D2 dopamine receptor localization on striatonigral neurons.

Two major pharmacological classes of dopamine receptors exist in the central nervous system. These receptors have been designated as D1 or D2 based upon their differing pharmacology and influence on the cyclic AMP second messenger system. Different genes for the D1 and D2 dopamine receptors have been isolated and are found to be expressed in high abundance. Within the neostriatum, however the cellular distribution of the dopamine receptors is equivocal. Dopamine receptors are the targets for drugs used to treat neurological dysfunctions such as Parkinson's disease and schizophrenia, and thus knowledge of their specific cellular location is important for devising future therapeutic manipulations. Using retrograde labeling methods combined with immunofluorescence of various receptor amino acid sequences, this study has examined the postsynaptic distribution of striatal D2 dopamine receptors. We have found that the D2 dopamine receptor can be visualized on a minimum of 60% of the neurons projecting from the neostriatum to the substantia nigra. However, some 65% of all D2 receptor positive cells are represented by other intrinsic neurons of this basal ganglia nucleus.     

D1 and D2 dopamine receptors differentially regulate c-fos expression in striatonigral and striatopallidal neurons.

The expression of Fos, the product of the proto-oncogene c-fos, is thought to be a marker of neuronal activity. D1, but not D2, dopamine receptor agonists have previously been shown to increase Fos immunoreactivity in striatonigral neurons ipsilateral to a 6-hydroxydopamine lesion of the nigrostriatal pathway. In the present study, it was demonstrated that the D1 receptor agonist SKF 38393 rarely increased Fos in striatopallidal neurons of the 6-hydroxydopamine denervated striatum. Conversely, in the intact striatum, the D2 receptor antagonist haloperidol enhanced Fos expression predominantly in striatopallidal neurons labelled retrogradely from the globus pallidus or with an oligonucleotide probe complementary to mRNA encoding enkephalin. These results are consistent with studies suggesting that D1 receptors are located predominantly on striatonigral neurons and that D2 receptors reside principally on enkephalin-containing striatopallidal neurons. They also provide a neuroanatomical basis for neurochemical and neurophysiological observations indicating that dopamine facilitates the activity of striatonigral neurons but inhibits striatopallidal neurons. In another experiment the selective D2 receptor agonist quinpirole was found to increase Fos immunoreactivity in the globus pallidus ipsilateral to a 6-hydroxydopamine lesion. It is proposed that this may have been due to a D2 receptor-mediated inhibition of enkephalin and GABA release from striatopallidal terminals that in turn disinhibited the pallidal neurons. In a final series of experiments, brain microdialysis was used to determine the location of dopamine receptors regulating striatal Fos expression. Local application of the selective D1 receptor agonist CY 208-243 in the 6-hydroxydopamine-denervated striatum, or of haloperidol in the intact striatum via the dialysis probe increased Fos immunoreactivity in the immediate vicinity of the probe. Hence, the inductive effects of these systematically administered compounds on Fos expression in the striatum are mediated at least partly by local dopamine receptors in the striatum. Taken together, these results suggest that the differential regulation of striatonigral and striatopallidal activity by dopamine is mediated by the largely separate location of D1 and D2 receptors on these outputs.     

Interactions between dopamine and γ-aminobutyrate in the substantia nigra: Implications for the striatonigral output hypothesis

Experiments employing a rodent circling model were conducted to test the predictive capacity of the theory which states that striatonigral γ-aminobutyrate neurones transmit striatal information influencing the animal's locomotion and orientation. In agreement with this proposal, blocking nerve conduction in one substantia nigra with procaine, or nigral γ-aminobutyrate receptors with bicuculline administered stereotaxically, frequently forced rats to move ipsiversively to systemic apomorphine, as though the treatment had impaired striatonigral transmission on that side of the brain. Attempts to reverse the direction of apomorphine circling by stimulating γ-aminobutyrate receptors with muscimol, by facilitating the amino acid's action with flurazepam, or by increasing its synaptic concentration either with a breakdown inhibitor (ethanolamine O-sulphate or 4-amino-hex-5-enoic acid) or an uptake blocker (cis-1,3-aminocyclohexane carboxylic acid) in one nigra, proved unsuccessful. In fact, ethanolamine O-sulphate, flurazepam and muscimol all gave the appearance of hindering rather than enhancing the passage of striatal-derived motor information through the nigra. Broadly speaking, these drugs gave predictable behavioral responses from the ventromedial thalamus, suggesting they were acting in accordance with known mechanisms.The anomalous behaviour with ethanolamine O-sulphate may be attributed to its elevating γ-aminobutyrate levels in other brain areas, since similar ipsiversive rotations occurred if γ-aminobutyrate catabolism was prevented at a wide variety of extranigral sites. A simple explanation for the paradoxical ipsiversive behaviours produced by intranigral flurazepam or muscimol in combination with systemic or intracerebral injection of dopamine agonists, is that they act via presynaptic receptors to inhibit the release of endogenous γ-aminobutyrate and thereby impede striatonigral outflow ipsilaterally.     

