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PubMed2005

Absence of amino acid-induced glomerular hyperfiltration in dopamine D3 receptor knockout mice.

Pharmacological inhibition of receptors of the dopamine D2-like family has been shown to abolish the glomerular hyperfiltration in response to amino acids. To further discriminate between the receptor subtypes within the D2-like family, we investigated the effects of amino acid infusion on renal function in dopamine D3 receptor knockout (-/-) mice. In clearance experiments pentobarbital-anesthetized D3 receptor (-/-) and wild-type (+/+) mice were infused with Ringer solution at baseline, followed by a continuous infusion of mixed amino acids (10%). Baseline glomerular filtration rate (GFR), assessed by renal clearance of [3H]-inulin, was the same in D3 receptor (-/-) mice (0.56+/-0.08 ml/min per g kidney weight) and wild-type animals (0.56+/-0.04 ml/min per g kw). During infusion of amino acids, GFR was significantly elevated by 50% in D3 receptor (+/+) mice. In contrast, this amino acid-induced response of GFR was abolished in D3 receptor (-/-) mice. Baseline urinary water and sodium excretion was not significantly different in both groups of mice. As observed in GFR, these renal excretory parameters were significantly elevated during amino acid infusion in D3 receptor (+/+) but not in D3 receptor (-/-) mice. Time controls, constantly infused with Ringer solution, did not show significant changes in GFR, renal water or sodium excretion during the entire experiment, indicating stable experimental conditions. Taken together, the data underline the involvement of dopamine D2-like receptors in the renal response to amino acid infusion and, in addition, attribute this effect to the dopamine D3 receptor subtype.

Amino Acids↗

PubMed2001

Role of D1-like receptors in amphetamine-induced behavioral sensitization: a study using D1A receptor knockout mice.

RATIONALE: The role played by D(1)-like receptors in amphetamine-induced behavioral sensitization has been examined using both the D(1)-like receptor antagonist, SCH 23390, and the D(1A) receptor knockout mouse (i.e. D(1A)-deficient mice). Studies using these two approaches have provided conflicting evidence about the importance of D(1)-like receptors for amphetamine-induced behavioral sensitization. OBJECTIVE: The purpose of the present study was to determine: (a) whether D(1A)-deficient mice exhibit amphetamine-induced locomotor sensitization after 3 and 17 drug abstinence days, and (b) whether SCH 23390, which binds to both D(1A) and D(1B) receptor subtypes, blocks development of amphetamine sensitization in wild-type and D(1A)-deficient mice. METHODS: In the first experiment, adult wild-type and D(1A)-deficient mice were injected with amphetamine (0, 1, 2, 4, or 8 mg/kg, IP) for 7 consecutive days. In the second experiment, wild-type and D(1A)-deficient mice were pretreated with SCH 23390 (0, 0.15, or 0.5 mg/kg, IP) 30 min prior to being injected with amphetamine (0 or 8 mg/kg, IP). After each daily amphetamine injection, mice were placed in activity chambers where distance traveled (i.e. horizontal locomotor activity) was measured for 60 min. On the test days, which occurred after 3 or 17 drug abstinence days, mice were injected with 1 mg/kg amphetamine and locomotion was measured for 120 min. RESULTS: Both wild-type and D(1A)-deficient mice exhibited amphetamine-induced locomotor sensitization. Pretreatment with 0.5 mg/kg SCH 23390 blocked the development of locomotor sensitization in wild-type mice, but did not alter the sensitized responding of D(1A)-deficient mice. CONCLUSIONS: It appears that D(1)-like receptors are necessary for the development of amphetamine sensitization in wild-type mice, while neither the D(1A) nor D(1B) receptor subtypes are necessary for the amphetamine-induced locomotor sensitization of D(1A)-deficient mice. A possible explanation for these conflicting results is that D(1A)-deficient mice may have a compensatory mechanism (not involving D(1B) receptors) that allows them to exhibit amphetamine-induced behavioral sensitization in the absence of the D(1A) receptor.

Amphetamine↗

PubMed2002

Extracellular serotonin in the prefrontal cortex is limited through terminal 5-HT(1B) autoreceptors: a microdialysis study in knockout mice.

