Comparative studies of various amphetamine analogues demonstrating different interactions with the metabolism of the catecholamines in the brain

Behavioral studies on the effects of amphetamine, methamphetamine, phenmetrazine, pipradrol, NCA and methylphenidate administered to rats pretreated with reserpine or αmethyltyrosine and additional biochemical analyses demonstrated that all six stimulants affected both brain dopamine and brain noradrenaline metabolism.     

Differential effects of reserpine and alpha-methyl-p-tyrosine on norepinephrine and dopamine induced behavioral activity

The locomotor activity of rats was monitored during the intraventricular infusion of either dopamine or norepinephrine after intraperitoneal pretreatment with saline, reserpine (5.0 mg/kg), or acute and chronic alpha-methyl-p-tyrosine (125 mg/kg-1 or 8 days). While the hyperactivity produced by norepinephrine was potentiated 24 h after reserpine, the response to dopamine was reduced by reserpine. Chronic, but not acute, alpha-methyl-p-tyrosine enhanced the effect of norepinephrine without altering the dopamine-induced activity. These results indicate: 1. dopamine-induced hyperactivity is due to its conversion to norepinephrine, and 2. prolonged depletion of central catecholamines may result in post-synaptic receptor supersensitivity.This research was supported by NIMH Grant No. MH18065 and No. MH23209.The authors gratefully acknowledge the surgical assistance of P. Josephine Branson and Edward Forney.This study is part of a dissertation submitted by the first author in partial fulfillment of the requirements for the degree of Doctor of Philosophy at the University of California, San Diego.     

On the cardiovascular action of dopamine in rats

Summary In rats anaesthetized with urethane the pressor effect of dopamine was not significantly altered by treatment with desipramine, which enhanced the action of noradrenaline on blood pressure and heart rate and abolished that of tyramine. Chemical sympathectomy with 6-hydroxydopamine in rats potentiated responses to noradrenaline and prevented the action of tyramine on blood pressure but did not significantly modify the pressor effects of dopamine. Furthermore, pretreatment with reserpine shifted the dose-response curves for dopamine and for tyramine on heart rate to the right. The dose-response curve for dopamine like that for noradrenaline on blood pressure was unaltered or shifted slightly to the left by reserpine. It is concluded that also in the rat an indirect, tyramine-like component contributes substantially to the cardiovascular action of dopamine.     

Diurnal rhythms in noradrenaline turnover and motility after reserpine and 6-hydroxydopamine

Experiments were performed in male Wistar rats synchronized by controlled conditions of light (0700--1900 hr) and of darkness (1900--0700 hr). Separately in each photo-period the effects of reserpine or 6-OHDA on the cardiac noradrenaline turnover. Whereas peripheral chemical sympathectomy did not greatly affect the diurnal rhythm in the motor activity were investigated. Initial depletion of the cardiac noradrenaline after acute application of either drug was significantly greater when injected at 2000 hr compared to 0800 hr. In both photo-periods the cardiac turnover of noradrenaline was increased after peripheral chemical sympathectomy with 6-OHDA as well as after amine depletion with reserpine. Inhibition of the protein synthesis had no effect, ganglionic blockade by chlorisondamine on the other hand abolished the rhythm in the motor activity, subacute treatment with reserpine differently affected motor activity in both photo-periods, depending on the time of drug application within 24 hr of a day. The results show that diurnal variations in the levels of neuronal and of motor activity are able to influence drug effects and have thus to be taken into account in animal studies.     

Dopamine and noradrenaline receptor stimulation: Reversal of reserpine-induced suppression of motor activity

The motor activity of reserpine treated mice was recorded after drug treatments causing stimulation of dopamine or noradrenaline receptors or both. The dopamine receptor stimulating agent apomorphine elicited an activation with stereotypies whereas the noradrenaline receptor stimulating agent clonidine was inefficient. Combined treatment with apomorphine and clonidine induced marked stimulation with jumping. Biochemically, clonidine did not significantly interfere with the metabolism of apomorphine. Administration of metatyrosine, which stimulates dopamine receptors, produced an activation with stereotypies. Administration of -methyldopa, which weakly stimulates dopamine receptors and strongly stimulates noradrenaline receptors, produced a slight activation. When metatyrosine was given in combination with clonidine, or when -methyldopa was given in combination with apomorphine, a substantial activation was found as after treatment with apomorphine plus clonidine. The results indicate that a dopamine receptor activity is of basic importance for motor activity and that changes in noradrenaline receptor activity can markedly affect the motor activity, qualitatively and quantitatively, provided that there is a certain dopamine receptor activity. It can also be concluded that the effects of drugs on the dopamine mechanisms in the corpus striatum and on the noradrenaline mechanisms in the spinal cord are of value in predicting behavioural effects.     

Mouse brain catecholamines, 5-hydroxytryptamine and the antinociceptive activity of pethidine.

The involvement of brain 5-hydroxytryptamine (5-HT), noradrenaline and dopamine in the antinociceptive activities of pethidine and morphine has been compared in the mouse. Differences have been shown in the activities of pethidine and morphine in mice treated with either 5-hydroxytryptophan or reserpine. No differences between the activities of pethidine and morphine were demonstrated in mice treated with either alpha-methyl-p-tyrosine, L-dopa or p-chlorophenylalanine. In reserpinised mice, pethidine's antinociceptive activity was either potentiated, unaffected or antagonised, dependent upon the reserpine dose schedule. Pethidine was shown to be able to raise brain 5-HT concentrations in reserpinised mice. This effect was also dependent upon the reserpine dose schedule used. Morphine, which was antagonised by all reserpine dose schedules, did not raise noradrenaline or dopamine in control or reserpinised mice. Although the reserpine schedule, which potentiated pethidine's antinociceptive activity, was the same as that in which pethidine had the most marked effects upon 5-HT, no definite connections between the two observations could be made. Naloxone abolished the antinociceptive activity of pethidine in reserpinised mice, but not the rise in 5-HT.     

