, whereas APP levels were still increased in this specific brain region. In conclusion, these results show the existence of a correlation among the D(3)R, NF1 and APP in mice brains and thus show the regional-specific regulation of NF1 in brains of D(3)R KO, which may contribute to gain insights into the comprehension of novel underlying mechanisms that regulate brain function.

Increasing evidence suggests a pivotal role of the D3 receptor (D3R) in cognitive processes and the involvement of endocannabinoid/endovanilloid signaling in the pathophysiology of neurodegenerative disorders such as Alzheimer's disease. This study was undertaken to investigate both the basal and beta-amyloid peptide 1-42 (BAP 1-42)-impaired cognitive performance of D3R((-/-)) mice, and the role therein of endocannabinoids/endovanilloids. D3R((-/-)) mice were either untreated or injected i.c.v. with 400 pMol BAP 1-42 or vehicle to be tested 14 days later in a step-through passive-avoidance paradigm. The CB(1) receptor antagonist, rimonabant (1mg/kg), or the transient receptor potential vanilloid-type 1 channel (TRPV1) antagonist SB366791, were injected intraperitoneally for 11 or 7 days. The retention test was performed 1, 7 and 14 days after the learning trial. Wild-type (WT) mice were subjected to the same procedures. D3R((-/-)) mice exhibited a better basal cognitive performance as compared to WT mice (p<0.001), which was reversed by TRPV1 antagonism. BAP 1-42 induced a pronounced worsening of the passive-avoidance response in all tests and in both genotypes (p<0.001). Rimonabant treatment never affected the cognitive performance of healthy mice, but fully counteracted BAP 1-42-induced amnesic effects in both D3R((-/-)) and WT mice only when administered for 11 days, whereas, when administered for 7 days, only transiently affected WT mice and caused more prolonged cognitive ameliorations in D3R((-/-)) mice. These results support the involvement of D3R and TRPV1 in cognitive processes and the concept that A beta peptides inhibit memory retention in mice through the involvement of endocannabinoids., ((c) 2010 Elsevier Ltd. All rights reserved.)

Dopamine and the endocannabinoids, anandamide and 2-arachidonoylglycerol, interact at several levels in the brain, with the involvement of both cannabinoid CB(1) receptors and transient receptor potential vanilloid type-1 (TRPV1) channels (which are alternative anandamide receptors). Using pharmacological, immunohistochemical and analytical approaches, we investigated the response of dopamine D(3) receptor null (D3R((-/-))) mice in models of epilepsy and anxiety, in relation to their brain endocannabinoid and endovanilloid tone. Compared to wild-type mice, D3R((-/-)) mice exhibited a delayed onset of clonic seizures, enhanced survival time, reduced mortality rate and more sensitivity to anticonvulsant effects of diazepam after intraperitoneal administration of picrotoxin (7 mg/kg), and a less anxious-like behaviour in the elevated plus maze test. D3R((-/-)) mice also exhibited different endocannabinoid and TRPV1, but not CB(1), levels in the hippocampus, nucleus accumbens, amygdala and striatum. Given the role played by CB(1) and TRPV1 in neuroprotection and anxiety, and based on data obtained here with pharmacological tools, we suggest that the alterations of endocannabinoid and endovanilloid tone found in D3R((-/-)) mice might account for part of their altered responses to excitotoxic and anxiogenic stimuli.

Patients affected by autosomic recessive juvenile parkinsonism (ARJP) exhibit parkin gene mutations with brain decrease in dopamine D2/D3 binding sites. To date, there are no data indicating whether the reduction in dopamine D3 receptors (DRD3) may be associated with the expression of specific parkin variants. In the present study we investigated parkin expression profile in DRD3 knock-out mice brains. RT-PCR analysis was performed to assess qualitative changes in parkin isoforms' distribution pattern and in exons' expression both in wild type controls and dopamine D3 receptor's knock-out mice. Real-time PCR was performed to quantify single exons mRNA. Results demonstrated that exons 1, 2, 4, 6, 7, 8, were more expressed in wild type compared to dopamine D3 receptor KO mice brains while some other (3, 9, 10) were lower expressed. The expression levels of exons 5, 11 and 12 did not change in both animal groups. Our analysis was confirmed by western blot, which showed that parkin protein levels were influenced by the absence of DRD3.

Evidence exists for a dopaminergic system dysregulation in mood disorders. In particular, depression may be accompanied by a relative fall of brain dopamine (DA) availability, while the increase of dopamine D2/D3 receptors (D2R/D3R) binding may reflect a compensatory change following primary reduction of mesolimbic DA levels. It is well established that D3Rs, acting as autoreceptors, inhibit DA synthesis and release, although lack of selective compounds have limited the progress in understanding D3Rs role in mood disorders. Aim of this study was to assess the behavioral responses of D3R-deficient (D3(-/-)) mice tested in the forced swim test (FST) and to evaluate their sensitivity to the treatment with different antidepressant drugs. Different groups of mice received one injection of the tricyclic compound, clomipramine (1, 5 and 10 mg/kg) or of one the selective serotonin reuptake inhibitors (SSRIs), paroxetine, sertraline or citalopram (1, 4 and 16 mg/kg), 30 min prior the behavioral test. Vehicle-injected wild type (WT) mice and D3(-/-) animals were used as controls and submitted to the same experimental procedure. In a preliminary experiment, vehicle-injected D3(-/-) mice, but not their littermates, failed to show an increased immobility time in FST as compared to intact controls, suggesting an increased resistance to injection-induced stress in the former. Clomipramine 1 mg/kg failed to affect behavioral responses of both D3(-/-) mice and WT animals. After the 5 mg/kg dose, D3(-/-) and WT mice showed a better performance in FST than vehicle-injected controls, with a lower immobility time exhibited by D3(-/-) mice than that shown by WT animals. No difference was found between WT mice treated with the highest dose of clomipramine (10 mg/kg) and the respective controls, although D3(-/-) mice exhibited a decreased immobility time as compared to vehicle-injected controls. In contrast to WT animals, when treated with 1 mg/kg sertraline and the 4 mg/kg dose of every SSRI D3(-/-) mice exhibited a decreased immobility time in FST in comparison to vehicle-injected controls. Furthermore, 16 mg/kg doses of citalopram, paroxetine or sertraline induced a greater reduction of immobility time in D3(-/-) mice than in WT-treated animals as compared to their respective controls. These data suggest that D3(-/-) mice, as being more resistant to stressful procedure than WT littermates, are more sensitive to antidepressants in FST paradigm than the former. Although the present data do not allow any conclusion on the neurochemical base of this difference, it might be possible that the greater sensitivity to antidepressants depends on a higher DA levels in mesolimbic pathways following the lack of D3Rs.