American ginseng extract reduces scopolamine-induced amnesia in a spatial learning task.

OBJECTIVE: To determine if HT-1001, an extract of American ginseng, affects scopolamine-induced memory and performance deficits in a spatial learning task, alters brain concentrations of aminergic neurotransmitters, and alters choline uptake in synaptosome preparations. DESIGN: Animal study. ANIMALS: 48 Sprague Dawley rats. INTERVENTIONS: Long-term oral administration of a test material or control solution. Intraperitoneal administration of scopolamine (2 mg/kg) 30 minutes before testing. OUTCOME MEASURES: Performance on Morris water maze task, choline uptake, aminergic neurotransmitter analysis, in vitro monoamine oxidase analysis (of compounds). RESULTS: HT-1001 protected against scopolamine-induced amnesia and increased choline uptake in synaptosomal preparations. HT-1001 did not alter brain concentrations of norepinephrine, dopamine, 5-HT (serotonin), 3,4-dihydroxyphenylacetic acid or 5-hydroxyindoleactic acid. HT-1001 had a very weak ability to inhibit monoamine oxidase activity in vitro. CONCLUSIONS: HT-1001 demonstrates a capacity to protect against scopolamine-induced memory deficits.

Effects of the antidepressant/antipanic drug phenelzine on GABA concentrations and GABA-transaminase activity in rat brain.

The effects of long-term (28-day) administration of several antidepressant/antipanic drugs [imipramine, desipramine, tranylcypromine and phenelzine (PLZ)] on gamma-aminobutyric acid-tranaminase (GABA-T) activity and GABA levels were investigated in rat frontal cortex. Of the drugs investigated, only PLZ inhibited GABA-T and elevated GABA levels. Additional short-term experiments were conducted with PLZ, and they demonstrated a dose-dependent inhibition of GABA-T in rat whole brain. Time-response studies on inhibition of GABA-T in whole brain demonstrated that at a dose of PLZ of 15 mg/kg i.p. inhibition of GABA-T remained relatively constant from 1 to 8 hr and that the enzyme was still inhibited by 23% at 24 hr after PLZ administration.

Differential effects of antidepressants on GABAB and beta-adrenergic receptors in rat cerebral cortex.

The effects of chronic administration of antidepressant drugs on beta-adrenergic and gamma-amino-butyric acid (GABA)B receptors have been assessed with radioligand binding. Tricyclics [imipramine (IMI), 30 mg/kg/day, and desmethylimipramine (DMI), 10 mg/kg day] or monoamine oxidase inhibitors [(+/-)-tranylcypromine (TCP), 1 mg/kg/day, and phenelzine (PLZ), 10 mg/kg/day] were administered to male Sprague-Dawley rats by constant infusion via Alzet 2ML4 osmotic minipumps for 28 days. Pumps were implanted s.c. in the interscapular region. On day 28 the animals were killed and their brains removed; [3H]GABA binding to GABAB receptors was measured in frontal cortex and the remaining cortical tissue was used to measure [3H]dihydroalprenolol ([3H]DHA) binding to beta-adrenoceptors. All drugs tested induced a significant decrease in density (Bmax) of [3H]DHA binding, although no significant changes in affinity (Kd) were observed. [3H]GABA binding was not altered significantly by chronic antidepressant treatment. TCP-treated animals showed a tendency towards increased [3H]-GABA binding, but the differences did not reach statistical significance. No effects on Kd were observed. These data do not support the proposal that an increase in the total population of cortical GABAB receptors is a common effect of chronic antidepressant treatment.

Depletion of striatal beta-phenylethylamine following dopamine but not 5-HT denervation.

The effects of lesions of the substantia nigra (electrolytic 2 mA 10 sec, or 6-OHDA 2 or 8 micrograms) and of the midbrain raphé nuclei (electrolytic 2 X 1.0 mA 10 sec) at 7 days postlesion on striatal levels of beta-phenylethylamine, DA, DOPAC, HVA, 5-HT and 5-HIAA and on hypothalamic levels of beta-phenylethylamine, DA, NA, 5-HT and 5-HIAA were investigated. In the presence of deprenyl (2 mg kg-1 2 hr SC), both electrolytic and 6-OHDA-induced dopamine-depleting lesions of the nigra but not 5-HT-depleting lesions of the raphé nuclei resulted in a marked decrease in the accumulation of beta-phenylethylamine. The marked reduction in accumulation of striatal beta-phenylethylamine in response to lesions of the substantia nigra indicates that the intraneuronal compartment is a major site of striatal beta-phenylethylamine synthesis. An equivalent decrease (approximately 40%) in the accumulation of 5-HT was observed following electrolytic lesions of the substantia nigra or raphé nuclei after administration of L-5-HTP (200 mg kg-1 hr IP). As L-5-HTP at the dose employed in this study is taken up non-selectively by both DA- and 5-HT-containing neurones the loss of L-AAD following nigral and raphé lesions was apparently equivalent. These results indicate that depletion of beta-phenylethylamine may not be simply attributable to a general loss of L-AAD following lesions of monoamine-containing neurones and suggest either co-localisation of beta-phenylethylamine and DA or the existence of distinct beta-phenylethylamine-containing neurones.

