The role of nigral projections to the thalamus in drug-induced circling behaviour in the rat

Unilateral injection of 6-hydroxydopamine (6-OHDA) into the ascending nigrostriatal pathway caused contraversive circling to apomorphine and ipsiversive circling to amphetamine respectively. An electrolesion of the ventromedial thalamic nucleus on the same side as the 6-OHDA lesion reduced apomorphine-induced circling, but not that to amphetamine. An electrolesion of the ventromedial thalamic nucleus on the side opposite to the 6-OHDA lesion reduced amphetamine circling but not that to apomorphine. Bilateral electrolesions of the ventromedial thalamic nucleus reduced neither apomorphine- nor amphetamine-induced circling. Electrolytic lesions of the parafascicular thalamic nucleus did not reduce apomorphine- or amphetamine-induced circling in animals with a unilateral 6-OHDA lesion of the nigrostriatal pathway. Knife cuts rostral and dorsal to the substantia nigra did not attenuate circling induced by injection of muscimol into the substantia nigra. Circling due to activition of nigral output pathways can be mediated by descending nigro-reticular pathways.     

Enhancement of reserpine-elicited dopaminergic supersensitivity by repeated treatment with apomorphine and alpha-methyl-p-tyrosine.

Pretreatment of rats with reserpine 5 mg/Kg/day for 2 days elicits an enhanced stereotyped response following injection of apomorphine or amphetamine which persists through the 17th day. Since apomorphine acts as a direct postsynaptic receptor agonist in dopaminergic neurons this effect may represent a postsynaptic supersensitivity. In an attempt to prevent the development of supersensitivity apomorphine was administered repeatedly during the reserpinization period. Contrary to expectations a further enhancement of supersensitivity was seen when animals were challenged days later with apomorphine. This may be the result of presynaptic dopamine-synthesis-inhibition following apomorphine. Apomorphine-induced enhancement of reserpine supersensitivity was not seen in animals challenged with amphetamine. Alpha-methyl-para-tyrosine, but not scopolamine, repeatedly administered during the reserpinization mimics the effect of apomorphine, supporting the concept that the potentiating effects of apomorphine are mediated presynaptically. Furthermore it is suggested that the direct presynaptic action of apomorphine, and not that mediated via cholinergic interneurons, is operant in the development of enhanced supersensitivity.     

Apomorphine Does Not Alter Amphetamine-Induced Dopamine Release Measured in Striatal Dialysates

Amphetamine facilitates the release of dopamine from nerve terminals, but the mechanisms underlying this effect have not been fully delineated. The present experiments were designed to test the extent to which amphetamine-induced dopamine release is dependent on impulse flow and autoreceptor function in dopaminergic neurons. Rats were pretreated with a low dose of apomorphine (0.05 mg/kg) to inhibit dopamine neuronal activity, and the striatal dopaminergic response to amphetamine (0.5 mg/kg) was assessed by in vivo dialysis in freely moving animals. Consistent with previous results, apomorphine alone substantially decreased, whereas amphetamine increased, striatal dialysate dopamine concentrations. However, whereas apomorphine pretreatment decreased the locomotor response to amphetamine, the amphetamine-induced increase in dialysate dopamine was unaffected. These results indicate that amphetamine-facilitated dopamine release is independent of neuronal firing and autoreceptor regulation, consistent with the putative accelerative exchange-diffusion mechanism of amphetamine-induced dopamine release. Other possible mechanisms underlying the inhibitory effects of apomorphine on amphetamine locomotor activation are discussed.     

Drug-induced circling after unilateral 6-hydroxydopamine lesions of the nigro-striatal pathway is mediated via the midbrain periaqueductal grey and adjacent reticular formation (angular complex)

Unilateral 6-hydroxydopamine (6OHDA) lesions of the nigrostriatal pathway resulted in contraversive rotation to apomorphine and ipsiversive rotation to amphetamine. Electrolytic lesioning of the nucleus reticularis gigantocellularis or kainic acid lesions of the nucleus tegmenti pedunculopontis on the same side as the 6OHDA lesion did not reduce apomorphine- or amphetamine-induced circling. An electrolesion of the angular complex (periaqueductal grey and adjacent reticular formation) on the same side as the 6OHDA lesion reduced apomorphine-induced circling and increased amphetamine-induced circling. Bilateral electrolesions of the angular complex reduced both apomorphine- and amphetamine-induced rotation. The decrease in rotation was due to a loss of postural asymmetry while locomotor hyperactivity was maintained. A unilateral kainic acid lesion of the angular complex alone caused weak ipsiversive rotation which was enhanced by apomorphine and amphetamine. When a unilateral kainic acid lesion of the angular complex was made on the same side as a prior 6OHDA lesion, both apomorphine and amphetamine induced ipsiversive rotation. The area of the angular complex is critically involved in the mediation of drug-induced circling in unilaterally 6OHDA lesioned rats and in particular the postural component.     

