Locomotor activity in D2 dopamine receptor-deficient mice is determined by gene dosage, genetic background, and developmental adaptations

Locomotor activity is a polygenic trait that varies widely among inbred strains of mice (). To characterize the role of D2 dopamine receptors in locomotion, we generated F2 hybrid (129/Sv x C57BL/6) D2 dopamine receptor (D2R)-deficient mice by gene targeting and investigated the contribution of genetic background to open-field activity and rotarod performance. Horizontal activity of D2R-/- mice was approximately half that of drug-naive, strain-matched controls but was significantly greater than haloperidol-treated controls, which were markedly hypokinetic. Wild-type 129/SvEv and C57BL/6 mice with functional D2 receptors had greater interstrain differences in spontaneous activity than those among the F2 hybrid mutants. Incipient congenic strains of D2R-deficient mice demonstrated an orderly gene dosage reduction in locomotion superimposed on both extremes of parental background locomotor activity. In contrast, F2 hybrid D2R-/- mice had impaired motor coordination on the rotarod that was corrected in the congenic C57BL/6 background. Wild-type 129/SvEv mice had the poorest rotarod ability of all groups tested, suggesting that linked substrain 129 alleles, not the absence of D2 receptors per se, were largely responsible for the reduced function of the F2 hybrid D2R-/- and D2R+/- mice. Neurochemical and pharmacological studies revealed unexpectedly normal tissue striatal monoamine levels and no evidence for supersensitive D1, D3, or D4 dopamine receptors in the D2R-/- mice. However, after acute monoamine depletion, akinetic D2R+/- mice had a significantly greater synergistic restoration of locomotion in response to SKF38393 and quinpirole compared with any group of D2R+/+ controls. We conclude that D2R-deficient mice are not a model of Parkinson's disease. Our studies highlight the interaction of multiple genetic factors in the analysis of complex behaviors in gene knock-out mice.     

Altered feeding responses in mice with targeted disruption of the dopamine-3 receptor gene.

Dopamine signaling has been implicated in the control of food intake and body weight. In particular, dopamine is important in the control of meal size and number and is thought to mediate the response to metabolic deprivation states. In the present experiments, the authors assessed the role of the dopamine-3 receptor (D?R) in the feeding responses to 2-deoxy-D-glucose, mercaptoacetate, and peripheral insulin. All 3 compounds increased food intake in wild-type mice, but the hyperphagic responses were blunted in D?R-/- mice. In other experiments, D?R-/- mice were hyperresponsive to the administration of amylin and leptin relative to wild-type mice. These results support the hypothesis that D?Rs chronically inhibit the effects of adiposity hormones, thereby contributing to a net anabolic state. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Reduced susceptibility to collagen-induced arthritis in mice deficient in IFN-gamma receptor

Collagen-induced arthritis (CIA) is an arthritic model that was developed after immunization with type II collagen (CII). Apparently, contradictory results have been reported regarding the role of IFN-gamma in the development of CIA. Therefore, we employed IFN-gamma R-deficient mice to study the role of IFN-gamma. To introduce the CIA susceptibility gene (H-2q), IFN-gamma R-deficient (H-2b/b/IFN-gamma R-/-) mice were mated with DBA/1 (H-2q/q/IFN-gamma R+/+) mice; next, the F1 mice were interbred to yield F2 offspring bearing different combinations of H-2 (H-2q/q, H-2q/b, and H-2b/b) and IFN-gamma R (IFN-gamma R+/+, IFN-gamma R+/-, and IFN-gamma R-/-) genes. Although the H-2q allele appeared to confer susceptibility to CIA, mice that were homozygous for the IFN-gamma R mutation showed a substantially decreased incidence and severity of CIA. The CII-specific IgG levels of serum samples, which are known to be involved in the development of CIA, were remarkably reduced in IFN-gamma R-/- mice. Furthermore, the anti-CII IgG2a levels controlled by IFN-gamma R were significantly reduced in IFN-gamma R-/- F2 mice compared with those seen in IFN-gamma R+/+ and IFN-gamma R+/- mice, although the levels of all IgG subclass Abs examined were lower in IFN-gamma R-/- mice than in IFN-gamma R+/+ mice. No clear evidence of the imbalance of Th1/Th2 cytokines was observed in CII-immunized, IFN-gamma R-deficient mice. Taken together, these results suggest that IFN-gamma exacerbates CIA by affecting, at least, levels of CII-specific IgG Ab rather than the imbalance of Th1/Th2 cells.     

