Dopamine presynaptically and heterogeneously modulates nucleus accumbens medium-spiny neuron GABA synapses in vitro

BACKGROUND: The striatal complex is the major target of dopamine action in the CNS. There, medium-spiny GABAergic neurons, which constitute about 95% of the neurons in the area, form a mutually inhibitory synaptic network that is modulated by dopamine. When put in culture, the neurons reestablish this network. In particular, they make autaptic connections that provide access to single, identified medium-spiny to medium-spiny neuron synaptic connections. RESULTS: We examined medium-spiny neuron autaptic connections in postnatal cultures from the nucleus accumbens, the ventral part of the striatal complex. These connections were subject to presynaptic dopamine modulation. D1-like receptors mediated either inhibition or facilitation, while D2-like receptors predominantly mediated inhibition. Many connections showed both D1 and D2 modulation, consistent with a significant functional colocalization of D1 and D2-like receptors at presynaptic sites. These same connections were subject to GABA(A), GABA(B), norepinephrine and serotonin modulation, revealing a multiplicity of modulatory autoreceptors and heteroreceptors on individual varicosities. In some instances, autaptic connections had two components that were differentially modulated by dopamine agonists, suggesting that dopamine receptors could be distributed heterogeneously on the presynaptic varicosities making up a single synaptic (i.e. autaptic) connection. CONCLUSION: Differential trafficking of dopamine receptors to different presynaptic varicosities could explain the many controversial studies reporting widely varying degrees of dopamine receptor colocalization in medium-spiny neurons, as well as more generally the diversity of dopamine actions in target areas. Longer-term changes in the modulatory actions of dopamine in the striatal complex could be due to plasticity in the presynaptic distribution of dopamine receptors on medium-spiny neuron varicosities

Dopamine neurons make glutamatergic synapses in vitro

Interactions between dopamine and glutamate play prominent roles in memory, addiction, and schizophrenia. Several lines of evidence have suggested that the ventral midbrain dopamine neurons that give rise to the major CNS dopaminergic projections may also be glutamatergic. To examine this possibility, we double immunostained ventral midbrain sections from rat and monkey for the dopamine-synthetic enzyme tyrosine hydroxylase and for glutamate; we found that most dopamine neurons immunostained for glutamate, both in rat and monkey. We then used postnatal cell culture to examine individual dopamine neurons. Again, most dopamine neurons immunostained for glutamate; they were also immunoreactive for phosphate-activated glutaminase, the major source of neurotransmitter glutamate. Inhibition of glutaminase reduced glutamate staining. In single-cell microculture, dopamine neurons gave rise to varicosities immunoreactive for both tyrosine hydroxylase and glutamate and others immunoreactive mainly for glutamate, which were found near the cell body. At the ultrastructural level, dopamine neurons formed occasional dopaminergic varicosities with symmetric synaptic specializations, but they more commonly formed nondopaminergic varicosities with asymmetric synaptic specializations. Stimulation of individual dopamine neurons evoked a fast glutamatergic autaptic EPSC that showed presynaptic inhibition caused by concomitant dopamine release. Thus, dopamine neurons may exert rapid synaptic actions via their glutamatergic synapses and slower modulatory actions via their dopaminergic synapses. Together with evidence for glutamate cotransmission in serotonergic raphe neurons and noradrenergic locus coeruleus neurons, the present results suggest that glutamatergic cotransmission may be the rule for central monoaminergic neurons