Reverse tolerance to amphetamine of mice bearing unilateral striatal lesions: effect upon the circling response to apomorphine

When mice bearing unilateral lesions of the striatum receive weekly doses of amphetamine, their circling responses increase with successive doses, i.e., they become reverse tolerant (1). The present work was undertaken to ascertain whether presynaptic dopaminergic changes might underlie this phenomenon. This was approached by observing whether the response to a direct dopaminergic agent would be affected by the development of reverse tolerance to amphetamine. The circling responses of unilaterally electrothermally lesioned mice to apomorphine, 0.4 mg/kg s.c., increased significantly after four weekly 4 mg/kg s.c. doses of d-amphetamine. The responses to apomorphine of mice not exposed to amphetamine declined over the same interval. The conclusion drawn is that presynaptic effects are not likely to underlie the phenomenon of reverse tolerance.     

The effect of cyclo (Leu-Gly) on chemical denervation supersensitivity of dopamine receptors induced by intracerebroventricular injection of 6-hydroxydopamine in mice

Chemical denervation supersensitivity of postsynaptic dopamine receptors was induced in mice by intracerebroventricular injection of 6-hydroxydopamine. Fourteen days after the 6-hydroxydopamine injection, mice exhibited greater spontaneous locomotor activity and hypothermic response when challenged intraperitoneally with apomorphine. Whole brain levels of dopamine were reduced by 80%. Daily subcutaneous administration of cyclo (Leu-Gly) (50 μg/mouse/day) for 14 days inhibited the development of dopamine receptor supersensitivity induced by 6-hydroxydopamine as evidenced by the blockade of an apomorphine induced locomotor and hypothermic effect. Cyclo (Leu-Gly) did not alter the depletion of brain dopamine induced by 6-hydroxydopamine. These data suggest that cyclo (Leu-Gly) can block the development of dopamine receptor supersensitivity induced by 6-hydroxydopamine without protecting the neurons from dopamine depletion.     

Interaction between dopaminergic and cholinergic systems under conditions of deficiency of mesencephalo-striatal dopamine in rats

In chronic behavioral experiments on rats with a unilateral deficiency of mesencephalo-striatal dopamine, we studied the effect of the blocker of M-cholinoreceptors atropine on the rotational motor activity induced by systemic injections of dopamine agonists exerting direct (apomorphine) and indirect (amphetamine) actions. We found that premedication with atropine increased significantly the intensity of the rotational movements induced by both apomorphine and amphetamine. We conclude that the mesencephalo-striatal dopaminergic system exerts inhibitory effects on cholinergic neurons of the neostriatum. Neirofiziologiya/Neurophysiology, Vol. 37, Nos. 5/6, pp. 459–462, September–December, 2005.     

The potentiating effect of naloxone upon apomorphine-induced hyperthermia

Intravenous or intracerebroventricular pretreatment with the narcotic antagonist naloxone in rabbits significantly enhanced the magnitude of the hyperthermic response to the dopaminergic agonist apomorphine. Naloxone did not potentiate the hyperthermic action of either amphetamine or lysergic acid diethylamide. Apomorphine-in induced hyperthermia was sensitive to antagonism by haloperidol, cyproheptadine and p-chlorophenylalanine. However in rabbits pretreated with any of the above antagonists, administration of naloxone five minutes prior to apomorphine challenge restored the hyperthermic effect of apomorphine. Increasing the dose of the apomorphine challenge likewise surmounted the antagonism. It was concluded from these data that naloxone exerts a potentiating influence upon apomorphine drug effect in naive rabbits as well as rabbits pretreated with antagonists of apomorphine-induced hyperthermia.     

