Donald N. Franz

Dorsal Root Potentials and Ventral Root Reflexes Evoked by Nonmyelinated Fibers

Electrical stimulation of C-fibers in the cat superficial peroneal nerve, with the A-fibers either conducting or blocked by cold, evoked dorsal root potentials having the same polarity as those evoked by A-fibers. Ventral root reflexes evoked by A-fibers were facilitated by a pure C-volley in the same or another nerve, but dorsal root potentials evoked by A-fibers were reduced by isolated dorsal root potentials from C-fibers. In the absence of anesthetics, single C-volleys produced brisk and prolonged reflex discharges in ventral roots.

Evidence for inhibition of sympathetic preganglionic neurons by bulbospinal epinephrine pathways

Two selective inhibitors of central epinephrine synthesis, LY 134046 and SKF 64139 (20 mg/kg, i.v.), gradually but markedly enhanced descending intraspinal transmission to sympathetic preganglionic neurons in spinal cats. Enhancement increased linearly to maximum values of 200% and 250%, respectively, at 4.5-5.5 h. Spinal sympathetic reflexes were not enhanced by either drug. The results support the proposal that bulbospinal epinephrine pathways depress the excitability of sympathetic preganglionic neurons by activating postsynaptic alpha 2-adrenergic receptors.

Depression of sympathetic preganglionic neurons by clonidine: evidence for stimulation of 5-HT receptors.

In unanesthetized spinal cats, clonidine HCl (5-50 microgram/kg, i.v.) rapidly and markedly depressed excitatory transmission through two spinal pathways to sympathetic preganglionic neurons. Depression through either pathway was dose-dependent and persisted for more than 3 hr but could be rapidly antagonized at any stage by tolazoline HCl in a dose-ratio of about 1:100. The two spinal pathways were also depressed transiently by L-dopa and for prolonged periods by 5-HTP; both precursors were shown to act by releasing 5-HT from bulbospinal 5-HT terminals and their depressant effects were also antagonized by tolazoline. In the absence of 5-HT-induced depression, L-dopa only enhanced transmission through both pathways by inducing release of catecholamines from bulbospinal NE terminals. These results indicate that clonidine depresses sympathetic activity by stimulating inhibitory 5-HT receptors on sympathetic preganglionic neurons, a mechanism that adequately accounts for its central vasodepressor effect.

Enhancement of central norepinephrine and 5-hydroxytryptamine transmission by tricyclic antidepressants

The relative abilities of 1–3 mg/kg of desipramine (DES), imipramine (IMIP), amitriptyline (AMI), and chlorimipramine (CI-IMIP) to enhance synaptic transmission mediated by either NE or 5-HT were determined by testing their effects directly on NE or 5-HT transmission to sympathetic preganglionic neurons in unanesthetized, spinal cats. Effects on NE transmission were assessed on intraspinal excitatory pathwasy which utilize NE as a transmitter. Effects on 5-HT transmission were assessed on 5-HT-mediated depression of spinal sympathetic reflexes produced by 30 mg/kg of 5-HTP.Both DES and IMIP markedly enhanced transmission through the intraspinal excitatory NE pathways whereas AMI and CI-IMIP depressed transmission. However, both AMI and CI-IMIP modestly enhanced transmission in cats depleted of central 5-HT by pretreatment with parachlorophenylalanine. The relative potencies of the four drugs on excitatory NE transmission were DES>IMIP>AMI>CI-IMIP. Each of the four drugs also enhanced the 5-HTP-induced depression of spinal sympathetic reflexes, but their relative potencies on 5-HT transmission were just the opposite to those found on NE transmission. Therefore, all four drugs enhanced transmission by both NE and 5-HT, but their relative selectivities for the two transmitters differed markedly and were complementary. In general, the results support those of previous studies based on less direct methods for assessing inhibition of amine reuptake by tricyclic antidepressants.

Functional roles of monoaminergic pathways to sympathetic preganglionic neurons.

Despite considerable progress in mapping the central monoaminergic pathways to sympathetic preganglionic neurons in the spinal cord, the respective functional roles of these pathways have not been resolved. Evidence for both excitation and inhibition has been advanced for each of the three monoamines, serotonin, norepinephrine, and epinephrine. Our previous studies on spinal sympathetic pathways to sympathetic preganglionic neurons support the prevailing opinion that serotonin pathways are inhibitory but did not satisfactorily resolve the functional role of the norepinephrine pathways. However, more recent studies showing that intraspinally evoked sympathetic discharges were rapidly and markedly enhanced by phosphodiesterase inhibitors and that this effect was prevented by clonidine have led to formulation of a coherent hypothesis which accommodates much of the conflicting evidence regarding norepinephrine. In addition, evidence for the role of the epinephrine pathways has been obtained by using a selective inhibitor of epinephrine synthesis. The results of these recent studies complement our previous results and suggest that the excitability of sympathetic preganglionic neurons is regulated by excitatory norepinephrine pathways and inhibitory epinephrine pathways that activate or suppress adenylate cyclase to control intraneuronal levels of cyclic AMP.