RATIONALE: Serotonin (5-HT) autoreceptors regulate extracellular 5-HT levels and have been suggested to limit the effects of acute treatment with selective serotonin reuptake inhibitors (SSRIs). OBJECTIVES: The role of terminal 5-HT(1B) autoreceptors was assessed by comparing the effects of a SSRI on extracellular 5-HT in wild-type and 5-HT(1B) receptor knockout (KO) mice and by using a 5-HT(1B) receptor antagonist. Since systemic SSRI administration also activates somatodendritic 5-HT(1A) autoreceptors, a SSRI was administered locally to study the role of terminal 5-HT(1B) autoreceptors. METHODS: In vivo microdialysis in wild-type and 5-HT(1B) receptor KO mice was used to study the effects of the 5-HT(1B) receptor agonist CP93129 (1 micro M), the SSRI fluvoxamine (0.3 micro M and 1.0 micro M) and the 5-HT(1B) receptor antagonist NAS-181 (1 micro M) on extracellular 5-HT in the medial prefrontal cortex. RESULTS: The 5-HT increase induced by local SSRI administration was augmented in 5-HT(1B) KO mice relative to wild-type mice and was augmented by simultaneous administration of a 5-HT(1B) receptor antagonist in the latter genotype. Basal 5-HT levels did not differ between the two genotypes. Activation of 5-HT(1B) receptors by CP93129 decreased extracellular 5-HT, whereas 5-HT levels in wild-type mice were not affected by the 5-HT(1B) receptor antagonist NAS-181. In 5-HT(1B) KO mice, NAS-181 did not affect extracellular 5-HT and did not further increase the effect of fluvoxamine, showing that NAS-181 is a selective 5-HT(1B) receptor antagonist. The greater increase in 5-HT levels following combined administration of a SSRI with NAS-181 in wild-type mice, relative to 5-HT(1B) KO mice, suggests possible adaptive changes in the KO mice. CONCLUSIONS: The present study shows that terminal 5-HT(1B) autoreceptors play a significant role in the regulation of 5-HT release in the prefrontal cortex.

Analysis of Variance↗

PubMed2003

Locomotor and discriminative-stimulus effects of cocaine in dopamine D5 receptor knockout mice.

RATIONALE: Dopamine D1-like antagonists block several effects of cocaine, including its locomotor-stimulant and discriminative-stimulus effects. Because these compounds generally lack selectivity among the dopamine D1 and D5 receptors, the specific roles of the subtypes have not been determined. OBJECTIVES: Dopamine D5 receptor knockout (DA D5R KO), heterozygous (HET) and wild-type (WT) mice were used to study the role of D5 dopamine receptors in the effects of cocaine. In addition, effects of the D1-like antagonist, SCH 39166 were also studied to further clarify the roles of D1 and D5 dopamine receptors in the discriminative-stimulus effects of cocaine. METHODS: DA D5R KO, HET and WT mice were treated with cocaine (3-30 mg/kg) or vehicle and their horizontal locomotor activity was assessed. The mice were also trained to discriminate IP injections of saline from cocaine (10 mg/kg) using a two-lever food-reinforcement (FR10) procedure. Doses of cocaine (1.0-10 mg/kg) were administered 5 min before 15-min test-sessions. RESULTS: Cocaine dose-dependently stimulated activity in each genotype, with the highest level of activity induced in the DA D5R WT mice. Both DA D5R KO and HET mice showed reduced levels of horizontal activity compared to WT mice. All three genotypes acquired the discrimination of 10 mg/kg cocaine; doses of 1.0-10.0 mg/kg produced dose-related increases in the number of cocaine-appropriate responses. SCH 39166, at inactive to fully active doses (0.01-0.1 mg/kg) produced predominately saline-appropriate responding. SCH 39166 produced a dose-dependent rightward shift in the cocaine dose-effect curve in all genotypes, with similar apparent affinities. CONCLUSIONS: The present data suggest an involvement of DA D5R in the locomotor stimulant effects of cocaine. In addition, the data indicate that there is little involvement of the DA D5R in the discriminative-stimulus effects of cocaine. In addition, the antagonism data suggest a role of the D1 receptor in the behavioral effects of cocaine.

