Stimulation of 3H-norepinephrine release by trifluoperazine from rat pineal glands.

Trifluoperazine (5-200 microM) stimulated the release of 3H-NE from isolated whole pineal glands in a dose dependent manner. Trifluoperazine-induced release was not dependent on extracellular Ca++, whereas 60 mM K+-evoked release was attenuated in the presence of EGTA and zero Ca++ Krebs. 60 mM K+ and 50 microM trifluoperazine produced an additive effect on 3H-NE release. Clonidine (5 microM) significantly reduced trifluoperazine-induced release by approximately 50% in the presence of Ca++, and in its absence, clonidine significantly attenuated the trifluoperazine response by 42%. Thus trifluoperazine may be acting upon the alpha 2 receptor or intracellular stores of Ca++. These intracellular interactions remain for further study.

Regulation of cyclic GMP levels in nerve tissue.

In rat superior cervical ganglia the regulation of cyclic GMP (cGMP) formation does not involve muscarinic or adrenergic transmitters or receptors. Marked increases in cGMP content during preganglionic axonal stimulation by electric currents, elevated K+, or drugs that cause transmitter release are unaffected by muscarinic and adrenergic receptor blockade. However, the cGMP response does require Ca2+ and intact preganglionic axonal terminals. Two possibilities exist: either cGMP accumulates in the preganglionic nerves or a noncholinergic, nonadrenergic transmitter activates guanylate cyclase in postsynaptic structures. Sodium azide and nitroprusside cause cGMP accumulation in denervated ganglia, which indicates that postsynaptic structures are capable of forming cGMP. In pineal glands elevated [K+]o releases [3H]norepinephrine and causes cGMP accumulation, which suggests a relationship between the two responses and the possibility that cGMP accumulation is involved in autoinhibition of transmitter release. The finding that phentolamine, alpha-adrenergic receptor antagonists, prevent the cGMP response to K+ is compatible with this review. However, clonidine, an alpha-receptor agonist, depresses norepinephrine release but has no effect on pineal gland cGMP. Conversely, large increases in pineal gland cGMP produced by nitroprusside do not affect K+-evoked norepinephrine release. For these reasons it is not possible to relate cGMP to the auto-inhibition of [3H]norepinephrine release that is mediated by prejunctional alpha-adrenergic receptors.

The regulation of cyclic nucleotides in a sympathetic ganglion.

Preganglionic nerve terminal stimulation in rat superior cervical ganglia causes marked increases in the levels of cyclic nucleotides. Results are similar when preganglionic nerve stimulation is compared with elevated [K+]0 or 4-aminopyridine. Although intact nerve terminals and Ca2+ are required for the response to occur, pharmacological studies indicate that acetylcholine and adrenergic transmitters are not involved in the cyclic nucleotide response. It is suggested that cyclic nucleotide accumulation occurs in the nerve terminals or an unknown transmitter or substance participates in the postsynaptic accumulation of the cyclic nucleotides. Polypeptides tested thus far do not seem to be implicated. Interrelationships among phospholipid turnover, Ca2+-exchange and cyclic nucleotide accumulation in rat sympathetic ganglia are considered, but are difficult to establish.

Cyclic guanosine 3':5'-monophosphate accumulation and 45Ca-uptake by rat superior cervical ganglia during preganglionic stimulation.

Repetitive preganglionic nerve stimulation increases cyclic guanosine 3':5'-monophosphate (cGMP) content in rat superior cervical ganglia by a mechanism requiring Ca++ but resistant to blockade by cholinergic receptor antagonists. Similarly, 45Ca-uptake during prolonged preganglionic nerve stimulation is unaffected by hexamethonium or atropine. These findings indicate that nerve stimulation increases cGMP accumulation and 45Ca-uptake by a noncholinergic mechanism Substance P, met-enkephalin and luteinizing hormone-releasing factor have little or no effect on cGMP content. By contrast, bethanechol causes a 3-fold increase in cGMP content and postganglionic cell firing. Thus, as reported by others, muscarinic receptor activation increases ganglionic cGMP[. 4-Aminopyridine causes an increase in cGMP of resting ganglia that requires Ca++ and the nerve terminal is blocked by tetrodotoxin but unaffected by atropine or hexamethonium. Ouabain also increases ganglionic cGMP content by a process that requires Ca++ and the nerve terminals. Like preganglionic nerve stimulation, 4-aminopyridine and ouabain cause cGMP accumulation in the nerve terminals or in the ganglion cells as a consequence of releasing a noncholinergic transmitter. The uptake of Ca++ by ganglion cells is not an adequate stimulus for cGMP accumulation because the nicotinic receptor agonist dimethylphenylpiperazinium increases 45Ca-uptake but has no effect on cGMP formation in ganglia.

Activation of the nigrostriatal dopaminergic pathway by injection of cholera enterotoxin into the substantia nigra.

Twenty-four hours after unilateral injection of cholera enterotoxin into the rat substantia nigra there is an increase, in the striatum on the injected side, of basal adenylate cyclase activity, 3,4-dihydroxyphenylacetic acid, and 3-methoxy-4-hydroxyphenylacetic acid. Moreover, there is an increase of motor activity, and rats tend to circle contralateral to the side of the injection. Injection of cholera enterotoxin into brain nuclei may be a useful procedure for pharmacologically activating selected neuronal systems of brain and for studying the pharmacology of drugs that are suspected of interacting with these systems.

The mechanism of anti-muricidal effects of chlordiazepoxide.

Muricidal activity of rats is suppressed by chlordiazepoxide (CDP). At appropriate doses the CDP effect is reversed by repeated testing, by pretreatment with CDP, and by concomitant dosing with caffeine. This points to the general behavioral depressant action of CDP which undergoes tolerance as being primarily responsible for the anti-muricidal activity of CDP.