Striatal Dopamine In Mice Research Articles

Human mutations in high-confidence Tourette disorder genes affect sensorimotor behavior, reward learning, and striatal dopamine in mice

Tourette disorder (TD) is poorly understood, despite affecting 1/160 children. A lack of animal models possessing construct, face, and predictive validity hinders progress in the field. We used CRISPR/Cas9 genome editing to generate mice with mutations orthologous to human de novo variants in two high-confidence Tourette genes, CELSR3 and WWC1. Mice with human mutations in Celsr3 and Wwc1 exhibit cognitive and/or sensorimotor behavioral phenotypes consistent with TD. Sensorimotor gating deficits, as measured by acoustic prepulse inhibition, occur in both male and female Celsr3 TD models. Wwc1 mice show reduced prepulse inhibition only in females. Repetitive motor behaviors, common to Celsr3 mice and more pronounced in females, include vertical rearing and grooming. Sensorimotor gating deficits and rearing are attenuated by aripiprazole, a partial agonist at dopamine type II receptors. Unsupervised machine learning reveals numerous changes to spontaneous motor behavior and less predictable patterns of movement. Continuous fixed-ratio reinforcement shows that Celsr3 TD mice have enhanced motor responding and reward learning. Electrically evoked striatal dopamine release, tested in one model, is greater. Brain development is otherwise grossly normal without signs of striatal interneuron loss. Altogether, mice expressing human mutations in high-confidence TD genes exhibit face and predictive validity. Reduced prepulse inhibition and repetitive motor behaviors are core behavioral phenotypes and are responsive to aripiprazole. Enhanced reward learning and motor responding occur alongside greater evoked dopamine release. Phenotypes can also vary by sex and show stronger affection in females, an unexpected finding considering males are more frequently affected in TD.

Caffeine and a selective adenosine A2A receptor antagonist induce sensitization and cross-sensitization behavior associated with increased striatal dopamine in mice

BackgroundCaffeine, a nonselective adenosine A1 and A2A receptor antagonist, is the most widely used psychoactive substance in the world. Evidence demonstrates that caffeine and selective adenosine A2A antagonists interact with the neuronal systems involved in drug reinforcement, locomotor sensitization, and therapeutic effect in Parkinson's disease (PD). Evidence also indicates that low doses of caffeine and a selective adenosine A2A antagonist SCH58261 elicit locomotor stimulation whereas high doses of these drugs exert locomotor inhibition. Since these behavioral and therapeutic effects are mediated by the mesolimbic and nigrostriatal dopaminergic pathways which project to the striatum, we hypothesize that low doses of caffeine and SCH58261 may modulate the functions of dopaminergic neurons in the striatum.MethodsIn this study, we evaluated the neuroadaptations in the striatum by using reverse-phase high performance liquid chromatography (HPLC) to quantitate the concentrations of striatal dopamine and its metabolites, dihydroxylphenylacetic acid (DOPAC) and homovanilic acid (HVA), and using immunoblotting to measure the level of phosphorylation of tyrosine hydroxylase (TH) at Ser31, following chronic caffeine and SCH58261 sensitization in mice. Moreover, to validate further that the behavior sensitization of caffeine is through antagonism at the adenosine A2A receptor, we also evaluate whether chronic pretreatment with a selective adenosine A2A antagonist SCH58261 or a selective adenosine A1 antagonist DPCPX can sensitize the locomotor stimulating effects of caffeine.ResultsChronic treatments with low dose caffeine (10 mg/kg) or SCH58261 (2 mg/kg) increased the concentrations of dopamine, DOPAC and HVA, concomitant with increased TH phosphorylation at Ser31 and consequently enhanced TH activity in the striatal tissues in both caffeine- and SCH58261-sensitized mice. In addition, chronic caffeine or SCH58261 administration induced locomotor sensitization, and locomotor cross-sensitization to caffeine was observed following chronic treatment of mice with SCH58261 but not with DPCPX.ConclusionsOur study demonstrated that low dosages of caffeine and a selective adenosine A2A antagonist SCH58261 elicited locomotor sensitization and cross-sensitization, which were associated with elevated dopamine concentration and TH phosphorylation at Ser31 in the striatum. Blockade of adenosine A2A receptor may play an important role in the striatal neuroadaptations observed in the caffeine-sensitized and SCH58261-sensitized mice.