Hallux rigidus: A cross-sectional study to evaluate clinical parameters

Background: Hallux rigidus (HR) is a common condition with history and physical examination used to help evaluate pathology, grade clinical changes and to inform treatment. Method: A cross-sectional study was undertaken to evaluate the demographics of and clinical parameters encountered in HR. In 110 subjects (180 feet) aged 18–70 years (mean 52 years) a standardized history and physical examination was undertaken. Clinical parameters associated with HR were evaluated. The Foot Health Status Questionnaire (FHSQ) was used to measure health-related quality-of-life dimensions. Results: Seventy (64%) subjects had bilateral HR and 73 (66%)were female. Mean HR onsetwas 44 (14–68 years) years and median HR duration 6 years (1–33 years). A history of 1st MTPJ trauma presented in 22% of subjects; 74% of whom had unilateral HR. Eighty-four (47%) feet had pes planus based on a positive Foot Posture Index. A correlation between pes planus and 1st MTPJ pain was found (r = 0.84, p = 0.05). In 74% of feet, hallux abductus interphalangeus angle (HAI◦) was greater than normal (≤10◦). A correlation between HAI and reduced 1st MTPJ ROM was found (r = 0.92, p = 0.05). Second toe length was the same as the hallux in 111 feet (62%). A correlation between valgus hallucal rotation and 1st MTP joint pain in HR was found (r = .78, p = .05). A positive relationship was found between 2nd toe length and 1st MTPJ pain (p = 0.001 < 0.05). A correlation between hallucal interphalangeal joint (IPJ) hyperextension and 1st MTPJ pain was found (r = 0.78, p = 0.01). A positive relationship was found between lesser MTPJ pain and supination at propulsion (p < 0.001). There was no evidence of Achilles tendon contracture. The FHSQ results concur with clinical findings. Conclusions: HR was associated with female gender, bilateral involvement, older age groups, increased HAI◦, 2nd toe length similar to hallux, hallucal IPJ hyperextension, lesser MTP joint pain, flat foot and certain gait alterations. HR was not associated with Achilles tendon tightness or footwear. The content validity of clinical parameters of HR needs to be established by formal research prior to their inclusion in a classification of H

Environmental enrichment has no effect on the development of dopaminergic and GABAergic fibers during methylphenidate treatment of early traumatized gerbils

It is widely believed, that environmental factors play a crucial role in the etiology and outcome of psychiatric diseases such as Attention-Deficit/Hyperactivity Disorder (ADHD). A former study from our laboratory has shown that both methylphenidate (MP) and handling have a positive effect on the dopaminergic fiber density in the prefrontal cortex (PFC) of early traumatized gerbils (Meriones unguiculatus). The current study was performed to investigate if enriched environment during MP application has an additional influence on the dopaminergic and GABAergic fiber densities in the PFC and amygdala in this animal model

Distinct roles of presynaptic dopamine receptors in the differential modulation of the intrinsic synapses of medium-spiny neurons in the nucleus accumbens

Background: In both schizophrenia and addiction, pathological changes in dopamine release appear to induce alterations in the circuitry of the nucleus accumbens that affect coordinated thought and motivation. Dopamine acts principally on medium-spiny GABA neurons, which comprise 95% of accumbens neurons and give rise to the majority of inhibitory synapses in the nucleus. To examine dopamine action at single medium-spiny neuron synapses, we imaged Ca2+ levels in their presynaptic varicosities in the acute brain slice using two-photon microscopy. Results: Presynaptic Ca2+ rises were differentially modulated by dopamine. The D1/D5 selective agonist SKF81297 was exclusively facilitatory. The D2/D3 selective agonist quinpirole was predominantly inhibitory, but in some instances it was facilitatory. Studies using D2 and D3 receptor knockout mice revealed that quinpirole inhibition was either D2 or D3 receptor-mediated, while facilitation was mainly D3 receptor-mediated. Subsets of varicosities responded to both D1 and D2 agonists, showing that there was significant co-expression of these receptor families in single medium-spiny neurons. Neighboring presynaptic varicosities showed strikingly heterogeneous responses to DA agonists, suggesting that DA receptors may be differentially trafficked to individual varicosities on the same medium-spiny neuron axon. Conclusion: Dopamine receptors are present on the presynaptic varicosities of medium-spiny neurons, where they potently control GABAergic synaptic transmission. While there is significant coexpression of D1 and D2 family dopamine receptors in individual neurons, at the subcellular level, these receptors appear to be heterogeneously distributed, potentially explaining the considerable controversy regarding dopamine action in the striatum, and in particular the degree of dopamine receptor segregation on these neurons. Assuming that post-receptor signaling is restricted to the microdomains of medium-spiny neuron varicosities, the heterogeneous distribution of dopamine receptors on individual varicosities is likely to encode patterns in striatal information processing

Clinical and radiographic evaluation of Wilson osteotomy for hallux valgus

Thirty-two Wilson osteotomies (26 patients) were evaluated after a mean follow-up time of 20 months. According to the classification of Bonney and MacNab, there were 90% good and excellent results. There was no correlation between the patient's appraisal of the result and the clinical result based on objective, functional, and radiographic data. The occurrence of metatarsalgia or callosities did not correlate with shortening or angulation. If there was a tendency to recurrence, there was a greater loss of correction with a longer duration of follow-up. In addition, patients over 50 seemed to have a greater tendency to recurrence than younger patients.SCOPUS: ar.jinfo:eu-repo/semantics/publishe