Monoaminergic markers in the optic tectum of the domestic chick.

The avian optic tectum has become a reliable model system to study the basic mechanisms that underlie the computation of visual stimuli. Many aspects of its cytoarchitecture, chemoarchitecture, connectivity and development are thoroughly characterized. However, knowledge about its monoaminergic innervation is still incomplete. As a prerequisite to understand a possible functional role of the monoaminergic neurotransmitters, the serotonergic, noradrenergic, and dopaminergic innervation of the optic tectum as well as the distribution of serotonin 2A receptors, the dopamine- and cAMP-regulated phosphoprotein DARPP-32 and calbindin D-28K was studied in domestic chicks by immunohistochemical techniques. Serotonergic, noradrenergic, and tyrosine hydroxylase positive axons and axon terminals were present in all layers of the optic tectum. Generally, the highest densities of serotonergic, noradrenergic, and tyrosine hydroxylase positive fibers were found in the superficial tectal layers 1-8, whereas only moderate densities of serotonergic, noradrenergic, and tyrosine hydroxylase positive fibers became obvious in the deep tectal layers 9-15. Serotonergic fibers were particularly abundant in layers 4, 5a and 7 and serotonin 2A receptors in layer 13. Noradrenergic fibers were densest in layers 4 and 5a, whereas tyrosine hydroxylase positive fibers showed a slightly different distribution pattern with additional dense labeling in layer 7. As revealed by double-labeling immunohistochemistry, serotonergic fibers were closely related to the cell bodies of calbindin-positive horizontal cells in layer 5b and tyrosine hydroxylase positive fibers often contacted DARPP-32+ dendritic shafts in layers 9 and 10. These findings indicate that the catecholaminergic innervation of the optic tectum consists of a noradrenergic and a dopaminergic component and that the noradrenergic, serotonergic, and dopaminergic system may be potentially involved in the modulation of retinal input in the superficial layers of the optic tectum as well as in the modulation of tectal output via the deep tectal layers.

Nondopaminergic mechanisms in levodopa-induced dyskinesia.

It has become increasingly apparent that Parkinson's disease involves many transmitter systems other than dopamine. This nondopaminergic involvement impacts on the generation of symptoms, on the neurodegenerative process, but, most tellingly, in the generation of side effects of current treatments, in particular, levodopa-induced dyskinesia (LID). Such mechanisms contribute not only to the expression of LID once it has been established but also to the mechanisms responsible for the development, or priming, of the dyskinetic state and the subsequent maintenance of the brain in that primed state. Within the basal ganglia, abnormalities in different nondopaminergic components of the circuitry have been defined in LID. In particular, a role for enhanced inhibition of basal ganglia outputs by the GABAergic direct pathway has been suggested as a basic mechanism generating LID. We speculate that the external globus pallidus and subthalamic nucleus may play distinct roles in different forms of dyskinesia, e.g., chorea/dystonia; peak/diphasic/off. At the cellular level, an appreciation of abnormal signaling by, among others, glutamatergic (NMDA and AMPA receptors in particular), alpha2 adrenergic, serotonergic (5HT), cannabinoid and opioid mechanisms in both priming and expression of LID has begun to emerge over the last decade. This is being consolidated, though in many cases questions remain regarding the specific sites of such abnormality within the circuitry. Very recently, at the molecular level, mechanisms controlling neurotransmitter release and impacting on the ability of neurons to maintain particular forms of firing patterning and synchronization, e.g., SV2A, have been identified. This increased understanding has already delivered and will continue to define novel approaches to treatment that target both pre- and postsynaptic signaling molecules throughout the basal ganglia circuitry.

Treatment enhances ultradian rhythms of CSF monoamine metabolites in patients with major depressive episodes.

Unipolar and bipolar depressions show abnormal behavioral manifestations of ultradian (less than 24 h) rhythms, but abnormal rhythms of the central neurotransmitters thought to be important for depression pathophysiology (eg dopamine (DA) and serotonin (5-HT)) have not been shown in this time frame. Since antidepressant treatments normalize disrupted rhythms in depression (eg rapid-eye-movement sleep and hormonal rhythms), we hypothesized that depression-related changes in ultradian oscillations of DA and 5-HT might be revealed during antidepressant treatment. Cerebrospinal fluid (CSF) samples collected q10 min for 24 h in 13 patients experiencing major depressive episodes (MDE) before and after treatment for 5 weeks with sertraline or bupropion were assayed for levels of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), and their ratio was calculated. Data were analyzed in the frequency domain using Fourier transforms and multivariate permutation testing. Antidepressant treatments were associated with decreased variance for 5-HIAA, increased variance for HVA, and markedly increased variance for the HVA : 5-HIAA ratio (p<0.05, p<0.02, and p<0.003, respectively). With treatment, the correlations between 5-HIAA and HVA weakened (p=0.06). Power spectral density (PSD-the Fourier magnitude squared) of the 5-HIAA signals at periods of 1.75 and 3.7 h (both p<0.05) decreased, while circadian cycling of HVA levels (p<0.05) and of the ratio (p<0.005) increased after treatment. The PSD of the full-length HVA : 5-HIAA ratio series after treatment increased in rapid variability (20-103 min periods, p<0.05). Spectrographic windowing demonstrated a focal span of enhanced HVA : 5-HIAA ratio variability following antidepressant treatment, in an approximately 84-min period through the evening (p<0.05). Periodic neurotransmitter relationships in depressed patients were altered by treatment in this analysis of a small data set. This may represent a baseline abnormality in the regulation of periodic functions involved in the depression pathophysiology, but it could also be due to an unrelated antidepressant effect. Further studies including comparisons with healthy subject data are in progress.