Differential sensitivity of four central sympathetic pathways to depression by clonidine

The dose-response effects of clonidine HCl (2.5-200 micrograms/kg i.v.) on transmission through somatospinal reflex, viscerospinal reflex, intraspinal, and spinal-bulbospinal reflex pathways were determined in spinal or chloralose-anesthetized cats to assess principle sites of drug action. Evoked sympathetic discharges were recorded from upper thoracic preganglionic rami. Clonidine rapidly produced parallel, dose-dependent depression of transmission through each pathway which was rapidly antagonized by tolazoline or yohimbine. The two spinal reflex pathways were least sensitive to depression which was identical and was limited to 60%. In contrast, both descending pathways could be depressed completely. Although the spinal-bulbospinal reflex pathway was more sensitive to depression than its efferent, descending intraspinal pathway alone, analysis of the relative depression of transmission at spinal and at brainstem levels indicates that the spinal site is more sensitive to clonidine that it is generally considered to be.

Biochemical Evidence for Alteration of Neostriatal Dopaminergic Function by 5,7‐Dihydroxytryptamine

Abstract: Unilateral injection of 5,7‐dihydroxytryptamine (DHT) into the rat neostriatum markedly reduced not only striatal tryptophan hydroxylase (TPH) activity but also striatal tyrosine hydroxylase (TH) activity and dopamine (DA) concentration measured 10‐15 days later. The decrease in striatal TH activity was dose related over the range of 8‐32 pg of DHT; a dose of 16 pg reduced striatal TH activity to 40‐50% of control, DA concentration to 38% of control, and TPH activity to 5520% of control. Intrastriatal injection of 16 pg of DHT reduced TH activity in the ipsilateral substantia nigra to 51% of control. Pretreatment with amfonelic acid, a potent DA uptake inhibitor, significantly reduced the effect of DHT on striatal and nigral TH activity and striatal DA concentration without affecting the DHT‐induced decrease in striatal TPH activity. Desmethylimipramine (5 and 25 mglkg) had no effect on the DHT‐induced decrease in striatal TH activity. Striatal choline acetyltransferase and glutamic acid decarboxylase activities were not decreased by 16 pg of DHT. The results indicate that DHT can alter dopaminergic function in the rat neostriatum through a direct effect of the drug on DA neurons.

Contrasting Effects of Clonidine and 5-Hydroxytryptophan on Spinal Sympathetic Pathways

The effects of clonidine HCI were compared with those of 5-HTP on transmission through two spinal sympathetic pathways, segmental spinal reflex pathways and descending intraspinal excitatory pathways, in unanesthetized spinal cats. Evoked sympathetic discharges were recorded from upper thoracic preganglionic rami. Clonidine (5-50 microgram/kg) produced a parallel, dose-dependent depression of transmission through each pathway. The intraspinal pathway was five time more sensitive than the spinal reflex pathway (ED50s, 6 and 30 microgram/kg), and the spinal reflex pathway could not be depressed by more than 60% even by higher doses. In contrast, 5-HTP was more effective in depressing the spinal reflex than the intraspinal pathway (ED50s 32 and 44 mg/kg), and both pathways could be depressed completely. Small doses of tolazoline or yohimbine rapidly antagonized the effects of clonidine but not 5-HTP. Clonidine and 5-HTP appear to depress the excitability of sympathetic preganglionic neurons by activating alpha2- and 5-HT receptors, respectively. Each mechanism may contribute independently to regulation of the sympathetic outflow.

L-dopa-induced hypotension: depression of spinal sympathetic neurons by release of 5-hydroxytryptamine.

In studies designed to determine the respective functional roles of two bulbospinal monoaminergic pathways to sympathetic preganglionic neurons, both L-dopa and precursors of 5-HT depressed transmission through excitatory spinal reflex and bulbospinal sympathetic pathways. Transmission through spinal reflex pathways was secondarily enhanced after L-dopa. Pharmacological tests indicated mediation of these affects by monoamines. After antagonism or depletion of central 5-HT, L-dopa only enhanced transmission through both pathways. The results indicate that hypotension and other sympathoinhibitory effects of L-dopa are produced at the spinal level by release of 5-HT from terminals of bulbospinal 5-HT pathways that are inhibitory to sympathetic preganglionic neurons. The excitatory effects of L-dopa are apparently mediated by release of catecholamines from bulbospinal noradrenergic pathways that are excitatory.

Clonidine prevents enhancement of spinal sympathetic transmission by phosphodiesterase inhibitors

Preganglionic sympathetic discharges, evoked by cervical stimulation in spinal cats, were rapidly and markedly enhanced for 1-2 h by aminophylline or isobutylmethylxanthine. Clonidine depressed intraspinal transmission and prevented enhancement by the xanthines; alpha 2-receptor antagonists blocked the effect of clonidine and not only restored but also markedly prolonged the enhancement by the xanthines. The results suggest that the excitability of sympathetic preganglionic neurons is regulated by cyclic AMP through activation of different subtypes of adrenergic receptors that are either positively or negatively coupled to adenylate cyclase.