Rat hypothalamic noradrenaline levels following midbrain raphé nuclei lesions.

Electrolytic lesions of the median and dorsal raphé nuclei resulted in statistically significant reductions in rat hypothalamic noradrenaline which were observed 1 or 2 days after lesioning, while no changes were observed 7 or 14 days after lesioning. The short term (1-2 days) raphé nuclei lesions produced no changes in hypothalamic 5-hydroxytryptamine or a small reduction in 5-hydroxyindole acetic acid while the expected marked reductions were observed after 7 days. The reduction in hypothalamic noradrenaline observed after short term raphé nuclei lesions suggests the existence of a positive feedback loop between 5-hydroxytryptamine neurons and noradrenaline terminals in the hypothalamus.

Behavioral and neurochemical effects of deprenyl and beta-phenylethylamine in Wistar rats.

The effects of 1-deprenyl (1-16 mg kg-1, 3.5 hr) on brain levels of endogenous beta-phenylethylamine were assessed in animals under three conditions: (1) experience of lateral hypothalamic self-stimulation; (2) electrode implantation but no self-stimulation experience; (3) no surgical intervention. The increase in striatal levels of beta-phenylethylamine with 1-deprenyl treatment was attenuated in the self-stimulation condition relative to conditions (2) and (3). This differential effect of 1-deprenyl was not observed at the level of the hypothalamus. Administration of 1-deprenyl did not affect self-stimulation behavior. Equivalent analysis of beta-phenylethylamine levels was carried out using animals injected with beta-phenylethylamine (0.5-4 mg kg-1, 0.5 hr 1P and 1-deprenyl (4 mg kg-1, 3.5 hr sc). Injected beta-phenylethylamine with deprenyl pretreatment increased self-stimulation rates; concomitant striatal levels of approximately 190 ng g-1 of beta-phenylethylamine were observed and were associated with increased brainstem 5-HIAA but no change in striatal HVA, indicating possible involvement of 5-HT in this response to beta-phenylethylamine. It is proposed that experience of electrical hypothalamic stimulation may alter endogenous striatal beta-phenylethylamine metabolism, possibly via an alteration of mechanisms governing synthesis and/or catabolism.

Tryptamine concentrations in areas of 5-hydroxytryptamine terminal innervation after electrolytic lesions of midbrain raphe nuclei.

The possible existence of tryptamine-containing neurons originating in the midbrain raphe is suggested by several reports of tryptamine-mediated responses to electrical stimulation of the raphe nuclei. To assess this hypothesis, we have investigated the effects of electrolytic lesions of the median and dorsal raphe nuclei on striatal, hypothalamic, and hippocampal concentrations of tryptamine, 5-hydroxytryptamine (5-HT), and 5-hydroxyindoleacetic acid. In addition, the rat striatal tryptophan concentrations were also determined. No changes in the concentrations of tryptamine were observed at 1 or 2 weeks after lesioning the dorsal and median raphe nuclei, at which time the other 5-hydroxyindoles were markedly reduced; furthermore, no reductions were observed in tryptamine concentrations in the striatum, hypothalamus, or hippocampus of rats pretreated with a monoamine oxidase inhibitor. The only change observed in these rats was a limited increase in striatal tryptamine and tryptophan observed at 1 day after lesioning. The results indicate that tryptamine concentration is independent of the integrity of 5-HT-containing neurons of the midbrain raphe nuclei. Furthermore, if tryptamine-containing neurons that have terminal projections to the striatum, hypothalamus, and hippocampus exist, their cell bodies are located in regions outside the dorsal and median raphe nuclei. Another possibility could be that tryptamine is located in glial cells.

Disruptive effects of lateral hypothalamic stimulation on the lick-interrupt cycle in rats.

Consummatory licking at a water spout was compared with licking at a dry spout maintained by electrical hypothalamic stimulation in the same rats. Both forms of licking, recorded photoelectrically, were maintained on a fixed ratio 8 schedule. Duration of reinforcement delivery was equated [300 ms]. A computer analysis of the temporal distribution of licks in each 1024 ms period from onset of reinforcement revealed that lateral hypothalamic stimulation decreased the occurrence of licking and disrupted the normally synchronous pattern of this behaviour. An analysis of the effects of delivering lateral hypothalamic stimulation contingent on water-maintained licking revealed that this effect of stimulation was clearly current-dependent. It is proposed that differences in licking rates maintained by water and by electrical hypothalamic stimulation, respectively, are due to response interference in the latter case. This interference effect is also proposed to be a major factor underlying higher reward thresholds for self-stimulation when licking is the operant response.

beta-Phenylethylamine and reinforcement.

beta-Phenylethylamine is an endogenous brain amine which has been characterised as an endogenous amphetamine. The rewarding properties of the structurally similar drug amphetamine in humans and other species indicate a possible role for endogenous beta-phenylethylamine in neural processes underlying reward or reinforcement. Evidence for reinforcing properties of beta-phenylethylamine in the drug self-administration and place preference paradigms is briefly reviewed. The possibility that endogenous beta-phenylethylamine may be involved in reinforcement processes is also considered in relation to studies of intracranial self-stimulation. The contrasting aversive stimulus properties of beta-phenylethylamine and of amphetamine are described.