Apomorphine induced biting and fighting behaviour in reserpinized rats and an approach to the mechanism of action

Various patterns of aggressive behaviour have been induced by drugs. In the present study, the biting and the fighting responses were induced in rats by apomorphine alone, and reserpine plus apomorphine combination respectively, and these could be blocked completely by a dopamine receptor blocking agent. Dopamine, norepinephrine and clonidine given intraperitoneally or intraventricularly failed to induce these responses. Chemical agents known to increase the concentration of dopamine in the brain, induced the biting, but not the fighting response, whereas these behavioural patterns were more intense due to apomorphine in the rats pretreated with reserpine and dopamine or α-methyltyrosine and reserpine combinations. In amphetamine pretreated rats, apomorphine induced intense biting after 10 min and a few bouts of fighting after 30 min. It is suggested that (i) the receptors on which apomorphine acts may be called ‘Apomorphine Receptor’ rather than ‘Dopamine Receptor’, (ii) dopamine incompletely activates these receptors which are sensitised in the absence of catecholamines and induce a higher degree of stereotyped behaviour i.e. fighting, due to apomorphine.     

Decreased ability to cope with heat and cold linked to a dysfunction in a central dopaminergic pathway in elderly rats

Rectal and tail skin temperature was measured in lightly restrained rats aged 2 to 24 months after either drug injection or exposure to a hot or cold environment. At 18 months the rats were significantly less able to maintain their core temperature within the physiological range when subjected to a heat load, and this deficit was even more pronounced at 24 months, when an inability to maintain their core temperature in the cold was also evident. The hypothermic response of 24 month old rats to apomorphine and amphetamine was significantly less than that in 2 month old rats. In contrast, the elderly animals were more susceptible to the hypothermic effects of oxotremorine. These results suggest that a dysfunction in a dopaminergic pathway in the central nervous system can, at least in part, explain the inability of elderly rats to cope with heat stress.     

gamma-Endorphin and N alpha-acetyl-gamma-endorphin interfere with distinct dopaminergic systems in the nucleus accumbens via opioid and non-opioid mechanisms

Low doses (10 ng) of the dopamine agonist apomorphine induced hypolocomotion when injected into the nucleus accumbens of rats. This behavioral response was antagonized by local treatment with either the opioid peptide gamma-endorphin (gamma E) or the non-opioid peptide N alpha-acetyl-gamma-endorphin (Ac gamma E) in a dose of 100 pg. High doses of apomorphine (10 micrograms) r amphetamine (2 micrograms) injected into the nucleus accumbens resulted in hyperlocomotion. This response was blocked by pretreatment with gamma E but not with Ac gamma E. This effect of gamma E could be prevented by local treatment with naloxone. Neither peptides interfered with the apomorphine-induced stereotyped sniffing when the substances were injected into the nucleus caudatus. It is concluded that gamma E and Ac gamma E differentially interact with distinct dopaminergic systems in the nucleus accumbens of the rat brain via an opioid and a non-opioid mechanism, suggesting that the peptide fragments originating from pro-opiomelanocortin may be specifically implicated in the control of dopaminergic activity in this brain area.     

Reserpine-induced hypothermia and its reversal by dopamine agonists

Prior treatments with reserpine altered the thermic response of mice to subsequently administered apomorphine and amphetamine. Thus, normal mice exhibited hypo- and hyper-thermic responses to apomorphine and (+)-amphetamine, respectively but did not respond to (-)-amphetamine. These responses were each readily attenuated by haloperidol. Reserpinized mice, on the other hand, exhibited hyperthermic responses to all three agonists and these responses were not attenuated by haloperidol. In addition to its hypothermic action, reserpine also produced hypoactivity which was reversed by (+)-amphetamine. This reversal of hypoactivity was attenuated by haloperidol. These data suggest that reversal of reserpine-induced hypothermia by dopamine agonists results through activation of mechanisms which are separate from those normally associated with agonist-induced thermic responses. Reversal of hypoactivity, on the other hand, appears to be due to reactivation of those systems which normally regulate locomotor activity.     

Effect of cyclo(Leu-Gly) on the supersensitivity of dopamine receptors in spontaneously hypertensive rats

Spontaneously hypertensive rats exhibited dopamine receptor supersensitivity as evidenced by a greater hypothermic response to apomorphine in comparision with normotensive Wistar-Kyoto rats. A single injection of cyclo(Leu-Gly) given prior to apomorphine administration did no alter apomorphine induced hypothermia in either the normotensive or the hypertensive rats. Chronic administration of cyclo(Leu-Gly) for 7 days did not affect apomorphine response in normotensive rats, but blocked the exaggerated response to apomorphine in the hypertensive rats. These studies suggest that cyclo(Leu-Gly) interacts with the dopamine receptors and that the central dopamine receptors may play a role in the pathophysiology of hypertension.     