Regulatory CD4(+) T cells expressing endogenous T cell receptor chains protect myelin basic protein-specific transgenic mice from spontaneous autoimmune encephalomyelitis

The development of T cell-mediated autoimmune diseases hinges on the balance between effector and regulatory mechanisms. Using two transgenic mouse lines expressing identical myelin basic protein (MBP)-specific T cell receptor (TCR) genes, we have previously shown that mice bearing exclusively MBP-specific T cells (designated T/R-) spontaneously develop experimental autoimmune encephalomyelitis (EAE), whereas mice bearing MBP-specific T cells as well as other lymphocytes (designated T/R+) did not. Here we demonstrate that T/R- mice can be protected from EAE by the early transfer of total splenocytes or purified CD4(+) T cells from normal donors. Moreover, whereas T/R+ mice crossed with B cell-deficient, gamma/delta T cell-deficient, or major histocompatibility complex class I-deficient mice did not develop EAE spontaneously, T/R+ mice crossed with TCR-alpha and -beta knockout mice developed EAE with the same incidence and severity as T/R- mice. In addition, MBP-specific transgenic mice that lack only endogenous TCR-alpha chains developed EAE with high incidence but reduced severity. Surprisingly, two-thirds of MBP-specific transgenic mice lacking only endogenous TCR-beta chains also developed EAE, suggesting that in T/R+ mice, cells with high protective activity escape TCR-beta chain allelic exclusion. Our study identifies CD4(+) T cells bearing endogenous alpha and beta TCR chains as the lymphocytes that prevent spontaneous EAE in T/R+ mice.     

Effects of aging and a high fat diet on body weight and glucose tolerance in glucagon-like peptide-1 receptor -/- mice

Disruption of glucagon-like peptide-1 (GLP-1) receptor signaling in mice results in mild glucose intolerance, principally due to elimination of the incretin effect of GLP-1. Despite the inhibitory effects of GLP-1 on food intake, 6- to 8-week-old GLP-1 receptor -/-(GLP-1R-/-) mice were not obese and did not exhibit disturbances of feeding behavior. As both diabetes and obesity frequently become more phenotypically evident in older rodents, we studied the consequences of aging and a high fat diet on glucose control and body weight in GLP-1R-/- mice. No evidence of obesity or deterioration in glucose control was detected in 11- and 16-month-old GLP-1R-/- mice (mean weight, 34.7 +/- 2.0, 30.5 +/- 1.5, and 34.6 +/- 2.8 g in male and 25.3 +/-1.6, 28.4 +/-1.2, and 31.9 +/- 2.9 g in female GLP-1R+/+, GLP-1R+/-, and GLP-1R-/- mice, respectively; P = NS). After 18 weeks of high fat feeding, GLP-1R-/- mice gained similar (males) or less (females) weight than age- and sex-matched CD1 controls. No significant deterioration in glucose tolerance was observed after high fat feeding in GLP-1R-/- mice. These observations demonstrate that long term disruption of GLP-1 signaling in the central nervous system and peripheral tissues of older mice is not associated with the development of obesity or deterioration in glucose homeostasis.     

Dopamine D3 and D4 receptor antagonists: synthesis and structure--activity relationships of (S)-(+)-N-(1-Benzyl-3-pyrrolidinyl)-5-chloro-4- [(cyclopropylcarbonyl) amino]-2-methoxybenzamide (YM-43611) and related compounds

In this study, we synthesized a series of (S)-N-(3-pyrrolidinyl)benzamide derivatives, 1, 2a-d, 5a-1, and 7, and their enantiomers, (R)-1 and (R)-5c-e, and evaluated their binding affinity for cloned dopamine D2, D3, and D4 receptors and their inhibitory activity against apomorphine-induced climbing behavior in mice. The results indicate that D2, D3, and D4 receptors have different bulk tolerance (D4 > D3 > D2) for the substituent of the 4-amino group (R1) on the benzamide nuclei and that cyclopropyl-, cyclobutyl-, and cyclopentylcarbonyl groups likely possess adequate bulkiness with respect to D3 and D4 affinity and selectivity over D2 receptors in this series. The results also suggested that the N-substituent (R2) on the pyrrolidin-3-yl group performs an important role in expressing affinity for D2, D3, and D4 receptors and selectivity among the respective subtypes. One of the compounds, (S)-(+)-N-(1-benzyl-3-pyrrolidinyl)-5-chloro-4-[(cyclopropylcarbonyl+ ++) amino]-2-methoxybenzamide (5c) (YM-43611), showed high affinity for D3 and D4 receptors (Ki values of 21 and 2.1 nM, respectively) with 110-fold D4 selectivity and 10-fold D3 preference over D2 receptors and weak or negligible affinity for representative neurotransmitter receptors. Compound 5c displayed potent antipsychotic activity in inhibiting apomorphine-induced climbing behavior in mice (ED50 value, 0.32 mg/kg sc).     