On the mode of amine uptake by the Auerbach plexus of guinea pig small intestine

The uptake of the 2 erythro-isomers of metaraminol (l-MA, d-MA) by the Auerbach plexus of the guinea pig small intestine exhibits a Na⁺-dependency. Kinetic studies reveal that the effect of lowered [Na⁺] on l-MA uptake is to decrease V_maxwithout altering the apparent K_m, suggesting that a stoichiometric system is involved. The inhibitory effect of a high [K⁺] on l-MA uptake was examined kinetically and the results were similar to that seen upon lowering [Na⁺]. A comparison of the efficacy of desipramine to inhibit l-MA uptake at both 20.0 and 148.4 mM Na⁺ was undertaken and the drug was observed to be approximately 10 times less potent at the lowered [Na⁺]. The plot of d-MA uptake vs. [N⁺] resulted in a single linear function, whereas a similar plot for l-MA was biphasic. Reserpine, 18 hr after injection, had no effect on d-MA uptake but greatly decreased l-MA uptake in both normal conditions and low [Na⁺]. After reserpine, one phase of the l-MA uptake vs. [Na⁺] curve was abolished, resulting in a single linear function. The effect of reserpine on l-MA uptake is relatively short-lived as compared with the effect of the drug on endogenous catecholamine levels. Thus, 48 hr after injection, reserpine had no significant effect on l-MA uptake.     

Lithium prevention of amphetamine-induced ‘manic’ excitement and of reserpine-induced ‘depression’ in mice: Possible role of 2-phenylethylamine

Repeated treatment of mice with lithium chloride (45 mg/kg, i.p., daily for 8 days) reduced the jumping, fighting, stereotypies, and hyperactivity induced by d-amphetamine (5 mg/kg, i.p.). Lithium also reduced the hypoactivity observed 1–3 h after reserpine (0.75 mg/kg, i.p.). In biochemical studies we found that 8-day treatment with lithium markedly reduced (to 45% of control) the recovery from brain of labelled 2-phenylethylamine (PEA) following i.p. injection of labelled L-phenylalanine, while decreasing recovery from brain of labelled PEA following its i.p. injection to 63% of control. In saline-treated mice, d-amphetamine appeared to increase PEA synthesis and to accelerate its disposition, whereas reserpine enhanced PEA synthesis and reduced disposition; all of these effects were antagonized by lithium pretreatments. Since PEA appears to be one of the most powerful behavioral stimulants among endogenous neuroamines, and because its deaminated metabolites are behavioral depressants, such antagonism of brain PEA metabolism may significantly contribute to the prophylactic action of lithium against both manic and depressive behavior.     

Effects of reserpine on brain and liver glycogen levels after pretreatment with pargyline in isolated and aggregated mice

Summary 1.5 mg/kg reserpine given after pargyline is about the LD₅₀ in aggregated mice and induces no lethality in isolated mice. In the aggregated group the mice died after a state of exhaustion. Brain and liver glycogen did not change in the isolated group. In the aggregated group in the state of depression the liver glycogen decreased, the brain glycogen did not change. During the excitation the brain glycogen increased, the liver glycogen however did not show any alteration.     

The role of dopamine in the maintenance and breakdown of D1/D2 synergism

The neurochemical factors involved in the maintenance and breakdown of dopamine D₁/D₂ receptor synergism were investigated by giving rats various pharmacological treatments that diminish the ability of dopamine to interact with its D₁ and/or D₂ receptors. Following these treatments, rats were observed for the expression of stereotyped motor behavior in response to independent stimulation of D₁ or D₂ receptors. Independent D₂-mediated responses were observed: (a) 2 h after the last of three daily reserpine (1 mg/kg) injections, (b) 48 h after bilateral 6-hydroxydopamine (6-OHDA) lesions of the mesostriatal pathways, (c) 24 h after a concentrated 48-h regimen (one injection/6 h) of eticlopride (0.5 mg/kg) or eticlopride + SCH 23390 (0.5 mg each), and (d) 2 h after a concentrated 48-h regimen (one injection/6 h) of α-methyl-p-tyrosine (αMPT; 100 mg/kg), but not after control treatments or a concentrated regimen of SCH 23390 alone. By contrast, independent D₁-mediated responses were observed only after three daily reserpine injections or 48 h after bilateral 6-OHDA lesions. Independent D₁-mediated stereotypy was not observed under control conditions or following a concentrated 48-h regimen of (a) SCH 23390 or eticlopride (0.5 mg/kg each) alone or in combination, (b) a high dose of SCH 23390 (1.0 mg/kg), (c) αMPT (100 mg/kg), or (d) αMPT (100 mg/kg)+SCH 23390 (1.0 mg/kg). Reserpine, bilateral 6-OHDA, and αMPT treatments produced striatal dopamine depletions of 96%, 92%, and 71%, respectively. These data indicate that the breakdown in D₁/D₂ synergism consists of two components: (a) D₁ independence from the controlling influence of D₂ receptors, and (b) D₂ independence from the controlling influence of D₁ receptors. The interaction of synaptic DA with its D₂ receptors plays a major role in determining whether these receptors can function independently of D₁ receptors, whereas reduced DA-D₁ activity alone appears insufficient to elicit D₁ independence.