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The response of non-dopamine neurons in substantia nigra and ventral tegmental area to amphetamine and apomorphine during hypermotility: the striatal influence.

The effects of haloperidol pretreatment in striatum on the motor response, and on concurrently recorded unit responses of nondopamine (DA) neurons in substantia nigra (SN) and ventral tegmental area (VTA) to systemic amphetamine and apomorphine, were investigated with the objective of determining the role of the striatum in the output of putative DA output neurons. Unit and motor activity were recorded in the male rat, chronically implanted with 9 electrodes in SN and VTA and with two cannulae for bilateral injections into striatum. The recording electrodes were 3 bundles of 3 wires, each wire in the bundle of a different length, but all 3 aimed at SN, pars reticulata, or VTA. In each recording session, unit activity was derived from 7 wires while gross motor activity was recorded with the open-ended wire technique. The subjects were tested under two conditions. In the first, the vehicle was injected bilaterally into striatum 90 min before one of the DA agonists was injected by the intraperitoneal route. In the second, the DA antagonist haloperidol was injected bilaterally into striatum before the systemic treatment with the DA agonist. In subjects which received injections of the vehicle into striatum, amphetamine induced a large motor response, and concurrently, a large increase in the rate of discharge of a portion of the identified non-DA neurons in SN and VTA. In subjects which received injections of haloperidol into striatum, amphetamine induced a smaller behavioral response, a smaller increase in the rate of discharge of these neurons in SN but not in VTA where the increase was of the same magnitude as controls. In control subjects, apomorphine induced an increase in motor activity and concurrently, an increase in the rate of firing of the identified non-DA neurons in SN and VTA. But the increases were of somewhate smaller magnitude and much shorter duration than the increases induced by amphetamine. In subjects which had been pretreated with haloperidol in striatum, apomorphine induced an increase in motor activity that was of the same magnitude as the insion that the striatum has the capacity to influence the output of non-DA neurons only in SN but also in VTA, indicating that, if there is a specialization of function, it is only relative.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗

Time-dependent changes in the sensitivity of dopamine neurons to low doses of apomorphine following amphetamine infusion.

Changes in dopamine autoregulatory mechanisms following a chronic infusion of amphetamine were studied. Rats were infused with D-amphetamine (4.8 mg/day) for 7 days by osmotic minipumps, and were studied at various times after withdrawal. In contrast to no changes in the spontaneous firing rate of single dopamine cells, the potency of apomorphine in the substantia nigra was markedly decreased soon after withdrawal, followed by an increase 7 days later. The ventral tegmental area showed no changes in either spontaneous firing rate or sensitivity to apomorphine following a 7-day withdrawal. Moderate decreases in striatal and tubercle dopamine concentrations were not accompanied by any significant decrease in basal dopamine synthesis. Under intact impulse-flow, the sensitivity of terminal dopamine synthesis to low doses of apomorphine was decreased immediately following withdrawal; by Day 7 supersensitivity was observed. Direct assessment of terminal autoreceptors following a 7-day withdrawal revealed normo- and supersensitivity of these receptors in the striatum and olfactory tubercle, respectively. Possible mediating mechanisms as well as implications of these findings for the development of characteristic behavioral syndromes during and after amphetamine infusion are discussed.

Action Potentials↗

Activation of mu opioid receptors in the nucleus raphe dorsalis blocks apomorphine-induced aggression in rats: serotonin appears not to be involved.

The role of mu opioid receptors in the nucleus raphe dorsalis (DR) in the control of apomorphine-induced aggression was studied in rats. Administration in the DR of a selective mu opioid receptor agonist, (D-Ala2,N-Me-Phe4,Gly5-ol)-enkephalin (DAGO), in doses ranging from 0.01 to 1 microgram/0.5 microliter, dose-dependently reduced aggression caused by apomorphine 20 mg/kg intraperitoneally. 0.01 microgram DAGO significantly reduced the time spent by the animals in aggressive posture and 0.1 and 1 microgram markedly reduced both aggressive postures and attacks. 5 micrograms (in 0.5 microliter) naloxone in the DR completely antagonized the anti-aggressive effect of DAGO (0.1 microgram/0.5 microliter) injected in the same area. 0.1 and 1 microgram but not 0.01 microgram DAGO significantly increased serotonin (5-HT) metabolism in the striatum, a terminal area almost exclusively innervated by DR, indicating that the activity of 5-HT cells in the DR was modified by DAGO. In animals given 6 micrograms/3 microliters 5,7-dihydroxytryptamine in the DR 11 days before, in which striatal 5-HT levels were markedly depleted, no significant changes were found in the time spent by the apomorphine-treated animals in aggressive postures, numbers of attacks or anti-aggressive effect of 0.1 and 1 microgram DAGO administered in the DR. The study shows for the first time that activation of mu opioid receptors in the DR has a powerful anti-aggressive effect in one model of experimental aggression by a mechanism apparently not involving changes in the activity of 5-HT cells in this area.