L-745,870, a subtype selective dopamine D4 receptor antagonist, does not exhibit a neuroleptic-like profile in rodent behavioral tests

This study examined the high-affinity, selective dopamine D4 receptor antagonist, L-745,870 (3-([4-(4-chlorophenyl)piperazin-1-yl]methyl)-1H-pyrrolo[2, 3-b]pyridine) in rodent behavioral models used to predict antipsychotic potential and side-effect liabilities in humans. In contrast to the classical neuroleptic, haloperidol, and the atypical neuroleptic, clozapine, L-745,870 failed to antagonize amphetamine-induced hyperactivity in mice or impair conditioned avoidance responding in the rat at doses selectively blocking D4 receptors. Furthermore, L-745,870 failed to reverse the deficit in prepulse inhibition of acoustic startle responding induced by the nonselective dopamine D2/3/4 receptor agonist apomorphine, an effect which was abolished in rats pretreated with the D2/3 receptor antagonist, raclopride (0.2 mg/kg s.c.). L-745,870 had no effect on apomorphine-induced stereotypy in the rat but did induce catalepsy in the mouse, albeit at a high dose of 100 mg/kg, which is likely to occupy dopamine D2 receptors in vivo. High doses also impaired motor performance; in rats L-745,870 significantly reduced spontaneous locomotor activity (minimum effective dose = 30 mg/kg) and in mice, L-745,870 reduced the time spent on a rotarod revolving at 15 rpm (minimum effective dose = 100 mg/kg). Altogether these results suggest that dopamine D4 receptor antagonism is not responsible for the ability of clozapine to attenuate amphetamine-induced hyperactivity and conditioned avoidance responding in rodents. Furthermore, the lack of effect of L-745,870 in these behavioral tests is consistent with the inability of the compound to alleviate psychotic symptoms in humans.     

Ambiguous role of interleukin-12 in Yersinia enterocolitica infection in susceptible and resistant mouse strains

Endogenous interleukin-12 (IL-12) mediates protection against Yersinia enterocolitica in C57BL/6 mice by triggering gamma interferon (IFN-gamma) production in NK and CD4+ T cells. Administration of exogenous IL-12 confers protection against yersiniae in Yersinia-susceptible BALB/c mice but exacerbates yersiniosis in resistant C57BL/6 mice. Therefore, we wanted to dissect the different mechanisms exerted by IL-12 during Yersinia infections by using different models of Yersinia-resistant and -susceptible mice, including resistant C57BL/6 mice, susceptible BALB/c mice, intermediate-susceptible wild-type 129/Sv mice, 129/Sv IFN-gamma-receptor-deficient (IFN-gamma R-/-) mice and C57BL/6 tumor necrosis factor (TNF) receptor p55 chain-deficient (TNFR p55-/-) mice. IFN-gamma R-/- mice turned out to be highly susceptible to infection by Y. enterocolitica compared with IFN-gamma R+/+ mice. Administration of IL-12 was protective in IFN-gamma R+/+ mice but not in IFN-gamma R-/- mice, suggesting that IFN-gamma R-induced mechanisms are essential for IL-12-induced resistance against yersiniae. BALB/c mice could be rendered Yersinia resistant by administration of anti-CD4 antibodies or by administration of IL-12. In contrast, C57BL/6 mice could be rendered more resistant by administration of transforming growth factor beta (TGF-beta). Furthermore, IL-12-triggered toxic effects in C57BL/6 mice were abrogated by coadministration of TGF-beta. While administration of IL-12 alone increased TNF-alpha levels, administration of TGF-beta or TGF-beta plus IL-12 decreased both TNF-alpha and IFN-gamma levels in Yersinia-infected C57BL/6 mice. Moreover, IL-12 did not induce toxicity in Yersinia-infected TNFR p55-/- mice, suggesting that TNF-alpha accounts for IL-12-induced toxicity. Taken together, IL-12 may induce different effector mechanisms in BALB/c and C57BL/6 mice resulting either in protection or exacerbation. These results are important for understanding the critical balance of proinflammatory and regulatory cytokines in bacterial infections which is decisive for beneficial effects of cytokine therapy.     