Effects of prodynorphin deletion on striatal dopamine in mice during normal aging and in response to MPTP

Dynorphins, endogenous neuropeptides found in striatonigral neurons, have been observed to exhibit dopamine-inhibitory actions and under some circumstances possess intrinsic neurotoxic activity. To test the hypothesis that dynorphin suppression mitigates effects of aging on the striatal dopaminergic system, HPLC quantitation of dopamine and related amines was performed on striatal homogenates of wild-type (WT) mice and mice lacking the prodynorphin ( Pdyn) gene at varying ages. Pdyn knockout (KO) mice at 10 and 20 months show significant elevations in striatal dopamine compared to 3-month mice. Differences in tyrosine hydroxylase (TH) immunoreactivity could not account for these findings, but phosphorylation of TH at Ser40, but not Ser31, was enhanced in aged Pdyn KO mice. Systemic administration of MPTP produced significant dopamine depletion in an age-dependent manner, but Pdyn deletion conferred no protection against MPTP-induced dopamine loss, arguing against a mechanism by which Pdyn deletion enhances dopaminergic neuron survival. The above findings demonstrate an age-dependent inhibitory effect of dynorphins on striatal dopamine synthesis via modulation of TH activity.

Neuroprotective effects of (±)-catechin against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity in mice

The neuroprotective effects of (±)-catechin against toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were investigated in mice. MPTP caused the death of dopaminergic neurons in the substantia nigra and decreased the level of striatal dopamine. Additionally, MPTP increased the level of phospho-c-Jun, a known substrate of c-Jun N-terminal kinase (JNK) and caused a rapid activation of GSK-3β, evidenced by the decrease in the level of phospho-Ser9 of GSK-3β. However, pretreatment with (±)-catechin was found to protect dopaminergic neurons in the substantia nigra against MPTP toxicity, and restore the depletion of striatal dopamine in mice. (±)-Catechin attenuated the phosphorylation of c-Jun and recovered the phosphorylation of GSK-3β (Ser9). These results suggested that the suppression of JNK and GSK-3β signaling cascades might contribute to the neuroprotective effect of (±)-catechin against toxicity of MPTP.

Prevention of MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) dopaminergic neurotoxicity in mice by chronic lithium: involvements of Bcl-2 and Bax

Lithium has been reported to exert neuroprotective activity in several neuronal cell cultures and in vivo models against glutamate toxicity. Since this action was reported to be associated with alterations in the antiapoptotic Bcl-2 family proteins, the effect of chronic lithium diet on the ability of the parkinsonism neurotoxin, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to deplete striatal dopamine in mice was determined. Mice were fed for with a diet containing 1.1, 2.2, 3.3, and 4.4 g/kg lithium chloride (LiCl) for 4 weeks, during which time serum levels of lithium were monitored. The 3.3 g/kg lithium diet gave serum level value very similar to what is observed in lithium therapy in man and the 4.4 g/kg well above this. At the end of this period the mice received 24 mg/kg MPTP i.p. once daily for 3 days. A direct relation was established with the increase in serum lithium and its ability to prevent MPTP induced depletion of striatal dopamine (DA) and its metabolites DPOAC and HVA. With the diet containing the highest lithium concentration there was an almost complete prevention of striatal dopamine depletion and the reduction in tyrosine hydroxylase activity and protein and it prevented the increase in dopamine turnover (DOPAC+HVA/DA) normally observed in MPTP treatment. Lithium did not interfere with the metabolism of MPTP, or with its brain uptake, since, the level of its monoamine oxidase (MAO) B derived metabolite, MPP+, in the striata of lithium and non-lithium treated mice were almost identical. Striatal Bcl-2 was significantly decreased, while Bax was increased in MPTP treated mice. Lithium treatment not only increased striatal Bcl-2 in control mice, but also prevented its reduction as induced by MPTP, and an opposing effect was seen with Bax. The neuroprotective action of lithium in this model of Parkinson’s disease has been attributed to its antiapoptotic activity which among other factors includes induction of Bcl-2 and reduction of Bax.

Tetrahydrobiopterin deficiency and dopamine loss in a genetic mouse model of Lesch-Nyhan disease.

Hypoxanthine-guanine phosphoribosyltransferase (HPRT) is an enzyme that catalyses the conversion of hypoxanthine and guanine into their respective nucleotides. Inherited deficiency of the enzyme is associated with a loss of striatal dopamine in both mouse and man. Although HPRT is not directly involved in the metabolism of dopamine, it contributes to the supply of GTP, which is used in the first and rate-limiting step in the synthesis of tetrahydrobiopterin (BH4). Since BH4 is required as a cofactor for tyrosine hydroxylase in the synthesis of dopamine, any limitation in the supply of GTP could interfere with the synthesis of dopamine. The current studies were designed to address the hypothesis that the reduced striatal dopamine in mice with HPRT deficiency results from reduced availability of BH4. The mutant mice had small reductions in striatal BH4, with normal BH4 levels in other brain regions. Liver BH4 was normal in HPRT-deficient mutant mice, and a phenylalanine challenge test failed to reveal any evidence for impaired hepatic phenylalanine hydroxylase, another BH4-dependent enzyme. Although striatal BH4 content is not normal, supplementation with BH4 or L-dopa failed to correct the striatal dopamine deficiency of the mutant mice, suggesting that BH4 limitation is not responsible for the dopamine loss.