Animals↗

PubMed2003

Effect of antipsychotic treatment on the prepulse inhibition deficit of mGluR5 knockout mice.

RATIONALE: Prepulse inhibition of the startle response (PPI), a model of sensorimotor gating, is deficient in persons with schizophrenia. In rodents, the reversal of induced deficits in PPI demonstrates predictive validity for identifying antipsychotic treatments. Metabotropic glutamate receptor 5 (mGluR5) has been implicated in schizophrenia, in part because mGluR5 knockout (KO) mice exhibit PPI deficits. OBJECTIVE: We examined whether mGluR5 KO mice might serve as a novel model for detecting antipsychotic treatments. METHODS: Using C57BL/6J or 129SvPasIco mice, we first determined doses of the typical antipsychotic raclopride or the atypical antipsychotic clozapine that were effective in blocking the PPI-disruptive effects of amphetamine or ketamine, respectively. We then examined the effects of these doses on the deficit in PPI in mGluR5 KO mice. RESULTS: Administration of raclopride or clozapine reversed either an amphetamine or a ketamine-induced PPI deficit, as had the novel mood stabilizer lamotrigine in previous studies. In contrast, the PPI deficit of the mGluR5 KO mice was not altered by administration of raclopride, clozapine, or lamotrigine. The serotonin(2A) antagonist M100,907 was also ineffective in reversing the mGluR5 KO deficit in PPI. CONCLUSIONS: Most of the compounds examined ameliorated at least a subset of pharmacologically induced PPI deficits. That none of the antipsychotic treatments attenuated the PPI deficit in the mGluR5 KO mice indicates that this model is not predictive of known treatments for schizophrenia, but does not preclude a role for the mGluR5 receptor in schizophrenia or other psychiatric disorders.

Animals↗

PubMed2004

Brain penetration of methadone (R)- and (S)-enantiomers is greatly increased by P-glycoprotein deficiency in the blood-brain barrier of Abcb1a gene knockout mice.

RATIONALE: Methadone maintenance treatment is complicated by the wide variability of efficacy among patients. The large interindividual variability of the plasma concentrations of methadone was previously thought to be responsible for the variable therapeutic efficacy. However, recent studies suggested that methadone may be a substrate of P-glycoprotein (P-gp). Therefore, the function of P-gp in blood-brain barrier (BBB) may affect the concentration of methadone at its site(s) of action in the central nervous system, thereby contributing to its therapeutic efficacy and/or adverse events. OBJECTIVE: To investigate the effect of P-gp on brain penetration of methadone (R)- and (S)-enantiomers and their major oxidative metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP). METHODS: We compared the tissue distribution of methadone (R)- and (S)-enantiomers and EDDP in the Abcb1a-/- gene knockout mice and the Abcb1a+/+ wild-type mice 1 h following intraperitoneal administration of 15 microg Rac-methadone/g mouse. RESULTS: Plasma concentrations of (R)- and (S)-methadone were similar between the two animal groups. However, the brain concentrations of (R)- and (S)-methadone in the Abcb1a-/- mice were markedly higher (15- and 23-fold, respectively, P<0.0001) than those of the Abcb1a+/+ wild-type mice. No statistically significant difference was found for other organs between the mutants and controls. No organ difference was found for EDDP between the mutants and controls. CONCLUSIONS: (R)- and (S)-methadone are substrates of P-gp. The P-gp in BBB greatly limits the brain entry of (R)- and (S)-methadone to their central nervous system acting sites. The interindividual variation in expression of P-gp in BBB may represent a source of variation for the access and effects of methadone in the brain.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2004

Reduced hypophagic effects of d-fenfluramine and the 5-HT2C receptor agonist mCPP in 5-HT1B receptor knockout mice.