Motor response to a dopamine D3 receptor preferring agonist compared to apomorphine in levodopa-primed 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine monkeys

The profile of dopamine receptor subtype activation contributing to the therapeutic efficacy and motor response complications of levodopa (nonselective pro-agonist) in Parkinson's disease remains unclear. Potent, selective, short-acting dopamine D2 receptor subfamily agonists show good antiparkinsonian efficacy but produce dyskinesias comparable to levodopa. Nonetheless, agonists displaying higher affinity for dopamine receptors other than the D2 subtype may have a better therapeutic index. To clarify this issue, we compared the nonselective dopamine D1/D2 receptor subfamilies agonist apomorphine to the dopamine D3 receptor preferring agonist [R-(+)-trans-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4 , 3-b]-1,4-oxazin-9-ol] (PD 128,907) in 6 levodopa-primed , 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned parkinsonian monkeys with reproducible dyskinesias. Single s.c. dosing with the lowest fully effective dose of apomorphine (averaging 27.9 +/- 4.5 microg/kg) and PD 128,907 (averaging 41.7 +/- 4.4 microg/kg) yielded equivalent antiparkinsonian efficacy on the behavioral scale and portable activity monitoring used. A comparable significant dose-dependent increase in the response magnitude and duration was seen with two higher doses. The severity of dyskinesia was also similar between the two drugs. When the lower dose for each drug was administered six times at a fixed 90-min interval, both drugs remained efficacious with no significant tolerance observed. The D3 receptor preferring antagonist U-99194A significantly reduced the motor effects of both apomorphine and PD 128,907. Thus, increased D3 receptor tone does not acutely ameliorate dyskinesias in levodopa-primed parkinsonian monkeys. Given the reported lack of affinity of PD 128,907 for central D1 receptors, our data support the concept that the pharmacological activation of D1 receptors is not mandatory for relief of parkinsonism and production of dyskinesia.     

Clinical significance of CMV-specific T helper responses in lung transplant recipients

BACKGROUND: Cytomegalovirus (CMV) disease continues to be a major problem for lung transplant patients who generate an inefficient immune response to control this viral infection. Both T helper and cytotoxic T cells are thought to play an important role in prevention and control of CMV disease. We investigated the clinical significance of CMV-specific memory responses in lung transplant recipients. METHOD: Peripheral blood samples (140) were collected from 99 lung transplant recipients. Patients were grouped according to their pre-transplant CMV serological status as recipient/donor (R-/D+, 25 patients), 28 R+/D+ patients, 35 R+/D- patients and 11 R-/D- patients. Memory responses to CMV whole antigen, 5 CMV proteins, and tetanus toxoid (TT) were measured in a 6-day proliferative assay. Results were expressed as the stimulation index (SI = experimental cpm/background cpm), and were considered positive if the SI was >3 and the cpm values were over 1,000. RESULTS: The frequency of positive CMV memory responses was similar in three groups: 64% for R-/D+, 63% for R+/D+ and 56% for R+/D- except for R-/D- (21%). The memory response to TT was similar for all four groups (70% of samples were positive). The level of responsiveness to individual CMV proteins was much higher in R+/D+ group (65%) than the other two groups (35% for R+/D-, and 31% for R-/D+). We determined the temporal relationship between the presence of CMV-specific memory responses and the diagnosis of CMV disease. In the R-/D+ group, 16 of 17 patients who had CMV disease eventually developed CMV-specific memory. In those patients (n = 3) who failed to develop CMV-specific T helper response for a prolonged time, all had recurrent CMV disease. In the R+/D+ group, 4 of 8 patients with CMV disease exhibited CMV-specific memory responses. Three of 4 patients in whom we observed a persistent absence of CMV-specific memory had multiple episodes of CMV pneumonitis. In the R+/D- group, only one of 4 patients with CMV disease had suppressed CMV-specific memory response after first episode of CMV pneumonitis and had recurrent disease. CONCLUSION: In lung transplant recipients, the loss or persistent lack of CMV-specific memory following infection was associated with chronic CMV disease. These data suggest that monitoring T helper memory responses following primary CMV infection or after augmented immunosuppression for treatment of rejection may identify those patients at risk for morbidity associated with recurrent CMV disease.     

