Sleep: Effects of d- and l-amphetamine in man and in rat

Almost identical results are reported in man and in rat for the effects of the amphetamine isomers on polygraphically recorded sleep. In both species, dextro-amphetamine produces a significantly greater increase in waking time. In both species, the two isomers have equal effects in reducing desynchronized sleep time. These findings combined with other recent data suggest that dopamine plays a direct role in wakefulness while norepinephrine is related inversely to amounts of desynchronized sleep.     

Amphetamine-induced taste aversion: a comparison of d- versus l-amphetamine

A comparison of the effects in rats of four dose levels of d- and 1-amphetamine (0.5, 1.0, 2.0 and 4.0 mg/kg) on development of a taste aversion to a 0.1% saccharin solution showed that d-amphetamine was approximately 4 times as potent as 1-amphetamine in inducing a taste aversion to saccharin. The aversion was obtained in both forced- and free-choice tests. A 2–4 fold differential in efficacy was found when the same dose levels of both amphetamine isomers were tested for their effects in reducing water intake. The approximately 4-fold greater effectiveness of the d-isomer suggested that the taste aversion may be mediated by a dopaminergic system. In addition, it was suggested that the taste aversion behavior represented a conditioned anorexic effect rather than being indicative of a noxious or aversive consequence of the amphetamine.     

Effect of d- and l-amphetamine on rat plasma prolactin levels

Although d- and l-amphetamine had no effect on plasma prolactin levels in untreated male rats, both d- and l-amphetamine reversed the increase in plasma prolactin levels produced by reserpine and 5-hydroxytryptophan (5-HTP). Only d-amphetamine significantly reversed the effect of alpha-methylparatyrosine (AMPT) on plasma prolactin levels. This reversal is probably due to a direct or indirect dopamine agonist effect of amphetamine, rather than to an effect on norepinephrine. This conclusion is based on the finding that apomorphine, a direct-acting dopamine agonist, reversed the reserpine-induced increase in prolactin secretion, while clonidine, a direct-acting alpha-adrenergic agonist, potentiated the reserpine-induced stimulation of prolactin secretion. The effect of d-amphetamine on the increase in plasma prolactin levels produced by reserpine, 5-HTP, or AMPT was always greater than that of the l-isomer, suggesting that the d-isomer has a more profound effect on dopaminerelease or neuronal reuptake, or both, than l-amphetamine. Chronic administration of d-amphetamine prior to reserpine did not inhibit the ability of d-amphetamine to reverse the reserpine-induced increase in plasma prolactin. Chronic administration of AMPT did not enhance the ability of d-amphetamine to reverse the AMPT-induced increase in plasma prolactin.     

Intravenous self-administration of d- and l-amphetamine by dog.

The relative potency of d- and l-amphetamine to maintain i.v. self-administration behavior was studied. 5 dogs were trained to work for response-contingent drug infusions until a stable drug intake per 4 hr daily session was achieved. Then 2 unit doses of d-amphetamine (0.05 and 0.10 mg/kg/infusion) and 3 unit doses of l-amphetamine (0.20, 0.40 and 0.80 mg/kg/infusion) were evaluated in a parallel line bioassay. Each combination of drug and unit dose was examined separately for 5 consecutive daily sessions. Order of treatment presentation was determined by a Latin square design. By comparing the unit doses of d- and l-amphetamine which yielded the same rate of self-administration it was found that 1 mg of the l-isomer is equivalent to 0.17 mg of the d-isomer.     

Drug level of d- and l-amphetamine during intravenous self-administration

Rats were allowed to self-administer dextro and levo isomers of amphetamine in doses of 0.25, 0.50, 0.75 and 1.0 mg/kg/injection for 6 h/day. Total body level of drug was calculated at the time of responding for each drug injection. Body level of amphetamine initially increased and then decreased (0–2 h), and thereafter remained relatively constant for the remainder of the experimental session (2–6 h). During 2–6 h of self-administration, calculated whole body levels of both d- and l-amphetamine remained relatively constant across injection doses. In another study, blood was removed several times during 2–6 h at the time of responding for drug injection. Again, no difference in blood level of ¹⁴C-amphetamine was found across a range of injection doses. Mean blood levels were 0.48 g/ml for l-amphetamine and 0.18 g/ml for d-amphetamine. Drug intake averaged 2.0 mg/kg/h for l-amphetamine and 0.79 mg/kg/h for d-amphetamine.     