RATIONALE: The possible role of compensatory changes in 5-HT2C receptors in the reduced hypophagic action of d-fenfluramine in 5-HT1B knockout (KO) mice was assessed by comparing their response to d-fenfluramine and the 5-HT2C receptor agonist mCPP. In addition we measured 5-HT(2C/A) receptor binding in 5-HT1B KO and wild-type (WT) mice and examined the effects of 5-HT1B receptor antagonists on d-fenfluramine-induced hypophagia in WT mice. METHODS: Hypophagic responses to d-fenfluramine (1-30 mg/kg) and mCPP (1-5.6 mg/kg) were measured using a behavioural satiety sequence paradigm. The effects of the 5-HT1B receptor antagonists GR 127,935 and SB 224289 in opposing the hypophagic action of d-fenfluramine were evaluated in WT mice. The binding of [3H]-mesulergine was compared in the brains of both mouse strains. RESULTS: The hypophagic effects of moderate doses of d-fenfluramine and mCPP were attenuated in 5-HT1B KO mice. Pretreatment of WT mice with the 5-HT(1B/1D) receptor antagonist GR 127,935, or food-deprived WT mice with the 5-HT1B receptor antagonist SB 224289, did not reproduce the reduction in sensitivity to the effects of d-fenfluramine on feeding behaviour observed in 5-HT1B KO mice. Estimates of 5-HT2C receptor binding were similar in 5-HT1B KO and WT mice. CONCLUSIONS: The hypophagic effect of d-fenfluramine in mice is unlikely to be mediated by the 5-HT1B receptor. Instead, the evidence suggests that an adaptive change in 5-HT2C receptor function occurs in 5-HT1B receptor KO mice and contributes to their reduced response to d-fenfluramine.

Animals↗

PubMed2004

Reduced sensitivity to reward in CB1 knockout mice.

RATIONALE: Previous studies have demonstrated that the activation and blockade of the cannabinoid type 1 receptor (CB1) leads to an enhancement and decrease of the consumption of food and other orally ingested reinforcers, respectively. OBJECTIVE: To gain further knowledge about the role of CB1 in sucrose/saccharin reinforcing efficacy and intake, we tested CB1 knockout (CB1-KO) and littermate wild-type (WT) control mice in several self-administration experimental protocols. METHODS: Operant (fixed or progressive ratio schedule) and non-operant conditioning procedures were used. In addition, a choice analysis based on the "matching law" as well as a microstructural analysis of the intra-session pattern of self-administration was performed. RESULTS: CB1-KO mice consume less sucrose under operant conditions or when using a two-bottle free choice procedure. Moreover, as revealed by additional behavioural analysis, CB1-KO mice exhibit a decreased sensitivity to the rewarding properties of sucrose. In agreement with this finding, the differences between WT and CB1-KO mice faded away when the palatability of sucrose was devaluated by adding quinine, but not when a non-caloric sweetener, saccharin, was available. CONCLUSIONS: These results demonstrate a modulatory role of CB1 in the determination of the rewarding properties of sucrose and probably, as suggested by previous studies, other reinforcers.

Animals↗

PubMed2004

Phenotypic assessment of galanin overexpressing and galanin receptor R1 knockout mice in the tail suspension test for depression-related behavior.

RATIONALE: Galanin and its receptors exert inhibitory neuromodulatory control over brain monoamines. Rat studies revealed that galanin expression is upregulated by exposure to stressors and that galanin manipulations modify neuroendocrine and behavioral responses to stress, leading to the hypothesis that galanin mediates depression-related behaviors. METHODS: In the present study, we examined the role of galanin in modulating antidepressant-related behavior in galanin overexpressing transgenic (GAL-tg) mice and galanin receptor R1 knockout (GAL-R1 KO) mice, using the tail suspension test (TST). Quantitative autoradiography for 5-HT(1A)-R and serotonin transporter binding density tested for changes in these two major regulatory components of the 5-HT system in galanin mutant mice. RESULTS: Baseline TST behavior was normal in GAL-tg and GAL-R1 KO mice, and intracerebroventricular administration of galanin failed to alter TST behavior in normal C57BL/6J mice. The TST anti-immobility effects of acute treatment with the serotonin reuptake inhibitor, fluoxetine (0-30 mg/kg), and the norepinephrine reuptake inhibitor, desipramine (0-30 mg/kg), were unaltered in galanin mutant mice. Hippocampal 5-HT(1A)-R density was significantly elevated in GAL-tg and GAL-R1 KO mice, while hippocampal 5-HTT density was reduced in GAL-R1 KO mice, relative to controls. CONCLUSION: Neither pharmacological nor molecular genetic manipulations of galanin altered depression-related profiles in the TST. Possible functional alterations in hippocampal 5-HT neurotransmission may have contributed to these negative results. These preliminary findings provide evidence against the hypothesis that galanin plays a central role in mouse depression-related behaviors. It remains possible that galanin modulates depression-related responses in other experimental paradigms and species.

