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Rats were treated chronically with a-methyl-p-tyrosine methyl-ester HCl (a-MT) twice daily for 0–14 days. At 1 h after the (last) a-MT injection, d-amphetamine sulphate was given and motor activity was measured in an ANIMEX activity meter for 4 h. Amphetamine-induced excitatory and stereotyped behaviour was scored according to a rating scale in a separate experiment. A single dose of a-MT markedly reduced the activity response after amphetamine. After 1–3 days of a-MT treatment, tolerance to its amphetamine-antagonistic affect started to develop, reaching a maximal degree after 7–14 days. The pattern of the amphetamine response, monophasic in control rats, became biphasic in the a-MT tolerant rats with an early (at 0–1 h) and a late (2–4 h) peak of motor activity. The late peak appeared within 3 days, while the early peak appeared after 7 days of a-MT treatment. The results on amphetamine-induced excitatory and stereotyped behaviour in essence agreed with the motor-activity data. It is concluded that tolerance to the amphetamine-antagonistic action of a-MT is not complete. Its rate of development varies in a complex pattern, indicating the presence of more than one mechanism of tolerance.

The selective 5-hydroxytryptamine (5-HT1A) receptor agonist 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT) induces a large number of pharmacological effects. In the present study we demonstrate that a novel 8-OH-DPAT analog, (S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin [(S)-UH-301], is able to antagonize completely the following (R)-8-OH-DPAT-induced effects in the rat: 1) reduction in brain 5-HT biosynthesis, measured as a decreased 5-hydroxytryptophan-accumulation after decarboxylase inhibition; 2) induction of the 5-HT1A behavior (flat body posture, forepaw treading and hindlimb abduction) in reserpine-pretreated animals; 3) reduction of body temperature; 4) inhibition of the cage-leaving response; and 5) reduction of 5-hydroxytryptophan- and quipazine-induced wet dog shakes. In addition, (S)-UH-301 reverses the 5-HT-induced inhibition of the forskolin stimulated cyclic AMP production in rat hippocampus without producing any effects per se in this assay. It is shown that high doses of (S)-UH-301 decrease rat brain biosynthesis of dopamine. These and previous data indicate that (S)-UH-301 also is a weakly potent dopamine-receptor agonist, but with a lower affinity for D2 as compared to 5-HT1A receptors. Thus, the data suggest that (S)-UH-301 is a 5-HT1A-receptor antagonist without intrinsic activity. Therefore, it is likely that (S)-UH-301 will become a valuable pharmacological tool in future 5-HT research.

The time-course and the dose-response relationship for the antagonistic effect of alpha-methyl-p-tyrosine methyl ester HCl H 44/68 (a-MT) on damphetamine (10.6 µmoles/kg) induced increase in motor activity was studied. The effect of amphetamine was gradually reduced from 30–60 min to a minimum at 1–4 h after the administration of 0.407 mmoles/kg of a-MT. From (4-) 8 h the amphetamine response started to reappear and the original response was restored completely at 16 h after a-MT. The dose-response curve showed, that between 0.051–0.41 mmoles/kg of a-MT, given 1 h before amphetamine, there was a gradual reduction of the amphetamine response; doses above 0.41 mmoles/kg did not cause any further effect.

Male Sprague-Dawley rats were given 0.407 mmoles/kg of D,l-a-methyl-p-tyrosine methylester HCl (H44/68; a-MT) at eleven time-points between 0–24h, or 8 doses between 0.013–1.628 mmoles/kg of the drug at 1 h before i. v. injection of 160 µCi tyrosine-2,6-3H. The rats were killed 15 min after tyrosine-3H and brain a-MT, tyrosine and catecholamines (endogenous and labelled), and plasma a-MT and tyrosine (-3H) were chromatographically isolated before being assayed spectrophotofluorimetrically (endogenous) or by liquid scintillation methods (labelled compounds).

The centrally active muscarinic agonist, oxotremorine, elicited an up to 2-fold dose-dependent (0.25-1.5 mg/kg) increase in the activity of tyrosine hydroxylase (TH) in the rat nucleus locus coeruleus (LC) and adrenal medulla. The response occurred in LC after 24 to 48 hours and in adrenal medulla by 4 to 8 hours, peaked in LC at 72 hours and adrenal medulla at 16 to 24 hours and persisted up to 2 weeks in both tissues. In brain the effect appeared confined to cell bodies of noradrenergic neurons. The activity of dopamine beta-hydroxylase increased in adrenal medulla (40%) but not in brain. Immunotitration with anti-TH serum demonstrated that the increase of TH activity in LC is due to increased catalytic activity (activation), whereas in adrenal medulla it is due to a transynaptically mediated accumulation of enzyme protein (induction). Physostigmine (1.0 mg/kg), pilocarpine (25-50 mg/kg) and nicotine (10 mg/kg) increased TH activity in LC and adrenal. We conclude that stimulation of central cholinergic receptors of the muscarinic type results in a delayed and protracted activaiton of TH but not of dopamine beta-hydroxylase in cell bodies of central noradrenergic neurons, and reflexly, to transynaptic induction of TH and dopamine beta-hydroxylase in the adrenal medulla.