Aggression↗

Long-term effects of early social isolation in Macaca mulatta: changes in dopamine receptor function following apomorphine challenge.

The hypothesis that early social isolation results in long-term alterations in dopamine receptor sensitivity was tested using older adult rhesus monkeys. Isolated and control monkeys were challenged with apomorphine (0.1 and 0.3 mg/kg), and the drug effects on spontaneous blink rate, stereotyped behavior, and self-injurious behavior were quantified using observational measures. Monoamine metabolites were quantified from cisternal CSF by HPLC-EC, prior to pharmacological challenge. Isolated and control monkeys did not differ in CSF concentrations of HVA, 5-HIAA, or MHPG. At the higher dose, apomorphine significantly increased the rate of blinking, the occurrence of whole-body stereotypies, and the intensity of stereotyped behavior (as measured by observer ratings) in isolated monkeys. The frequency of occurrence of self-injurious behavior was too low to allow for meaningful comparisons. These significant differences in response to apomorphine challenge support the hypothesis that long-term or permanent alterations in dopamine receptor sensitivity, as assessed by drug challenge, are a consequence of early social deprivation.

Animals↗

Apomorphine as a discriminative stimulus, and its antagonism by haloperidol.

At a non-stereotypogenic dose (0.16 mg/kg, s.c.), apomorphine was shown to produce a discriminative stimulus in rats. The apomorphine-produced stimulus was found to be effectively antagonized by haloperidol. It is suggested that apomorphine's ability to stimulate central dopamine receptors is directly related to its cueing action.

Animals↗

Absence of a 'cholinergic link' in the apomorphine-induced feedback inhibition of dopamine synthesis in rat striatum.

The blocking effect of apomorphine on the rise in striatal dopamine (DA) content, induced by 1-hydroxy-3-amino-pyrrolidone-2 (HA-966) was taken as a measure for the intrastriatal feedback inhibition of DA synthesis. The effects of cholinergic drugs on this feedback system were assessed in order to verify the hypothesis that this mechanism is mediated via an intrastriatal cholinergic link. We presumed that DA receptors were located on a cholinergic neuron, while the cholinergic terminals in turn made direct or indirect axon-axonal contact with the dopaminergic nigro-striatal pathway (N.S.P.). Although cholinergic agents could modify the effect of HA-966 on striatal DA content, it proved to be impossible to counteract the blocking effect of apomorphine with cholinergic drugs as was to be expected. Therefore we concluded that the effect of apomorphine was not brought about in the way which had been postulated.

Animals↗

Apomorphine-induced locomotor stimulation in developing rats treated with 6-hydroxydopa.

Apomorphine-induced locomotor stimulation was investigated in the developing rat following injection with 6-hydroxydopa at birth. Treatment with 6-hydroxydopa potentiated locomotor responsiveness to apomorphine in the 20-day-old rat. The 6-hydroxydopa-treated animal at 30 days, however, was less sensitive to the drug than was the control. Apomorphine again elicited more locomotor stimulation in 6-hydroxydopa-treated animals than in the controls on day 50. These results suggest that the altered sensitivity of dopamine receptors induced with 6-hydroxydopa, is influenced by the onset of activity of other "inhibitory" neurons on day 30.

Animals↗

Climbing behaviour induced by apomorphine in mice: a potential model for the detection of neuroleptic activity.

Apomorphine and the putative dopamine agonist, 2-(N, N-dipropyl)-amino-5, 6-dihydroxytetralin induced dose-dependent climbing behaviour in the mouse which was measured in wire mesh lined cages as the percentage of time spent climbing in the 30 min period following the first climb and as the maximum time spent in a single climb throughout the drug effect. These These two measures were generally found to parallel excepting when the interacting agent caused muscular hypotonia. All potential interacting agents were given as pretreatments to determine changes in motor function which may interfere with the climbing induced by 1.0 mg/kg s.c. apomorphine. The possibility of a change in the apomorphine response to a sterotyped biting, which would also interfere with climbing, was also considered. Excluding these non-specific changes, climbing behaviour was shown to be antagonised, dose-dependently, by low doses of typical and atypical neuroleptic agents (haloperidol, fluphenazine, loxapine, pimozide, oxiperomide, clozapin, thioridazine, sulpiride, tiapride and metoclopramide) but not specifically by other psychoactive agents. Climbing behaviour was modified by serotonergic agents; the agonist quipazine reduced or abolished, whilst the antagonists, methysergide and cyproheptadine, enhanced the response. Picrotoxin specifically reduced climbing behaviour but sodium valproate exerted non-specific effects, precluding conclusions as to a GABA involvement. Cholinergic and noradrenergic involvements with climbing were also apparently eliminated by the ineffectiveness of atropine, aceperone, piperoxan and propranolol. The involvement of serotonin with climbing was extended to the actions of the neuroleptics: the antagonistic effects of typical neuroleptics (haloperidol, fluphenazine, loxapine) were markedly enhanced by combination with methysergide or cyproheptadine whilst the effects of clozapine, sulpiride and thioridazine were significantly reduced. The actions of metoclopramide, oxiperomide, pimozide and tiapride were not generally modified by such combinations. These differences are discussed in terms of differential abilities to induce extrapyramidal disturbances and the mouse climbing model is forwarded as a test with potential to detect antipsychotic agents of different activity spectra.