Affinity of Noradrenaline and dopamine for neural alpha-receptors mediating negative feedback control of noradrenaline secretion in human vasoconstrictor nerves.

Isolated superfused field stimulated biopsy specimens of human peripheral arteries and veins, preincubated with 3H-( - )-NOradrenaline (NA) to label the neural stores of NA, were used to study the potency of dopamine (DA) and of NA as triggers of alpha-adrenoceptor mediated negative feedback control of sympathetic neurotransmitter secretion, evoked by stimulation with trains of 300 shocks at 1 Hz. In this preparation DA was found to be only slightly less potent than NA in depressing both the secretion of 3h-na, and the contractile response, evoked by nerve stimulation. DA depressed the contraction evoked by exogenous NA as well, but to a very much smaller extent. On the other hand, DA was a very weak agonist on the alpha receptors of the smooth muscle; nearly 1000 times higher concentrations of DA were required to mimick contractions evoked by exogenous NA. The results show that the neural alpha-receptor function involved in control of NA secretion differs considerably from the alpha-receptors of e.g. smooth muscle, with respect to sensitivity to DA. It seems possible that the observed depressing effect of DA on NA secretion may be of pharmacological and clinical interest; it may at least in part explain the vasodilating effect of DA infusions in man.     

Activation of dopamine D2 receptors decreases DARPP-32 phosphorylation in striatonigral and striatopallidal projection neurons via different mechanisms.

The vast majority of striatal neurons are GABAergic medium-sized spiny neurons. These cells receive glutamatergic input from the cortex, thalamus and limbic areas and dopaminergic input from the mesencephalon. Most relevant evidence indicates that dopamine D1 receptors are located on striatonigral projection neurons, and that adenosine A2A receptors and most dopamine D2 receptors are located on striatopallidal projection neurons (see, however, Refs I and 13). Here we have utilized regulation of the phosphorylation of dopamine- and cyclic AMP-regulated phosphoprotein of mol. wt 32,000 (DARPP-32) to study the possible interactions among nigrostriatal dopaminergic neurons and the two classes of dopaminoceptive target neurons. We show that, in striatal slices, the D2 receptor agonist, quinpirole, strongly inhibits the phosphorylation of DARPP-32 induced by either the D1 receptor agonist, SKF 81297, or the A2A receptor agonist, CGS 21680. Tetrodotoxin abolished the effect of quinpirole on the D1 agonist-induced but not the A2A agonist-induced phosphorylation of DARPP-32. These data indicate that: (i) adenosine A2A and dopamine D2 receptors interact within the same striatopallidal neurons, and (ii) D2 receptors present on the striatopallidal neurons modulate the effects of D1 receptors on the striatonigral neurons. Thus, a single neurotransmitter is capable of activating distinct classes of receptors on distinct populations of target neurons, which, in turn, interact with each other through intercellular communication.     

Muscarinic antagonists attenuate neurotensin-stimulated accumbens and striatal dopamine metabolism.

The effect of scopolamine and atropine upon the increase in extracellular 3,4-dihydroxyphenylacetic acid induced by central injection of neurotensin was examined in the nucleus accumbens and the striatum of anaesthetized rats using in vivo differential pulse voltammetry with carbon fibre electrodes. Scopolamine (1 and 3 mg/kg, i.p.) and atropine (20 micrograms, i.c.v.) did not alter the 3,4-dihydroxyphenylacetic acid level in the nucleus accumbens or the striatum, measured for 60 min after administration. Neurotensin (10 micrograms, i.c.v.) increased the 3,4-dihydroxyphenylacetic acid peak height in both regions. Pretreatment with scopolamine (1 mg/kg) 15 min before neurotensin injection blocked the increase in extracellular 3,4-dihydroxyphenylacetic acid in the striatum but not in the nucleus accumbens whilst scopolamine (3 mg/kg) partially attenuated the effect of neurotensin in the nucleus accumbens and blocked the increase in 3,4-dihydroxyphenylacetic acid in the striatum. Atropine partially attenuated the effect produced by neurotensin in the nucleus accumbens and blocked the increase in 3,4-dihydroxyphenylacetic acid induced by the peptide in the striatum. However, the increase in extracellular 3,4-dihydroxyphenylacetic acid induced by haloperidol (1 mg/kg, s.c.) was not altered by scopolamine (1 mg/kg) or atropine. Also, the increase in dopamine metabolism in the nucleus accumbens and the striatum after centrally injected haloperidol (10 micrograms, i.c.v.) was not altered by atropine (20 micrograms, i.c.v.). Together, the results demonstrate a functional interaction between muscarinic antagonists and neurotensin on in vivo dopamine metabolism in the nucleus accumbens and the striatum but with a greater effect in the latter region.     