Animals↗

PubMed2005

Importance of D(1) receptors for associative components of amphetamine-induced behavioral sensitization and conditioned activity: a study using D(1) receptor knockout mice.

RATIONALE: Repeated exposure to psychostimulant drugs results in conditioned activity and behavioral sensitization. Nonassociative cellular changes are necessary for behavioral sensitization, while associative processes appear to modify the sensitized response. OBJECTIVE: The purpose of the present study was to determine whether the absence of the D(1) receptor would disrupt associative processes modulating sensitization and conditioned activity. METHODS: Wild-type and D(1) receptor knockout mice (i.e., D(1)-deficient mice) were injected with amphetamine (AMPH; 8 mg/kg, IP) before being placed in a previously novel test chamber (AMPH-Test group) or before being returned to the home cage (AMPH-Home group). Separate groups of mice were injected with saline (SAL) at the same time points. Distance traveled was measured 60 min each day, with the preexposure phase lasting 1 or 7 days. Sensitization was subsequently assessed after an injection of AMPH (1 mg/kg, IP), while conditioned activity was assessed after an injection of SAL. RESULTS: After a 1-day preexposure phase, wild-type and D(1)-deficient mice exhibited similar patterns of sensitization and conditioned activity. After a 7-day preexposure phase, (1) D(1)-deficient mice exhibited more robust context-specific sensitization than wild-type mice, (2) only D(1)-deficient mice showed context-independent sensitization, and (3) only D(1)-deficient mice showed conditioned activity. CONCLUSIONS: Repeatedly treating D(1)-deficient mice with AMPH appears to cause a general increase in responsivity. The reason for this hyper-responsivity is uncertain, but it is possible that cues from the testing environment were unable to inhibit responding (i.e., associative processes were disrupted). Alternatively, compensatory mechanisms (e.g., increases in D(2)-like receptors) may affect processes underlying sensitization and conditioned activity.

Amphetamine↗

PubMed2005

Blockage of histamine H1 receptor attenuates social isolation-induced disruption of prepulse inhibition: a study in H1 receptor gene knockout mice.

RATIONALE: Histaminergic neurotransmission has been implicated in the pathophysiology of stress-related psychiatric diseases. Although several atypical antipsychotics are potent H1 antagonists, the clinical significance of interaction between atypical antipsychotics and H1 receptors is still unknown. OBJECTIVE: In this study, we investigated the effects of H1 receptors blockage on social isolation-induced behavioral changes in H1 receptor gene knockout (H1KO) mice and their wild-type (WT) mice. METHODS: Both H1KO and their WT mice were subjected to 4-week social isolation rearing after weaning (21 postnatal days). After the 4-week isolation period, mice behavioral changes were evaluated using behavioral tests. RESULTS: Locomotor activity in home cages was significantly lower in isolation-reared WT mice than in socially reared WT mice. However, no change in locomotor activity was observed between socially and isolation-reared H1KO mice. Social isolation significantly impaired prepulse inhibition (PPI) of startle response in WT mice but not in H1KO mice. In addition, social isolation significantly impaired spatial learning and memory in WT mice but not in H1KO mice. Furthermore, H1KO mice treated with methamphetamine (METH) showed no enhancement in isolation-induced disruption of PPI. A neurochemical study revealed that isolation-reared WT mice had significantly lower dopamine (DA) levels and slightly increased DA turnover in the cortex than socially reared WT mice. Conversely, isolation-reared H1KO mice showed significantly higher DA contents as compared with socially reared H1KO mice. CONCLUSION: The results of our study indicate that blockage of H1 receptor-mediated neurotransmission attenuates social isolation-induced behavioral changes and that the therapeutic effects of atypical antipsychotics are mediated, at least in part, by interaction with H1 receptors in the brain.

Animals↗

PubMed2006

Mid-aged and aged wild-type and progestin receptor knockout (PRKO) mice demonstrate rapid progesterone and 3alpha,5alpha-THP-facilitated lordosis.

