Reduced Tyrosine Hydroxylase Levels Research Articles

Antagonists of the Neurokinin‐1 or Dopamine D1 Receptors Confer Protection from Methamphetamine on Dopamine Terminals of the Mouse Striatum

Methamphetamine (METH) is a highly addictive compound that induces toxicity of the dopamine (DA) terminals of the neostriatum. Exposure to METH induces long-term deficits in dopamine transporter (DAT) and tyrosine hydroxylase (TH) levels as well as induction of glial fibrillary acidic protein (GFAP) in the caudate putamen (CPu) and the nucleus accumbens (NAc). The primary effect of exposure to METH is elevation of the level of extracellular DA; therefore, we assessed the role of the DA D1 receptor (D1R) and neurokinin-1 receptor (NK-1R) on the expression of toxicity. METH was injected intraperitoneally (10 mg/kg) four times at 2-h intervals (an acute toxic dose), and the mice were sacrificed three days after the treatment. Exposure to METH resulted in marked reduction of DAT sites (reduced to 30 and 21% relative to control in medial and lateral aspects of the CPu) assessed by binding of [125I]RTI-121 by autoradiography or Western blot analysis. Pretreatment with the nonpeptide NK-1R antagonist WIN-51,708 (10 mg/kg) 30 min prior to the first and fourth injections of METH prevented the loss of DAT sites of the CPu. Moreover, pretreatment with WIN-51,708 also prevented the reduction of TH levels induced by METH as well as the induction of GFAP in astrocytes. Pretreatment with the D1R antagonist SCH-23390 (0.25 mg/kg) 30 min before the first and fourth injections of METH conferred partial protection on DAT sites of the CPu. These results demonstrate that receptors postsynaptic to the DA terminals of the CPu are needed in order to express the neurotoxic effects of METH on integral components of the DA terminals of the nigrostriatal projection.

Long-term potentiation and adenosine sensitivity are unchanged in the AS/AGU protein kinase Cγ-deficient rat

The AS/AGU rat is a spontaneously occurring mutation which exhibits locomotor abnormalities, reduced tyrosine hydroxylase levels in substantia nigra and lower extracellular levels of dopamine, making it a valuable model for some human locomotor disorders, and spontaneous chronic degeneration. The molecular defect is an absence of protein kinase Cγ (PKCγ), an enzyme suggested to play a role in synaptic plasticity. We have therefore examined long-term potentiation (LTP) in hippocampal slices from the mutant animals compared with the normal control strain of Albino Swiss rat. In the CA1 region, LTP was of the same magnitude in mutant and control animals, and the presynaptic inhibitory effects of adenosine were unchanged in naı̈ve slices or following LTP. Paired-pulse inhibition and facilitation were normal. It is concluded that the absence of PKCγ in this strain does not modify synaptic plasticity or presynaptic sensitivity to adenosine.

Pharmacological analysis of extracellular dopamine and metabolites in the striatum of conscious as/agu rats, mutants with locomotor disorder

The as/agu rat is a spontaneously occurring mutation which exhibits locomotor abnormalities, reduced tyrosine hydroxylase levels in the substantia nigra and lower extracellular levels of dopamine. The animal could represent a model of some human locomotor disorders. High-potassium medium evoked a 460% rise of dopamine levels in control rats but double this in mutants. Amphetamine increased extracellular dopamine by 710% in controls and 1480% in mutants. Clorgyline produced a small increase of dopamine levels in controls but an 1170% increase in mutants. The uptake inhibitor nomifensine increased dopamine levels by 910% in controls but only 270% in mutants. After treatment with benserazide plus l-DOPA, an acute injection of l-DOPA evoked a release of dopamine which was twice as large in the as/agu rats compared with controls. The results show reduced extracellular dopamine in as/agu rats when the locomotor disorder is apparent, but there has been little loss of tyrosine hydroxylase. The responses to drugs are qualitatively different from those obtained using 6-hydroxydopamine. Overall, the effects of compounds affecting aminergic neurons suggest that one possible mechanism for the neuronal abnormality in as/agu rats is a defective regulation of dopamine release from striatal terminals.

Adrenergic regulation of neonatal brown fat adenylyl cyclase and Gs alpha activity.

Norepinephrine (NE)-stimulated adenylyl cyclase (AC) activity increases during the perinatal period in rat brown adipose tissue (BAT), and this increase is associated with changes in the activities of both the catalytic subunit (C) and Gs alpha, the GTP-binding protein that mediates activation of C. The present study examined the role of the sympathetic nervous system in the postnatal sensitization of AC. The sympathetic innervation of BAT increased 7- to 13-fold after birth, and this increase was temporally correlated with the postnatal enhancement of AC responsiveness. 6-hydroxydopamine (6-HDA) treatment of neonates reduced tyrosine hydroxylase levels by greater than 90%. This treatment greatly reduced the perinatal increase in NE- and NaF-stimulated AC and completely abolished the increase in forskolin-Mn(2+)-stimulated activity. However, sympathectomy did not alter the postnatal increase in Gs alpha-specific activity and did not prevent the postnatal reduction in Gs alpha levels. These results demonstrate that the sympathetic innervation of BAT develops fully after birth and is essential for the postnatal increase in the activity of C but not of Gs alpha.