Effects of d- and l-amphetamine on habituation and sensitization of the acoustic startle response in rats

In a series of 3 experiments the effects of 2, 4, 8, or 16 mg/kg d-amphetamine and 4, 8, 16, or 32 mg/kg l-amphetamine on acoustic startle amplitude in the rat were investigated. d-Amphetamine was 4–5 times as potent as l-amphetamine in augmenting startle amplitude. Startle potentiation was associated with vigorous stereotypies but the resultant cage movement could not account for the change in startle. Pretreatment with -methyl-p-tyrosine (100 mg/kg, 1 hr before) had only a slight depressant effect on startle but essentially eliminated augmentation of startle by either d-amphetamine (8 mg/kg) or l-amphetamine (32 mg/kg). d-Amphetamine did not have a direct effect on startle but instead enhanced sensitization produced by the startle stimuli without altering sensitization produced by background white noise or habituation. The results suggest that startle sensitization is enhanced by increased availability of catecholamines and, by virtue of the different potencies of the d- and l-isomers, that dopamine and norepinephrine may affect startle differently.     

Functional and biochemical effects of d- and l-amphetamine on central catecholamine neurons

Summary d- and l-amphetamine were tested for effect on turning of unilaterally striatotomized rats and effect on flexor reflex activity. Their capacity for eliciting hypermotility as well as their biochemical effectsin vivo in mice brains were also investigated. The two isomers had similar effects on flexor reflex activity and bio-chemically they were at low dose levels equipotent in releasing noradrenaline. d-amphetamine was more potent than l-amphetamine in eliciting hypermotility, turning and stereotypies. Some differences were also obtained in their respective biochemical effect on central dopaminergic mechanisms. It is concluded that the difference between d- and l-amphetamine in eliciting hypermotility may be due to their different effect on central dopamine neurons.     

Differential effects of d- and l-amphetamine on mouse-killing behavior in rats.

Muricidal behavior in rats was selectively antagonized by both the d- and the l-isomer of amphetamine. However, d-amphetamine was approximately 8 times as potent as l-amphetamine as an inhibitor of mouse killing. The results of this study suggest that amphetamine antagonizes muricidal behavior in rats primarily via noradrenergic mechanisms. In addition, these results, as well as those in previous reports, imply that agents which modify the level of activity at central noradrenergic receptors may significantly alter the mouse-killing response of rats.     

Effects of d- and l-amphetamine on dorsal and ventral hypothalamic self-stimulation in three inbred strains of mice.

The effects of intraperitoneal injections of increasing doses of d- and l-amphetamine on self-stimulation behaviour in dorsal and ventral hypothalamic areas, were studied in BALB/c Orl., DBA/2 Orl, and C57BL/6 Orl inbred mice. Both isomers improved and disrupted self-stimulation as a function of the doses injected. However, the improvements obtained with d-amphetamine were higher than those obtained with 1-amphetamine. In contrast the 1 isomer generally provoked the highest disruptions. In addition, the three strains presented various sensitivities to d-amphetamine, which improved self-stimulation first in BALB/c (0.25 and 0.50 mg/kg), then in DBA/2 (0.50 and 1.0 mg/kg) and finally in C57BL/6 (2.0, 4.0 and 8.0 mg/kg). The dorsal hypothalamic self-stimulation system presented a greater sensitivity to d-amphetamine than the ventral system; while the two reward systems reacted identically to 1-amphetamine. The differential effects observed are set into relationship with neurochemical data concerning the central catecholaminergic mechanisms.     

