Evidence for D1 dopamine receptor-mediated modulation of the synaptic transmission from motor axon collaterals to Renshaw cells in the rat spinal cord.

The possible modulatory role of D1 dopamine receptors on the excitability of lumbar spinal Renshaw cells was studied in anesthetized rats spinalized at T4 level. Burst responses elicited by single electrical shocks to ipsilateral ventral roots L6 (frequency 0.5 Hz, stimulus width 0.1 ms) and spontaneous activity were recorded extracellularly using conventional 3 M KCl filled glass micropipettes. The specific D1 agonist SKF 38393 (0.5-1 mg/kg i.v.) enhanced Renshaw cell burst responses by 20-60% (n = 7) and increased their spontaneous discharge rate (n = 3). This effect was clearly antagonized by the specific D1 antagonist SCH 23390 (1 mg/kg i.v.) although SCH 23390 proved ineffective per se. We conclude that SKF 38393 induced facilitation was due to activation of the specific D1 receptors which could be the functional counterpart of the presynaptic D2 receptors described earlier by us in the same synapse.

Supersensitivity of spinal dopaminergic receptors in rat after chronic haloperidol.

In order to examine the effect of chronic neuroleptics on spinal dopaminergic system, rats were treated with haloperidol (0.5 mg/kg IP) for 21 days and the monosynaptic mass reflex (MMR) as well as dopamine (DA) metabolism were investigated. MMR, recorded from ventral root L6 following supramaximal stimulation to ipsilateral dorsal root L6 in spinalized rats, were found to be unaffected following chronic haloperidol treatment when compared to control. Apomorphine (0.1 mg/kg IV) caused 10-20% depression of MMR in control animals which was augmented to 40-50% in chronically haloperidol-treated animals suggesting an upregulation of DA receptors in the spinal cord. DA content of lumbar region of the spinal cord was unaffected whereas its major metabolite, homovanillic acid, was significantly reduced in chronic haloperidol-treated animals. This decreased utilization of DA may compensate the upregulation of DA receptors to maintain the physiological homeostasis of the spinal dopaminergic system.

Presynaptic dopaminergic inhibition of the spinal reflex in rats.

Dopaminergic influence on spinal monosynaptic transmission was examined in rats. Monosynaptic mass reflex (MMR) was recorded from the ventral root L6 following supramaximal stimulation (0.2 Hz; 0.1 ms) to the ipsilateral dorsal root L6 in spinalized rat under pentobarbitone sodium (40 mg/kg, i.p.) anaesthesia. MMR was inhibited by intravenous administration of the dopaminergic agonist, apomorphine (50-200 ug/kg) in a dose-dependent manner. The attenuatory effect of apomorphine (200 ug/kg i.v.) on the reflex could be reversed by the dopaminergic antagonist haloperidol (0.5 mg/kg, i.v.). Under tetanic stimulation (200 Hz; 15s), the pretetanic relative inhibition induced by apomorphine (200 ug/kg, i.v.) was increased only for a short period immediately after the cessation of tetanic stimulation. The results indicate existence of presynaptic dopamine receptors on the afferent terminals converging on the motoneurone which may functionally modulate the spinal motor output.

Enhancement of reaching performance via self-speech in people with Parkinson's disease.

OBJECTIVE: To evaluate the effects of self-speech as an internal cue on reaching performance in people with Parkinson's disease. SUBJECTS: Eight people with Parkinson's disease were voluntarily recruited from the upstate New York community. DESIGN AND SETTING: This study was a repeated measure analysis of reaching performance under four randomized counterbalanced vocalization (speech) conditions that include a no vocalization control condition. The study was conducted in a university-based motion analysis laboratory. Participants performed a simple sequential daily reaching performance of reaching for a bottle, grasping and placing it on a simulated cabinet. Under counterbalanced randomized conditions, before each performance, participants either self-vocalized the word 'yaah' (self-cue), listened to the word 'yaah' vocalized by the experimenter (external cue), imagined vocalizing the word 'yaah', or just simply performed the task without any vocalization (control - no vocalization). MAIN MEASURES: The following dependent kinematic measures were extracted from the movement: total movement time, total movement unit, peak velocities and durations of reaching and placing segments. RESULTS: People with Parkinson's disease took significantly shorter time under self-vocalization conditions (2390.00 (326.63) ms) compared with the other three conditions including control - no vocalization conditions (no_voc, 3015.66 (340.83) ms; ext_voc, 2853.12 (376.44) ms; imaginary-voc, 3000.37 (320.54) ms). Under self-vocalization conditions the movements were also significantly smoother as evidenced by significantly lower numbers of movement units (3.43 (0.41)) compared with the other three conditions (no_voc, 4.47 (0.57); ext_voc, 4.16 (0.51); imaginary-voc, 4.16 (0.55)). CONCLUSIONS: Self-vocalization of a positive reinforcing word enabled people with Parkinson's disease to perform a daily upper extremity task faster and more smoothly.

Haloperidol on rat phrenic hemidiaphragm.

The butyrophenone neuroleptic haloperidol (10.65-85.2 microM) blocked the indirectly elicited twitch response of rat phrenic nerve diaphragm preparation. The depression was poorly reversible and was not mediated through dopamine receptors since neither dopamine nor apomorphine could alter the haloperidol blockade. Experiments on the isolated phrenic nerve indicated that the excitability of the nerve was blocked by haloperidol (42.6 microM) and that this blocking effect was minimized in presence of a high concentration of Ca2+ (5 mM) in the bathing fluid. Haloperidol (10.65-85.2 microM) also concentration-dependently inhibited acetylcholine (2.7 microM) contracture, without affecting the potassium chloride (0.5 M) and caffeine (15 mM) contracture. We conclude that haloperidol acts as a local anaesthetic on the motor nerve, probably by affecting calcium channels.

Dopaminergic influence on the excitability of antidromically activated Renshaw cells in the lumbar spinal cord of the rat.

The interaction between dopaminergic and cholinergic systems in the mammalian central nervous system, which is thought to have important implications in the pathophysiology of major extrapyramidal disorders, has never been adequately demonstrated in vivo. Renshaw cell burst responses to single electrical shocks to lumbar ventral roots in spinalized and decerebrated rats were studied. In this monosynaptic cholinergic pathway, apomorphine, a dopaminergic receptor agonist, inhibited whereas the D2-antagonist sulpiride facilitated the burst responses. The mutual antagonism of the two drugs and the depression coupled with the faster decay of post-tetanic potentiation of Renshaw cells by apomorphine demonstrate the involvement of presynaptic D2-receptors through which dopamine can modulate acetylcholine-mediated central synaptic transmission in vivo. The study also provides further evidence for the involvement of the spinal cord in extrapyramidal disorders.

Metoclopramide on rat phrenic hemidiaphragm.

The effect of metoclopramide on skeletal muscle and its neurotransmission was studied employing innervated and denervated rat diaphragm. Metoclopramide, at concentrations from 0.035 to 0.14 mM, inhibited the twitch contractions of rat diaphragm stimulated either directly or indirectly. Inhibition was greater in indirectly stimulated preparations, at a given concentration of metoclopramide, than in directly stimulated preparations. Inhibition of indirect twitch by metoclopramide could be intensified by raising the concentration of magnesium chloride, but was unaffected by physostigmine or d-tubocurarine. Metoclopramide also inhibited the submaximal contractures of denervated diaphragm elicited by potassium chloride and acetylcholine. In calcium-free physiological solution, metoclopramide inhibited the caffeine-induced contractures of denervated diaphragm as a function of its concentration. It is suggested that metoclopramide possesses a calcium antagonistic action in the rat diaphragm.