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Repeated, high-dose methamphetamine (METH) administrations cause persistent dopaminergic deficits in rodents, nonhuman primates, and humans. In rats, this treatment also causes the formation of high-molecular mass (greater than approximately 120 kDa) dopamine transporter (DAT)-associated complexes, the loss of DAT monomer immunoreactivity, and a decrease in DAT function, as assessed in striatal synaptosomes prepared 24 h after METH treatment. The present study extends these findings by demonstrating the regional selectivity of DAT complex formation and monomer loss because these changes in DAT immunoreactivity were not observed in the nucleus accumbens. Furthermore, DAT complex formation was not a consequence limited to METH treatment because it was also caused by intrastriatal administration of 6-hydroxydopamine. Pretreatment with the D2 receptor antagonist, eticlopride [S-(-)-3-chloro-5-ethyl-N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-hydroxy-2-methoxybenzamide hydrochloride], but not the D1 receptor antagonist, SCH23390 [R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride], attenuated METH-induced DAT complex formation. Eticlopride pretreatment also attenuated METH-induced DAT monomer loss and decreases in DAT function; however, the attenuation was much less pronounced than the effect on DAT complex formation. Finally, results also revealed a negative correlation between METH-induced DAT complex formation and DAT activity. Taken together, these data further elucidate the underlying mechanisms and the functional consequences of repeated administrations of METH on the DAT protein. Furthermore, these data suggest a multifaceted role for D2 receptors in mediating METH-induced alterations of the DAT and its function.
Choline uptake by the high affinity choline transporter (CHT) is the rate-limiting step in acetylcholine synthesis. Induction of CHT is therefore a critical step in cholinergic differentiation, and we examined the developmental expression of CHT in cholinergic sympathetic neurons that innervate rodent sweat glands. During postnatal development the earliest sympathetic axons in the rear footpads are noradrenergic, containing intense tyrosine hydroxylase immunoreactivity and lacking CHT-immunoreactivity (CHT-IR). By postnatal day 7 (P7) in mouse, and P10 in rat, weak CHT-IR appeared in axons associated with the sweat gland anlagen. CHT staining intensity increased during the following weeks in conjunction with plexus arborization and gland maturation. The pattern of CHT-immunoreactivity (CHT-IR) in the sweat gland innervation was similar to staining for the vesicular acetylcholine transporter and vasoactive intestinal peptide. Immunoblots of tissue from sympathectomized rats confirmed that most of the CHT in footpad was contained in sympathetic neurons. Although CHT expression has been reported in noradrenergic sympathetic neurons of the superior cervical ganglion, these data indicate that in the sympathetic neurons projecting to sweat glands CHT is present at detectable levels only after association with the glands.
Clinically relevant autonomic dysfunction can result from either complete or partial loss of sympathetic outflow to effector organs. Reported animal models of autonomic neuropathy have aimed to achieve complete lesions of sympathetic nerves, but incomplete lesions might be more relevant to certain clinical entities. We hypothesized that loss of sympathetic innervation would result in a predicted decrease in arterial pressure and a compensatory increase in heart rate. Increased heart rate due to loss of sympathetic innervation is seemingly paradoxical, but it provides a mechanistic explanation for clinical autonomic syndromes such as neuropathic postural tachycardia syndrome. Partially dysautonomic animals were generated by selectively lesioning postganglionic sympathetic neurons with 150 mg/kg 6-hydroxydopamine hydrobromide in male Sprague-Dawley rats. Blood pressure and heart rate were monitored using radiotelemetry. Systolic blood pressure decreased within hours postlesion (Delta>20 mm Hg). Within 4 days postlesion, heart rate rose and remained elevated above control levels. The severity of the lesion was determined functionally and pharmacologically by spectral analysis and responsiveness to tyramine. Low-frequency spectral power of systolic blood pressure was reduced postlesion and correlated with the diminished tyramine responsiveness (r=0.9572, P=0.0053). The tachycardia was abolished by treatment with the beta-antagonist propranolol, demonstrating that it was mediated by catecholamines acting on cardiac beta-receptors. Partial lesions of the autonomic nervous system have been hypothesized to underlie many disorders, including neuropathic postural tachycardia syndrome. This animal model may help us better understand the pathophysiology of autonomic dysfunction and lead to development of therapeutic interventions.
Sympathectomy has been achieved by a variety of methods but each has its limitations. These include lack of tissue specificity, incomplete lesioning, and the age range of susceptibility to the lesioning. To circumvent these drawbacks, an immunotoxin was constructed using a monoclonal antibody against the noradrenergic specific enzyme dopamine beta-hydroxylase (D beta H) coupled via a disulfide bond to saporin, a ribosomal inactivating protein. Three days after intravenous injection of the anti-D beta H immunotoxin (50 micrograms) into adult Sprague-Dawley rats, 66% of neurons in the superior cervical ganglia were chromatolytic. Superior cervical ganglia neurons were poisoned in 1 day old and 1 week old (86% of neurons) neonatal rats following subcutaneous injection of 3.75 and 15 micrograms, respectively. The anti-D beta H immunotoxin will be a useful tool in the study of the peripheral noradrenergic system in adult and neonatal animals.