A comparative study of d- and l-amphetamine on the open field performance of rats

Behavioural effects in the Open Field test following the administration of d- and l-amphetamine were compared in rats. A significant difference was found between the effects of the two isomers on horizontal activity, d-amphetamine alone causing horizontal stereotypy. In both cases dose-response relations were curvilinear. On the other hand, although both isomers produced vertical stereotypy, the dose-response relations were generally monotonic increasing with no signifiacnt differences between isomers. These differential effects on behaviour have been explained on the basis of stereospecificity of adrenergic neurons for amphetamine. The results of the study are consistent with earlier hypotheses that the horizontal and vertical stereotyped behaviours of rats in the Open Field situation are functions of brain noradrenergic and dopaminergic systems, respectively.     

Differential actions of d- and l-amphetamine on the metabolism of 3H-norepinephrine in rat brain

Approximately equieffective doses of d- and l-amphetamine, using suppression of operant fixed-ratio responding for food reinforcement as the determinant of potency, were compared for their ability to alter the disposition of the major and minor metabolites of NE in push-pull perfusates from rat brain lateral ventricle. While 3 mg d-amphetamine/kg and 6 mg l-amphetamine/kg both increased total ³H and the relative amounts of the minor metabolites ³H-normetanephrine and ³-dihydroxymandelic acid, only l-amphetamine caused a significant increase in the major ³H-NE metabolite, methoxyhydroxyphenylethylene-glycol. The data is discussed in relation to the abilities of the isomers of amphetamine to stereoselectively interact with noradrenergic neurons at doses that produce similar effects upon operant behavior.     

Behavioural specific tolerance following chronic d- or l-amphetamine treatment: lack of involvement of p-hydroxynorephedrine

In a free-running Y-maze exploratory task mice tend to enter the least recently visited compartment (spontaneous alternation). Treatment with d- or l-amphetamine produced a dose-dependent increase in locomotor activity and resulted in animals successively exploring two compartments of the Y-maze only (perseveration). Whereas five daily injections of d-amphetamine (10 mg/kg) or /-amphetamine (45 mg/kg) did not result in tolerance to the locomotor-stimulating properties of the drug, a dose-dependent attenuation of the perseverative tendency was observed. Moreover, symmetrical cross-tolerance between the isomers was apparent. Since formation of p-hydroxynorephedrine is stereo-specific to the d-isomer, these data suggest that this possible false transmitter does not play a primary role in the development of the tolerance. Alternative explanations which may account for the behaviour-specific tolerance were considered.     

Does tolerance develop to low doses of d- and l-amphetamine on locomotor activity in rats?

An observational study of the behavioural effects of chronic regimens of d- and l-amphetamine was designed to investigate possible mechanisms underlying any parallel behavioural changes: (1) Accumulation of p-hydroxynorephedrine in noradrenergic nerve terminals; (2) Altered sensitivity of dopaminergic receptors. The study revealed that locomotor activity seen with low doses of both isomers (2.0 mg/kg d- and 6.0 mg/kg l-) decreased with chronic once daily treatment. However, this was accompanied by an increase in directed sniffing activity and the behaviour came to resemble that seen with higher doses of amphetamine (8.0 mg/kg d- and 16.0 mg/kg l-). Nonsignificant decreases in locomotor activity and increases in directed sniffing to apomorphine administration were observed during chronic amphetamine treatment. These findings suggest that (1) p-hydroxynorephedrine, a metabolite of d- but not 1- amphetamine, does not play an important role in these alterations in behaviour with chronic treatment and (2) the tolerance to amphetamine observed under these conditions is due to an increased, rather than decreased, sensitivity of the rats to amphetamine.     

Effects of indorenate on food intake: a comparison with fenfluramine and amphetamine

Indorenate (TR3369, 5-methoxytryptamine b-methylcarboxylate HCl) is a 5-HT₁-like receptor agonist with hypotensive activity. Here, we describe that indorenate also decreases food intake (ED₅₀ 26.1 mg/kg) without an appreciable effect in water intake (the estimated ED₅₀ for water was 589.8 mg/kg). The anorectic activity of indorenate was compared to the effects of amphetamine and other serotonin agonists; the effect of indorenate was smaller than those of the other compounds; however, the effect of indorenate was specific to food, whereas all the other drugs also produced significant decrements in water intake. The serotonin antagonists cinanserin, cyproheptadine, methergoline and methysergide effectively prevented the decrease in food intake produced by indorenate and fenfluramine. Haloperidol, a dopaminergic antagonist, was ineffective in preventing the effect of indorenate although it prevented the anorectic effect of amphetamine. The present results suggest the participation of serotoninergic, but not dopaminergic mechanisms, in the decrease in food intake produced by indorenate.     