In vitro affinity of piribedil for dopamine D3 receptor subtypes, an autoradiographic study

Receptor binding autoradiography, using the selective ligand [3H]7-OH-(R)DPAT (R(+)-2-dipropylamino-7-hydroxy 1,2,3,4-tetrahydronaphthalene), showed that piribedil is a potent inhibitor at dopamine D3 receptors in limbic regions (island of Calleja), with affinity (IC50) between 30 and 60 nM. The in vitro IC50 of piribedil for inhibition of [3H]spiperone binding to receptors of the dopamine D2-like family (D2, D3 and D4), ranged between 10(-7) and 10(-6) M in different brain regions (medial and lateral caudate putamen, olfactory tubercles, and nucleus accumbens). At the highest concentration tested (10(-5 M) piribedil inhibited dopamine D1 receptor binding by < 50%. It is concluded that piribedil has 20 times higher affinity for dopamine D3 than for dopamine D2-like receptors, and very low affinity for the dopamine D1 receptor subtype in rat brain. How this pattern of receptor affinity is related to the pharmacological profile of piribedil deserves further investigation.     

Motor effects of lamotrigine in naive and dopamine-depleted mice

Lamotrigine (3,5-diamino-6-[2,3-dichlorphenyl]-1,2,4-triazine) has been hypothesised to possess antiparkinsonian activity, by inhibiting the release of glutamate from basal ganglia neurones. This study therefore examined the motor effects of lamotrigine in naive and reserpine-treated mice and its interactions with dopaminergic agonists. In normal mice, lamotrigine (5-80 mg/kg i.p.) decreased spontaneous locomotor activity with high doses (> or = 40 mg/kg) causing moderately severe impairment to posture and gait. In mice treated 24 h beforehand with reserpine (5 mg/kg i.p.), lamotrigine (5-40 mg/kg i.p.) had no effect on akinesia by itself and did not alter the locomotion induced with the selective dopamine D1 receptor agonist 2,3,4, 5-tetrahydro-7,8-dihydroxy-1-phenyl-1 H-3-benzazepine hydrochloride (SKF 38393, 30 mg/kg i.p.). By contrast, motor responses to the dopamine D2 receptor-selective agonist N-n-propyl-N-phenylethyl-p-(3-hydroxyphenyl)ethylamine (RU 24213, 5 mg/kg s.c.) and to the dopamine precursor L-3,4-dihydroxyphenylalanine (L-DOPA, 150 mg/kg i.p. in the presence of benserazide, 100 mg/kg i.p.), were significantly potentiated by 10 and 40 mg/kg i.p. lamotrigine respectively. It is suggested that lamotrigine may enhance the antiakinetic action of L-DOPA in parkinson-like mice by increasing motor responding mediated by dopamine D2 but not dopamine D1 receptors. This interaction profile of lamotrigine with dopamine D1 and D2 receptor mechanisms is opposite to what one sees with antagonists of glutamate receptors.     

Protective effect of the insulin-like growth factor I receptor on apoptosis induced by okadaic acid

Okadaic acid (OKA), a potent inhibitor of serine phosphatases at concentrations as low as 20-25 nM, induces apoptosis of R- mouse embryo fibroblasts, which are 3T3-like cells devoid of type 1 insulin-like growth factor receptors (IGF-IRs). From R- cells, we have generated (by stable transfection) cell lines with IGF-IR numbers ranging from 0 (R- cells) to >10(6) receptors per cell. The wild-type IGF-IR protects R- cells from OKA-induced apoptosis, its protective effect being exquisitely dependent on the number of receptors. A small increment in wild-type receptor number (from 15 x 10(3) to 22 x 10(3) receptors/cell) is sufficient to change R(-)-derived cells from sensitive to resistant to apoptosis. We have also studied the effect of various mutations of the IGF-IR on its ability to protect R(-)-derived cells from OKA-induced apoptosis. Our data indicate a correlation between protection from apoptosis and the ability of the receptor to respond to insulin-like growth factor I with mitogenesis.     