Studies on the mechanism of post-etorphine catalepsy. Modyfying effect of amphetamine, apomorphine and dihydroxy-phenylalanine (L-dopa) on etorphine-induced concentrations of dopamine and noradrenaline in the rat central nervous system

Studies on the mechanism of post-etorphine catalepsy. Modyfying of amphetamine, apomorphine and dihydroxyphenyl-alanine (L-DOPA) on etorphine-induced concentrations of dopamine and noradrenaline in the rat central nervous system. Acta Physiol. Pol., 1979, 30 (2): 279--287. During stereotypy induced with amphetamine, apomorphine and 1-dihydroxyphenylalanine (L-DOPA) increased concentrations of dopamine (DA) and noradrenaline (NA) were found in the motor centres of the central nervous system (CNS). In post-etorphine catalepsy the concentrations of DA and NA were also increased in the frontal cortex, striopallidum, pons and cerebellum and in the lumbosacral spinal cord. However, these stereotypy-inducing agents used in premedication of post-etorphine catalepsy delayed significantly its onset and reduced its duration.     

Dopaminergic modulation of visual responses in toads I. Apomorphine-induced effects on visually directed appetitive and consummatory prey-catching behavior

This study confirms for a phylogenetically basal terrestrial vertebrate that dopaminergic modulations interfere with the visually directed appetitive and consummatory feeding behaviors orienting and snapping, respectively. (1) In common toads Bufo bufo, intralymphatic administration of the dopamine D₂/D₁-receptor agonist apomorphine led to a dose-dependent facilitation of prey-snapping in response to moving objects. The snapping activity reached a maximum 15–35 min after apomorphine injection. (2) To changes in configurational stimulus features, the basic pattern of discrimination was maintained; however, the acuity of discrimination was reduced due to the high snapping response level. (3) The apomorphine-induced facilitation of snapping was accompanied by a suppression of prey-oriented lunging and turning. Toads snapped only if prey occurred frontally in the visual field at a relatively short distance. The snapping behavior was fixed in its form and stereotyped regarding its immediate release. (4) About 90 min after apomorphine administration, prey-oriented turning behavior was restored and displayed a facilitatory rebound. (5) In comparative experiments with the species B. marinus, both prey-oriented turning and snapping responses were suppressed by apomorphine in a dose-dependent manner. (6) After pre-treatment with the dopamine antagonist haloperidol, apomorphine showed no measurable effect on the visual release of prey orienting or snapping. (7) The results contribute to the sensorimotor and the motivation hypothesis of dopamine function proposed for higher vertebrates and stimulate a comparative discussion of anatomic homologies and functional analogies. Accepted: 10 July 1996     

Amphetamine-induced locomotion and gene expression are altered in BDNF heterozygous mice

Administration of amphetamine overstimulates medium spiny neurons (MSNs) by releasing dopamine and glutamate from afferents in the striatum. However, these afferents also release brain-derived neurotrophic factor (BDNF) that protects striatal MSNs from overstimulation. Intriguingly, all three neurochemicals increase opioid gene expression in MSNs. In contrast, striatal opioid expression is less in naive BDNF heterozygous (BDNF(+/-)) vs. wild-type (WT) mice. This study was designed to determine whether partial genetic depletion of BDNF influences the behavioral and molecular response to an acute amphetamine injection. An acute injection of amphetamine [5 mg/kg, intraperitoneal (i.p.)] or saline was administered to WT and BDNF(+/-) mice. WT and BDNF(+/-) mice exhibited similar locomotor activity during habituation, whereas BDNF(+/-) mice exhibited more prolonged locomotor activation during the third hour after injection of amphetamine. Three hours after amphetamine injection, there was an increase of preprodynorphin mRNA in the caudate putamen and nucleus accumbens (Acb) and dopamine D(3) receptor mRNA levels were increased in the Acb of BDNF(+/-) and WT mice. Striatal/cortical trkB and BDNF, and mesencephalic tyrosine hydroxylase mRNA levels were only increased in WT mice. These results indicate that BDNF modifies the locomotor responses of mice to acute amphetamine and differentially regulates amphetamine-induced gene expression.     