Animals↗

Oral bioavailability of apomorphine in the rat with a portacaval venous anastomosis.

Orally administered apomorphine failed to produce stereotyped behavior in sham-operated rats, but did so following portacaval venous anastomosis. Brain and serum levels of apomorphine were highly correlated and corresponded with ratings of stereotypy. Tissue levels were undetectable after oral administration of apomorphine in intact rats but in shunted rats, were similar to those found after s.c. injection. These results suggest that a strong first-pass hepatic metabolism may account for the low oral bioavailability of catechol-aporphines.

Administration, Oral↗

Lack of effect of choline and narcotic antagonists upon apomorphine discrimination.

Rats were trained to discriminate between the stimulus properties of intraperitoneal 0.16 mg/kg apomorphine and saline in a two-lever, food-motivated operant task. Subjects were then injected with either 79 mg choline chloride, 0.02 mg/kg haloperidol, 10 mg/kg naloxone or 10 mg/kg naltrexone prior to apomorphine or saline discriminative testing. Only haloperidol pretreatment was observed to significantly alter the rats' ability to discriminate apomorphine. The results are discussed in relation to the possible mechanism(s) of action of narcotic antagonist and cholinomimetic drug effects upon dopaminergically mediated behaviors.

Animals↗

Haloperidol-induced supersensitivity to the discrimination of apomorphine.

Rats were trained to discriminate between the stimulus properties of intraperitoneal 0.16 mg/kg apomorphine and saline in a two-lever, food-motivated operant task. Once trained, the rats were tested with the ED50 of apomorphine (0.02 mg/kg) or saline before and 1-22 days after a ten-day regimen of daily 2.0 mg/kg administrations of haloperidol. Chronic haloperidol treatment produced increased discrimination of, and lever selection perseverance to, the low dose of apomorphine when rats were tested at 12 days after the withdrawal of haloperidol and this increased discrimination returned to pre-haloperidol levels by the sixteenth day. The results suggest the development of supersensitivity by prolonged pharmacologic blockade of central dopaminergic receptors with haloperidol and indicate the peak and duration of this effect.

Animals↗

p-Chlorophenylalanine and p-chloroamphetamine pretreatment of apomorphine-challenged rats: effects on solitary and social behavior.

Following an initial rise in locomotor activity, apomorphine in large doses causes a concurrent rise in brain serotonin levels, locomotor akinesia, and stereotypic gnawing. However, reports to date have failed to observe any effect of pretreatment with serotonin depletors parachlorophenylalanine (pCPA) or parachloroamphetamine (pCA) on apomorphine-induced stereotypy. In the present study the effects of pCPA (250 or 400 mg/kg i.p., 3 days) and pCA (6.4 or 10.4 mg/kg i.p., 3 days) pretreatment on apomorphine-induced (5.0 mg/kg s.c., 5 min) behavior of male rats in the open-field were compared. For half of the trials in the 78 min session, the rats were alone and for half of the trials they were paired with an untreated male rat. pCA pretreatment increased the frequency of line-crossing and of jumping, whereas pCPA pretreatment increased the duration of bouts of locomotion and gnawing. These behavioral differences may be related to the interaction of pCA and pCPA with dopaminergic subsystems in the brain.

Amphetamines↗

Estrogens antagonize apomorphine-induced yawning in rats.

The administration of a small dose of apomorphine (50 micrograms/kg s.c.) induced repeated episodes of yawning in male rats. Short-term (3 days) treatment with 17 beta-estradiol antagonized apomorphine-induced yawning in male rats. Moreover, apomorphine induced yawning much less effectively in female than in male rats. These results suggest that both endogenous or exogenously administered estrogens induce subsensitivity of the DA receptors mediating yawning in rats.

Animals↗

Cardiovascular effects in the rat of intrathecal injections of apomorphine at the thoracic spinal cord level.