RATIONALE: Progesterone (P) and its 5alpha-reduced metabolite, 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP), facilitate sexual behavior of rodents via agonist-like actions at intracellular progestin receptors (PRs) and membrane GABA(A)/benzodiazepine receptor complexes (GBRs), respectively. OBJECTIVE: Given that ovarian secretion of progestins declines with aging, whether or not senescent mice are responsive to progestins was of interest. METHODS: Homozygous PR knockout (PRKO) or wild-type mice that were between 10-12 (mid-aged) or 20-24 (aged) months of age were administered P or 3alpha,5alpha-THP, and the effect on lordosis were examined. Effects of a progestin-priming regimen that enhances PR-mediated (experiment 1) or more rapid, PR-independent effects of progestins (experiments 2 and 3) on sexual behavior were examined. Levels of P, 3alpha,5alpha-THP, and muscimol binding were examined in tissues from aged mice (experiment 4). RESULTS: Wild-type, but not PRKO, mice were responsive when primed with 17beta-estradiol (E(2); 0.5 microg) and administered P (500 microg, subcutaneously). Mid-aged wild-type mice demonstrated greater increases in lordosis 6 h later compared to their pre-P, baseline test than did aged wild-type mice (experiment 1). Lordosis of younger and older wild-type, but not PRKO, mice was significantly increased within 5 min of intravenous (IV) administration of P (100 ng), compared with E(2)-priming alone (experiment 2). However, wild-type and PRKO mice demonstrated significant increases in lordosis 5 min after IV administration of 3alpha,5alpha-THP, an effect which was more pronounced in mid-aged than in aged animals (100 ng-experiment 3). In tissues from aged wild-type and PRKO mice, levels of P, 3alpha,5alpha-THP, and muscimol binding were increased by P administration (experiment 4). PR binding was lower in the cortex of PRKO than that of wild-type mice. CONCLUSIONS: Mid-aged and aged PRKO and wild-type mice demonstrated rapid P or 3alpha,5alpha-THP-facilitated lordosis that may be, in part, independent of activity at PRs.

Aging↗

PubMed2005

Characterization of conditioned place preference to cocaine in congenic dopamine transporter knockout female mice.

RATIONALE: The dopamine transporter (DAT) is thought to play a major role in the rewarding effects of cocaine. Therefore, it is surprising that cocaine reveals conditioned effects in DAT knockout (DAT-KO) mice. OBJECTIVES: To examine these findings further, we obtained complete dose-effect curves for DAT-KO and DAT wild-type (DAT-WT) mice in a cocaine conditioned place preference (CPP) procedure. METHODS: Congenic C57BL6 background female DAT-KO and DAT-WT mice were conditioned in a three-compartment place preference apparatus. Conditioning consisted of three 30-min sessions with cocaine (2.5, 5.0, 10.0, 20.0, or 40.0 mg/kg) and three 30-min sessions with saline. The distribution of time in each choice compartment was determined after each pair of conditioning sessions (one cocaine and one saline session). RESULTS: DAT-WT mice revealed CPP over a wide range of cocaine doses (5.0-40 mg/kg), whereas DAT-KO mice revealed CPP over a more restricted range of doses, with consistent CPP only occurring with 10 mg/kg of cocaine. CONCLUSIONS: CPP for cocaine develops in both DAT-KO and DAT-WT mice; however, the dose range at which CPP develops is much more restricted in DAT-KO mice than in DAT-WT mice. These observations corroborate the significant role of DAT inhibition in cocaine's conditioned effects.

Animals↗

PubMed2006

The nicotinic antagonist mecamylamine has antidepressant-like effects in wild-type but not beta2- or alpha7-nicotinic acetylcholine receptor subunit knockout mice.