Conditioned response to apomorphine in nigro-striatal system-lesioned rats: the origin of undrugged rotational response

Development and time-course characteristics of Early rotational response (ER) to apomorphine in 6-hydroxydopamine-lesioned rats is explored. We show here how this ER can be considered a conditioned response that arises when the drug is repeatedly administered, according to a classical conditioning paradigm. In this way, the ER to apomorphine can be considered a non-pharmacological, conditioned, placebo response, the drug action being the unconditioned stimulus (UCS). In our model, the undrugged rotational response elicited by saline injections two weeks after drug treatment can be considered as the conditioned response (CR) to the conditioned stimulus, the CS being the environment associated with the drug treatment. This CR had not previously been identified during the drug treatment. Thus, we studied the acquisition of the ER, nonexistent after the first injection of apomorphine. Furthermore, we distinguish between this ER and the later, strictly pharmacological rotational response (LR) to apomorphine. Finally, we related this ER to the undrugged, paradoxical response to saline. In conclusion, we demonstrate the paradigm of pharmacological conditioning using this animal model of Parkinson's disease, supported by our own results and those of Silverman and Ho (1981).     

Amphetamine-induced aggression is enhanced in rats pre-treated with the anabolic androgenic steroid nandrolone decanoate

Aggression is one of the most commonly reported psychiatric side effects among anabolic-androgenic steroids (AAS) users. Furthermore, anecdotal stories say the aggression is even more profound when a current, or former, AAS-user consumes other drugs of abuse such as amphetamine and alcohol. In the present study, we examined the effect of amphetamine on defensive reactivity and defensive aggression in Sprague-Dawley rats after chronic AAS treatment (daily intramuscular [i.m.] injections with 15 mg/kg nandrolone decanoate [ND] for 14 days). Defensive reactions in rodents occur in response to a real threat, but also to perceived provocation, for example, elicited by innocuous stimuli as reaction towards the experimenter. The defensive reactivity and aggression test employed in this study evaluates each rat's reaction towards four different stimuli (I: approach of a rod; II: startle to an air puff; III: poking with a rod at the flanks, and IV: capturing with a gloved hand) at two different occasions. Immediately following the ND treatment period, no change in the defensive response was found. Nevertheless, an amphetamine challenge given 3 weeks after the last ND or vehicle injection induced a marked increased defensive aggressive response in the ND, compared to vehicle-pre-treated rats. Both ND- and vehicle-pre-treated rats receiving amphetamine were found to be more aggressive than comparable groups receiving a saline injection. It can be concluded that pre-treatment with ND modulates the behavioral response to amphetamine and induces long lasting changes in the behavioral response.     

Undrugged rotational response in nigro-striatal system-lesioned rats is related to the previous early response to apomorphine when repeatedly administered

Development and time-course characteristics of undrugged rotational response weeks or months after repeated apomorphine administration in 6-hydroxydopamine-lesioned rats were explored. In one series of experiments, all groups received several drug doses two-three weeks post-lesion and remained undrugged at different intervals from the last drug injection. Weeks or months later, they were injected with saline in the same environment where they previously had received apomorphine. In this way we studied acquisition, time-course and extinction of the rotational response after saline. Furthermore, we related this undrugged response which does not fully develop until two weeks after treatment, and which previously had not been related to a specific parameter of the rotational response to the drug, to a critical point of the time-course response to the drug, i.e., the early rotational response in the first minute after injection. This early response is a learning phenomenon based on the environmental cues where drug has been repeatedly administered. Finally, we state the concept of pharmacological conditioning using this animal model of Parkinson's disease, in agreement with our own results and the previous results of Silverman and Ho (1981).     

Effect of angiotensin II and saralasin on motor activity and the passive avoidance behavior of rats

One nmole of angiotensin II (ANG II) or saralasin, given intracerebroventricularly, failed to alter the motor activity of rats in open field. A combined injection of both peptides caused a significant decrease of the number of crossings and rearings. In the electromagnetic motimeter horizontal activity of animals was changed by neither of the peptides while the vertical activity was increased by ANG II. Again, a combined injection of saralasin and ANG II inhibited both horizontal and vertical activity. Stereotypies evoked by both apomorphine (2 mg/kg) and amphetamine (6.5 mg/kg), given intraperitoneally, were markedly intensified by ANG II and saralasin. A five-fold increase of the re-entry latencies in the passive avoidance situation was observed after pre-test administration of ANG II or saralasin but not the two in combination. These results suggest that ANG II and saralasin may improve processes related to learning and memory through an unspecific mechanism involving central dopamine systems.