Intrathecal (i.t.) administration of apomorphine at the upper thoracic level lowered blood pressure and heart rate in awake rats. This decrease was dose-dependent and competitively antagonized by haloperidol (i.v. and i.t.) or domperidone (i.t.) but not by domperidone (i.v.). Furthermore, these effects of apomorphine were not affected by alpha- and beta-blocking drugs (i.t.). The results suggest a spinal site, at least in part, for the cardiovascular effect of apomorphine.

Animals↗

Evidence for heterogeneous rotational responsiveness to apomorphine, 3-PPP and SKF 38393 in 6-hydroxydopamine-denervated rats.

Several novel dopamine (DA) agonists (SKF 38393, 3-PPP, TL-99) have been reported to induce rotational behavior (RB) in rats unilaterally denervated of the nigro-striatal pathway by 6-hydroxydopamine. Other reports have indicated no RB, however, and these drugs do not cause other behavioral manifestations of postsynaptic DA agonism. In the present experiments, two groups of 6-hydroxydopamine-denervated rats were distinguished by their relative responsiveness to apomorphine-induced RB. A highly sensitive group showed maximal RB in response to doses as low as 0.03 mg/kg, while a less sensitive group exhibited comparable RB only in response to 15- to 20-fold higher doses. The high sensitivity group exhibited RB in response to SKF 38393, 3-PPP and pergolide, but the low sensitivity group did not show appreciable RB after these drugs, even at doses 50 to 100-fold higher. Haloperidol markedly attenuated apomorphine-induced RB in the low sensitivity subgroup, but only reduced by approximately one-half the number of turns induced by apomorphine or SKF 38393 in the high sensitivity group. The atypical antipsychotics, clozapine and RMI 81582, and the muscle relaxant, methocarbamol, reduced RB in all groups, but only at doses that caused performance impairment in a rotorod test. These results appear to reflect qualitative differences in responsiveness to different DA agonists. Behavioral preselection of 6-hydroxydopamine-denervated animals is necessary to achieve consistent pharmacological results with the 6-hydroxydopamine RB model.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

Influence of peripheral and central administration of apomorphine and morphine on intragastric pressure in the dog.

Apomorphine was about 30 times more potent in inducing gastric relaxation when applied intracerebroventricularly (i.c.v.) than when injected intravenously (i.v.) in the conscious dog. In the anesthetized dog, the dose of apomorphine producing gastric relaxation via the vertebral artery was at least 10 times lower than that needed to produce gastric relaxation via the i.v. route. For morphine, similar doses had to be given i.c.v. and i.v. to obtain the same degree of gastric relaxation in the conscious dog; in the anesthetized dog, morphine was 3 times more potent via the vertebral artery than i.v. The results suggest that apomorphine-induced gastric relaxation in the dog is mediated via a central site located in the region supplied by the vertebral artery, but that the gastric relaxatory effect of morphine is mediated by both a peripheral and a central site of action.

Animals↗

Behavior performed at onset of drug action and apomorphine stereotypy.

This study tests the hypothesis that stereotyped behavior induced by apomorphine reflects strengthening of behavior observed at the onset of drug action. Rats (n = 26) were injected with apomorphine (1.25 mg/kg) while being engaged in copulation. Contrary to the hypothesis, apomorphine did not strengthen ongoing copulation but arrested it. Instead of mating the males became engaged in behavior typically exhibited by rats injected with the drug. It is speculated that stereotyped behavior may be an expression of a drug-induced shift of attention or responsiveness to some particular range of stimuli.

Animals↗

Evidence that apomorphine induces penile erection and yawning by releasing oxytocin in the central nervous system.

Oxytocin (10 and 30 ng) injected into a lateral ventricle (i.c.v.) or the dopamine agonist apomorphine (40 and 80 micrograms/kg) injected subcutaneously induced repeated episodes of penile erection and yawning in male rats. The concomitant administration of the two substances did not produce any further increase in the number of penile erection and yawning episodes. Penile erection and yawning induced by either oxytocin or apomorphine were antagonized in a dose-dependent manner by i.c.v. pretreatment with the oxytocin antagonists [d(CH2)5Tyr(Me)-Orn8]vasotocin, [Pen1,Phe(Me)2,Thr4,Orn8]oxytocin and [d(CH2)5Tyr(Me)-Arg8]vasopressin, with a rank order of potency that follows their antioxytocic activity. (i.e. [d(CH2)5Tyr(Me)-Orn8]vasotocin congruent to [Pen1,Phe(Me)2,Thr4,Orn8]-oxytocin greater than [d(CH2)5Tyr(Me)-Arg8]vasopressin). The results suggest that apomorphine induces penile erection and yawning by releasing oxytocin in the central nervous system.

Animals↗