RATIONALE: Increases in cholinergic transmission are linked to depression in human subjects and animal models. We therefore examined the effect of decreasing nicotinic acetylcholine receptor (nAChR) activity in tests of antidepressant efficacy using C57BL/6J mice. OBJECTIVES: We determined whether the noncompetitive nAChR antagonist mecamylamine had antidepressant-like effects in the forced swim test (FST) and tail suspension test (TST). These experiments were repeated in mice lacking either the beta2- or alpha7-nAChR subunits to identify the nAChR subunits involved in mediating the antidepressant response to mecamylamine. MATERIALS AND METHODS: Adult mice on the C57BL/6J background were acutely administered mecamylamine i.p. 30 min before testing in the FST or TST. RESULTS: A dose-response study showed that mecamylamine significantly decreased immobility time in the TST at the 1.0-mg/kg dose but did not alter baseline locomotor activity. The competitive nAChR antagonist dihydro-beta-erythroidine, but not the blood-brain barrier impermeant antagonist hexamethonium, also decreased immobility in the TST. One milligram per kilogram of mecamylamine also significantly decreased time immobile in the FST whereas both beta2- and alpha7-knockout mice were insensitive to the effects of mecamylamine in the FST. CONCLUSIONS: Decreased activity of central nAChRs has antidepressant-like effects in both the TST and FST and these effects are dependent on both beta2 and alpha7 subunits. Therefore, compounds that decrease nAChR activity may be attractive new candidates for development as antidepressants in humans.

Animals↗

PubMed2006

The psychostimulant and rewarding effects of cocaine in histidine decarboxylase knockout mice do not support the hypothesis of an inhibitory function of histamine on reward.

RATIONALE AND OBJECTIVES: Lesion studies have shown that the tuberomammillary nucleus (TM) exerts inhibitory effects on the brain reward system. To determine whether histamine from the TM is involved in that reward inhibitory function, we assessed the stimulant and rewarding effects of cocaine in knockout mice lacking histidine decarboxylase (HDC KO mice), the histamine-synthesizing enzyme. If histamine actually plays an inhibitory role in reward, then it would be expected that mice lacking histamine would be more sensitive to the behavioral effects of cocaine. MATERIALS AND METHODS: The first experiment characterized spontaneous locomotion and cocaine-induced hyperactivity (0, 8, and 16 mg/kg, i.p.) in wild-type and HDC KO mice. The rewarding effects of cocaine were investigated in a second experiment with the place-conditioning technique. RESULTS: The first experiment demonstrated that histidine decarboxylase mice showed reduced exploratory behaviors but normal habituation to the test chambers. After habituation to the test chambers, HDC KO mice were slightly, but significantly, less stimulated by cocaine than control mice. This finding was replicated in the second experiment, when cocaine-induced activity was monitored with the place-conditioning apparatus. Furthermore, a significant place preference was present in both genotypes for 8 and 16 mg/kg cocaine, but not for 2 and 4 mg/kg. CONCLUSIONS: Our data confirm previous results demonstrating that HDC KO mice show reduced exploratory behaviors. However, contrary to the hypothesis that histamine plays an inhibitory role in reward, histamine-deficient mice were not more responsive to the psychostimulant effects of cocaine.

Animals↗

PubMed2000

Serotonin releasers increase prepulse inhibition in serotonin 1B knockout mice.

RATIONALE: Prepulse inhibition (PPI) is the normal reduction of the startle response which occurs when an abrupt startling stimulus is preceded by a weak pre-stimulus and is decreased in several neuropsychiatric disorders. OBJECTIVE: The role of the serotonin 1B (5-HT(1B)) receptor in modulating PPI was investigated using 5-HT-releasing agents in wild-type (WT) and 5-HT1B knockout (1BKO) mice. Whether the differential effects of 5-HT-releasing agents on PPI in WT and 1BKO mice resulted from lack of the 5-HT1B receptor or altered development was also assessed. METHODS: PPI was assessed in WT and 1BKO mice treated with the 5-HT-releasing agents (+)3,4-methylenedioxy-N-methylamphetamine (MDMA: 0, 10 mg/kg) or (+/-)N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine (MBDB: 0, 10 mg/kg). Additionally, intact 129 Sv mice received pre-treatments of the 5-HT1B/1D antagonist GR 127935 (0, 0.75, 1.5, 3.0 mg/kg) and treatments of MDMA (10 mg/kg). RESULTS: MDMA and MBDB increased PPI in 1BKO mice, but did not alter PPI in WT mice. Intact 129 Sv mice receiving 3.0 mg/kg GR 127935 and 10 mg/kg MDMA exhibited increases in PPI. CONCLUSIONS: The ability of GR 127935 to increase PPI in intact MDMA-treated mice suggests that lack of the 5-HT1B receptor, and not altered development, is responsible for the PPI-increasing effects of 5-HT releasers in 1BKO mice. 5-HT release activates multiple 5-HT receptor subtypes, which individually may increase or decrease PPI and together have a combined effect on PPI. Our finding that MDMA and MBDB increase PPI in 1BKO, but not WT mice, indicates that the activation of 5-HT1B receptors by 5-HT disrupts PPI.