脑电反馈控制系统的研制

本文介绍了基于IBM PC/XT计算机的新型双闭环脑电反馈控制系统的研制及在系统中抑制噪声干扰、使系统具有临床实用性的具体措施。该系统将脑电生物反馈和物理刺激的反馈控制加以结合,能有效地进行脑电反馈控制,并具备多种脑电指标的CRT显示和打印机输出。     

Short-loop feedback control of luteinizing hormone in the rabbit.

A radioimmunoassay for rabbit luteinizing hormone (rLH) in which rLH shows no significant cross-reaction with human LH (hLH) or human chorionic gonadotropin (HCG) was employed to test for the existence of a short-loop feedback for LH in the rabbit. Two weeks after castration, hCG and hLH were administered intravenously to rabbits, and the effects on circulating rLH were measured. Purified hLH (10 ng or 100 IU) produced significant depression of blood rLH within 30-60 min of intravenous injection. Saline administered to the same animals produced no changes in rLH. Injection of hCG (2,000 IU) under the same conditions also produced a significant fall in rLH. However, hCG administered to rabbits castrated 6 wk prior to study failed to suppress endogenous rLH. These data demonstrate, by direct radioimmunoassay quantification of blood hormones, the existence of a short-loop negative feedback for LH in the rabbit. They also suggest that the sensitivity of the short-loop changes with time after castration.     

Sensory feedback in artificial control of human mobility.

Artificial motor control systems may reduce the handicap of motor impaired individuals. Sensors are essential components in feedback control of these systems and in the information exchange with the user. The objective of this paper is to give an overview of the applications of sensors in the artificial control of human mobility. These applications may either require an accurate estimate of the measured physical quantities or can be based on learning the relation between sensory information and control actions by example. Actual use of sensors in artificial motor control systems requires that the user experienced complexity of the system is not increased, while improving the repeatable and flexible functioning of the system. Therefore, the sensors need to be integrated with the mechanical part of the artificial support system or implanted, the information exchange between sensor and controller should be wireless and automatic in-use calibration is a desired feature.     

Optimal feedback control and the long-latency stretch response

There has traditionally been a separation between voluntary control processes and the fast feedback responses which follow mechanical perturbations (i.e., stretch “reflexes”). However, a recent theory of motor control, based on optimal control, suggests that voluntary motor behavior involves the sophisticated manipulation of sensory feedback. We have recently proposed that one implication of this theory is that the long-latency stretch “reflex”, like voluntary control, should support a rich assortment of behaviors because these two processes are intimately linked through shared neural circuitry including primary motor cortex. In this review, we first describe the basic principles of optimal feedback control related to voluntary motor behavior. We then explore the functional properties of upper-limb stretch responses, with a focus on how the sophistication of the long-latency stretch response rivals voluntary control. And last, we describe the neural circuitry that underlies the long-latency stretch response and detail the evidence that primary motor cortex participates in sophisticated feedback responses to mechanical perturbations.     

Visual and haptic feedback in the control of force

The ability to control index finger and elbow flexion forces was measured while subjects used either haptic feedback or both haptic and visual feedback to control the forces exerted. Over a 120-s time period subjects were able to control the finger forces ranging from 2 to 6 N to within 1 N using only haptic feedback, and elbow flexion forces to within 4.5 N over a force range of 10-30 N. At the same force amplitude there was no significant difference between the two muscle groups in the precision or accuracy with which the force could be controlled, suggesting that there is not a proximal to distal gradient in force control as has been found for the control of limb movement and position.     

The role of testosterone in the feedback control of male FSH and LH secretion

Summary Intramuscular administration of 250 mg testosterone oenanthate per week over a period of 21 weeks treatment rapidly and sustainedly suppressed serum LH as well as FSH levels in seven normal males, while serum testosterone rose by a factor of approximately two. These together with other data provide increasing evidence for a feedback control of FSH secretion by gonadal steroids in the male in addition to the already described but as yet undefined tubular testicular factor.     

Depression and the role of genes involved in dopamine metabolism and signalling

Major depressive disorder (MDD) is a common psychiatric disorder and leading cause of disability worldwide. It is associated with increased mortality, especially from suicide. Heritability of MDD is estimated around 40%, suggesting that genotyping is a promising field for research into the development of MDD. According to the dopamine theory of affective disorders, a deficiency in dopaminergic neurotransmission may play a role in the major symptoms of MDD. Specific polymorphisms in genes that affect dopamine transmission could increase susceptibility to MDD. To determine the extent to which these genes influence vulnerability to MDD, we discuss genes for crucial steps in dopamine neurotransmission: synthesis, signalling and inactivation. The val158met polymorphism of the COMT gene exemplifies the lack of consensus in the literature: although it is one of the most reported polymorphisms that relates to MDD vulnerability, its role is not corroborated by meta-analysis. Gene–gene interactions and gene–environment interactions provide more explanatory potential than single gene associations. Two notable exceptions are the DRD4 and DAT gene: both have variable tandem repeat polymorphisms which may have a “single gene” influence on susceptibility to MDD.