D1 receptors mediate dopamine action in the fetal suprachiasmatic nuclei: studies of mice with targeted deletion of the D1 dopamine receptor gene

Studies in rodents suggest the presence of a dopaminergic system that influences the function of a biological clock in the hypothalamic suprachiasmatic nuclei (SCN). To provide insights into mechanisms of dopamine action in the SCN, we studied transgenic mice that had either one allele (+?-) or both alleles (-/-) of the D1 dopamine receptor gene deleted, along with normal (+/+) littermates. As expected, receptor labelling autoradiography studies using [125I]SCH 23982 showed a complete absence of D1 dopamine receptor binding sites in the SCN of -/- animals. When pregnant mice from +?- x +?- matings were injected with the D1 receptor agonist SKF 38393, or the dopamine reuptake blocker GBR 12909 at day 19 of gestation, c-fos mRNA expression was observed in the SCN of +/+ fetuses. In contrast, c-fos mRNA induction was not seen in -/- or +?- litter mates. Injection of cocaine into pregnant dams also resulted in robust SCN c-fos mRNA expression in +/+ mice. Increases in SCN c-fos mRNA expression were also seen in +?- and -/- mice suggesting that cocaine action in the SCN involves both D1 receptor-dependent and -independent mechanisms. Collectively, our studies of transgenic mice deficient in D1 receptors support the presence of a functional dopaminergic system in the fetal SCN. We also identify D1 receptors as the prominent transducer of dopamine action in the fetal SCN.     

How often does oral treatment of toenail onychomycosis produce a disease-free nail? An analysis of published data

A series of N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)nicotinamide derivatives were prepared and evaluated for their binding to 5-HT3 and dopamine D2 receptors. Among them, the 5-bromo-2-methoxy-6-methylaminonicotinamide 16 and its (R)-isomer were found to have potent affinities for both receptors. The affinities of (R)-16 for 5-HT3 and dopamine D2 receptors are approximately 3-fold higher than those of the corresponding benzamide (R)-1 (IC50: 1.1 and 12 nM vs. 2.9 and 35 nM, respectively).     

Espresso Reward Learning, Hold the Dopamine: Theoretical Comment on Robinson et al. (2005).

Question: Is dopamine needed for reward learning? Answer: No--at least, not in the brain of a caffeinated dopamine-deficient (DD) mutant mouse. That is the conclusion of an important paper in this issue by S. Robinson, S. M. Sandstrom, V. H. Denenberg, and R. D. Palmiter (see record 2005-01705-001). Those authors demonstrate that reward learning can proceed normally in the brains of DD mice, even though they contain no dopamine at the time of learning, if the mice are given caffeine just before learning. Caffeine activates the DD mice by a nondopaminergic mechanism, allowing them to learn where to obtain food reward in a T-maze runway. Their reward-learning-without-dopamine is revealed on a subsequent test day, when dopamine function is restored by L-dopa administration. Robinson et al. conclude that dopamine is not needed for normal learning about rewards, or for hedonic "liking" of rewards during learning, but rather specifically for a motivational "wanting" component of reward, such as incentive salience. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Role of substance P and the neurokinin 1 receptor in acute pancreatitis and pancreatitis-associated lung injury

Substance P, acting via the neurokinin 1 receptor (NK1R), plays an important role in mediating a variety of inflammatory processes. However, its role in acute pancreatitis has not been previously described. We have found that, in normal mice, substance P levels in the pancreas and pancreatic acinar cell expression of NK1R are both increased during secretagogue-induced experimental pancreatitis. To evaluate the role of substance P, pancreatitis was induced in mice that genetically lack NK1R by administration of 12 hourly injections of a supramaximally stimulating dose of the secretagogue caerulein. During pancreatitis, the magnitude of hyperamylasemia, hyperlipasemia, neutrophil sequestration in the pancreas, and pancreatic acinar cell necrosis were significantly reduced in NK1R-/- mice when compared with wild-type NK1R+/+ animals. Similarly, pancreatitis-associated lung injury, as characterized by intrapulmonary sequestration of neutrophils and increased pulmonary microvascular permeability, was reduced in NK1R-/- animals. These effects of NK1R deletion indicate that substance P, acting via NK1R, plays an important proinflammatory role in regulating the severity of acute pancreatitis and pancreatitis-associated lung injury.     