3,4-Methylenedioxyamphetamine↗

PubMed2000

Lack of operant ethanol self-administration in dopamine D2 receptor knockout mice.

RATIONALE: Dopamine D2 receptors are postulated to play an important role in modulating the reinforcing effects of abused drugs including ethanol. OBJECTIVES: This experiment examined operant ethanol self-administration in dopamine D2 receptor knockout (KO) mice and wild-type (WT) mice using a continuous access procedure. METHODS: Adult male KO and WT mice were trained in 30-min sessions to perform a lever press response for access to 10% v/v ethanol. After training, the mice were placed in test chambers on a continuous (23 h/day) basis with access to food (one lever press, i.e., FR1), 10% v/v ethanol (four lever presses, i.e., FR4), and water from a sipper tube (phase 1). After 30 consecutive sessions, response patterns were determined for 0, 5, 10, 20 and 30% v/v ethanol (phase 2). Saccharin (0.2% w/v) was subsequently added to the ethanol mixture and responding was examined for 0, 5, 10 and 20% ethanol (phase 3). RESULTS: During phase 1, WT mice displayed higher ethanol-lever responding compared to KO mice. Food lever responding and water intake was the same in both genotypes. During phase 2, WT mice displayed concentration-dependent ethanol lever responding, whereas KO mice responded at low rates regardless of ethanol concentration. WT mice also responded more for food compared to KO mice. Each genotype showed similar water intakes except at the 20% ethanol concentration, where WT mice had lower intakes. During phase 3, WT mice continued to show higher responding for all concentrations including saccharin alone. WT mice also continued to respond more for food compared to KO mice, but drank less water. In each phase, WT mice displayed episodic (bout) responding on the ethanol lever. KO mice did not respond for ethanol in bouts. CONCLUSIONS: Reduced responding in the KO mice for several reinforcers including ethanol indicates a more general role for dopamine D2 receptors in motivated responding rather than a specific role in ethanol reinforcement.

Animals↗

PubMed2001

Ethanol consumption and reward are decreased in mu-opiate receptor knockout mice.

RATIONALE: Differences in mu-opiate receptor (MOR) gene expression may modulate the rewarding effects of ethanol. OBJECTIVE: The effects of MOR gene knockout (KO) were examined in wild-type (+/+), heterozygote MOR KO (+/-), and homozygote MOR KO (-/-) mice on voluntary ethanol consumption, conditioned place preference produced by ethanol, and locomotor responses to ethanol in separate groups of mice. METHODS: Voluntary ethanol consumption (2-32% v/v) was examined in a two-bottle home-cage consumption test. The conditioned place preference paradigm was a biased design. Mice received four pairings of ethanol (2.0 g/kg IP) on the initially preferred side and four pairings on the initially non-preferred side with saline. The difference in time spent on the initially non-preferred side (pre- versus post-conditioning) was the measure of drug-induced preference. After habituation to a novel locomotor test chamber mice were tested, on subsequent sessions, for ethanol induced locomotion (0.0, 0.5, 1.0, and 2.0 g/kg IP). RESULTS: Heterozygous and homozygous MOR KO mice consumed less ethanol than wild-type mice. These effects appeared to be greater in female KO mice than in male KO mice. MOR KO mice, especially females, exhibited less ethanol reward in a conditioned place preference paradigm. These effects on ethanol reward were produced by reductions in MOR expression levels as small as 50%. MOR KO mice exhibited less ethanol-stimulated locomotion than did wild-type mice, an effect that was also largest in females. CONCLUSIONS: These data fit with the reported therapeutic efficacy of MOR antagonists in the treatment of human alcoholism. Allelic variants that confer differing levels of MOR expression could provide different degrees of risk for alcoholism.

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