Attenuation of the euphoriant and activating effects of d- and l-amphetamine by lithium carbonate treatment

Seven of nine depressed patients experienced a 4.3-fold increase in rated euphoria and activation following 30 mg d-amphetamine in a replicated dose, double blind study. d-Amphetamine was 2 to 2.3-fold more effective in producing activation, euphoria, and antidepressant effects than the same dose of l-amphetamine.Co-treatment with lithium carbonate produced a 60% (P<0.001) attenuation of the activation and euphoria responses to d-amphetamine. The responses to l-amphetamine were almost completely abolished by lithium. This study raises the possibility of lithium carbonate use as an adjunct in the treatment of amphetamine addiction.     

A comparison of the kinetics of d- and l-amphetamine in the brain of isolated and aggregated rats

The kinetics of d- and l-amphetamine were investigated in isolated and aggregated male rats. The i.p. injection of 15 mg/kg of d- or l-¹⁴C-amphetamine was followed by the determination of drug concentrations in the cerebral cortex, hypothalamus, medulla oblongata-pons, cerebellum, striatum, hippocampus, and the whole brain after solvent extraction.In isolated rats, the disappearance curves of the labelled amphetamines were monoexponential. The half-lives of d- and l-amphetamine in whole brain were 1.2±0.1 and 1.3±0.1 h, respectively. In whole brains of aggregated rats the disappearance curves were biexponential (half-lives: d-amphetamine, 0.9±0.1 and 2.3±0.2 h; l-amphetamine, 0.7±0.1 and 2.3±0.1 h).For the brain areas of isolated rats, the elimination curves of amphetamines were monoexponential and the half-lives of d- and l-amphetamine were almost identical. In aggregated rats certain differences were observed. d-Amphetamine was eliminated from the striatum and hippocampus as a biexponential function, and l-amphetamine elimination was biphasic only in the striatum. In other brain regions both d- and l-amphetamine were eliminated as a monoexponential function. The half-lives of d-amphetamine in different brain areas were, however, shorter than those of the l-isomer.The observed differences between d- and l-amphetamine kinetics in brain areas of isolated and aggregated rats may explain certain aspects of the pharmacological activities of these drugs.     

Morphine and self-stimulation: evidence for action on a common neural substrate

Recent studies have demonstrated that the self-stimulation phenomenon may provide a useful technique for investigating the rewarding properties of potentially addictive drugs such as morphine. The present study attempted to examine the nature of morphine's effects on self-stimulation by observing changes in rate-intensity functions following morphine administration. The results indicate that morphine markedly enhanced bar pressing for low intensity stimulation when the intensities were presented in an ascending sequence but morphine produced only slight changes in self-stimulation rates when a descending series was used. The failure of morphine to facilitate responding in the descending series suggests that adaptation of the self-stimulation system can block morphine's effects on this system. These findings appear to support the hypothesis that morphine affects the excitability of the neural system which mediates self-stimulation.     

Naloxone reduces fluid intake: Effects of water and food deprivation

Food and fluid deprived and nondeprived male rats showed 36% and 46% decreases, respectively, in sucrose consumption 15-min after injection with 2 mg/kg of naloxone in one hr tests. The magnitude of this decrease was not correlated with an index of naloxone's ability to produce a sickness, as measured by the conditioned taste aversion test. Tests with animals scheduled to drink water in a 15-min daily session showed naloxone had similar effects in reducing water intake in 23-hr and 47-hr water deprived rats. Morphine, when self-administered, produced an increase in water intake during 6-hr sessions. The data support the idea that naloxone disrupts a component of normal regulation of ingestion.