Effects of dopaminergic drugs on innate pheromone-mediated reward in female mice: A new case of dopamine-independent "liking."

Male sexual pheromones are innately rewarding to adult female mice, but the role of dopamine in this natural reward is unknown. The authors have tackled this issue by assessing the effects of intraperitoneal injections of dopamine D? (SCH 23390, 0.02- 0.05mg/kg) and D? (sulpiride, 20.00 mg/kg) antagonists, a dopamine releasing agent (amphetamine, 0.50 -2.00 mg/kg), and D? (SKF 38393, 10.00 -20.00 mg/kg) and D? (quinpirole, 0.20 -1.00 mg/kg) agonists on the chemoinvestigation displayed by female mice in male- versus female-soiled bedding 2-choice tests. Dopamine antagonists and quinpirole failed to affect the unconditioned preference displayed by females towards male chemosignals, whereas both amphetamine and SKF 38393 abolished it. Finally, D? and D? antagonists did not block the induction of operant place conditioning by male chemosignals. As the female mice were tested in their first encounter with male sexual pheromones, their behavior can only be influenced by the "liking" component of reward. Therefore, the results suggest that dopamine mediates neither the hedonic properties of male sexual pheromones nor the acquisition of conditioned place preference. However, dopamine acting on D1 receptors might inhibit female mice attraction towards male chemosignals. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Alterations in dopamine release but not dopamine autoreceptor function in dopamine D3 receptor mutant mice

Dopamine (DA) autoreceptors expressed along the somatodendritic extent of midbrain DA neurons modulate impulse activity, whereas those expressed at DA nerve terminals regulate both DA synthesis and release. Considerable evidence has indicated that these DA autoreceptors are of the D2 subtype of DA receptors. However, many pharmacological studies have suggested an autoreceptor role for the DA D3 receptor. This possibility was tested with mice lacking the D3 receptor as a result of gene targeting. The basal firing rates of DA neurons within both the substantia nigra and ventral tegmental area were not different in D3 receptor mutant and wild-type mice. The putative D3 receptor-selective agonist R(+)-trans-3,4,4a, 10b-tetrahydro-4-propyl-2H,5H-(1)benzopyrano(4,3-b)-1,4-oxazin+ ++-9-ol (PD 128907) was equipotent at inhibiting the activity of both populations of midbrain DA neurons in the two groups of mice. In the gamma-butyrolactone (GBL) model of DA autoreceptor function, mutant and wild-type mice were identical with respect to striatal DA synthesis and its suppression by PD 128907. In vivo microdialysis studies of DA release in ventral striatum revealed higher basal levels of extracellular DA in mutant mice but similar inhibitory effects of PD 128907 in mutant and wild-type mice. These results suggest that the effects of PD 128907 on dopamine cell function reflect stimulation of D2 as opposed to D3 receptors. Although D3 receptors do not seem to be significantly involved in DA autoreceptor function, they may participate in postsynaptically activated short-loop feedback modulation of DA release.     

A heroin-, but not a cocaine-expecting, self-administration state preferentially alters endogenous brain peptides

The effects of L-type voltage-dependent Ca2+ channel blockers on apomorphine, bromocriptine and morphine-induced changes in locomotor activity were examined in mice. Apomorphine (4 mg/kg) and morphine (20 mg/kg) produced locomotor stimulation. Bromocriptine (8 mg/kg) produced a biphasic effect on motor behaviour, an early depressant phase, followed by locomotor stimulation. Amlodipine (2.5 mg/kg), nicardipine (10 mg/kg), diltiazem (10 mg/kg) and verapamil (10 mg/kg), which by itself did not affect locomotor activity, inhibited the stimulant phase of bromocriptine without altering the depressant phase, while they did not affect apomorphine- and morphine-induced locomotor stimulation. Apomorphine, bromocriptine and morphine-induced locomotor stimulation was decreased by SCH 23390 (R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7- ol) (0.05 mg/kg) or haloperidol (0.1 mg/kg). These results indicate that L-type voltage-dependent Ca2+ channels are involved in the motor stimulant effect of bromocriptine, but not in apomorphine- and morphine-induced locomotor stimulation. The effects of Ca2+ channel blockers on the dopaminergic system appears not to be directly related to dopamine receptor blockade.