Acute exposure to organochlorine pesticides does not affect striatal dopamine in mice.

The purpose of this study was to evaluate the possible association between the risk of developing Parkinson's disease (PD) and exposure to organochlorine pesticides in the mouse model. Animals were treated with a single subcutaneous injection of either dieldrin (40 and 80 mg/kg) or 2,4-dichlorophenoxyacetic acid (100 and 200 mg/kg, 2,4-D) and levels of dopamine (DA) and DA metabolites were measured in the striatum at the 7-day time point. Dieldrin exposure did not affect the striatal concentrations of DA, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). Administration of 2,4-D did not produce any changes with the exception of a slight (15%), but statistically significant decrease in DOPAC using the higher dose of the pesticide. No neurochemical signs of dopaminergic injury were found following the combined treatment with either dieldrin or 2,4-D plus diethyldithiocarbamate (DDC), a compound known to potentiate the effects of the dopaminergic toxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Furthermore, neither dieldrin nor 2,4-D caused additional damage in animals previously lesioned with MPTP. Data failed to support the hypothesis that acute exposure to organochlorine compounds or synergistic interactions involving these pesticides may cause significant damage to dopaminergic terminals and therefore contribute to nigrostriatal degeneration in PD.

Chronic Nicotine Administration in the Drinking Water Affects the Striatal Dopamine in Mice

PIETILÄ, K. AND L. AHTEE. Chronic nicotine administration in the drinking water affects the striatal dopamine in mice. PHARMACOL BIOCHEM BEHAV 66(1) 95–103, 2000.—Although tobacco contains a large variety of substances, its addictive properties are most probably due to the reinforcing actions of nicotine that motivates continued tobacco use. Animals and humans self-administer nicotine, a response that appears to involve the mesolimbic dopamine system and to be common to other abused drugs. The present article reviews animal models to administer nicotine chronically. We also describe a new animal model in which nicotine is given to mice in drinking water as their sole source of fluid. This treatment produced nicotine plasma concentrations comparable to or above those found in smokers. We found that mice withdrawn from nicotine were tolerant to the effects of nicotine challenge on striatal dopamine metabolism as well as on body temperature and locomotor activity. Furthermore, 3H-nicotine binding in the cortex and midbrain was significantly increased in mice withdrawn from nicotine. The last part of the article will focus on the effects of this chronic nicotine treatment on striatal dopamine. Dopamine and its metabolites and locomotor activity were increased in the forenoon in mice still drinking nicotine solutions. We also report recent data in which chronic nicotine administration in the drinking water enhanced the effect of dopamine receptor agonist, quinpirole, on striatal metabolism. The animal model described appears to be a relevant method for studying the mechanisms that are thought to be involved in nicotine dependence.

Partial protective effect of MK-801 on MPTP-induced reduction of striatal dopamine in mice

The protective effect of MK-801, an N- methyl- d-aspartate (NMDA) receptor antagonist on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced reduction of striatal dopamine (DA) was examined in C57 BL/6 mice. Striatal DA levels were significantly higher in animals receiving parenteral MK-801 before and for 48 h following MPTP administration after 28 days than in animals receiving MPTP alone. The effect was not due to inhibition of monoamine oxidase-B (MAO-B) by MK-801. These data suggest that NMDA receptors may be involved in some of the neurotoxicity produced by MPTP.

Oral versus parenteral efficacy of 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP): Differential effects on depletion of heart norepinephrine and of striatal dopamine in mice

Oral versus parenteral efficacy of 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP): Differential effects on depletion of heart norepinephrine and of striatal dopamine in mice

Characterization of the neurotoxic potential of m-methoxy-MPTP and the use of its N-ethyl analogue as a means of avoiding exposure to a possible Parkinsonism-causing agent.

1-Methyl-4-(3-methoxyphenyl)-1,2,3,6-tetrahydropyridine (2) produced persistent depletion of striatal dopamine in mice after four daily injections, although it was less potent than 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP has been implicated as a cause of Parkinsonism in drug abusers who inadvertently self-administered it and in industrial chemists who were exposed to it. Our results suggest that the m-methoxy compound has the same neurotoxic potential to cause destruction of nigrostriatal dopamine neurons that would lead to Parkinsonian symptoms in humans. In contrast, 1-ethyl-4-(3-methoxyphenyl)-1,2,3,6-tetrahydropyridine (11) had no effects on striatal dopamine in mice, even at doses 8 times those of MPTP. A method of preparing 11 and using it as an intermediate in the synthesis of potential analgesic drugs, thus avoiding a potentially neurotoxic intermediate, is described.

Persistent depletion of striatal dopamine in mice by 1-Methyl-4-(2-thienyl)-1,2,3,6-tetrahydropyridine (MTTP)

Persistent depletion of striatal dopamine in mice by 1-Methyl-4-(2-thienyl)-1,2,3,6-tetrahydropyridine (MTTP)