Prostaglandin inhibition of apomorphine-induced circling in mice

The effect of prostaglandins (PGs) on apomorphine (apo)-induced circling was examined in unilaterally lesioned mice. Intraventricularly injected PGD₂, PGE₂, and PGF_2α at a dose of 1.0 nmole/g all inhibited apo-induced circling. When injected directly into the striatum, these same PGs also inhibited circling in a dose range of 0.01–0.1 nmole/g, while the PGE₂ metabolite, 13, 14-dihydro-15-keto-PGE₂, was inactive at 0.1 nmole/g. For both routes of administration, PGF_2α appeared to be the most potent of the PGs tested. PGs administered alone by either route to unilaterally lesioned mice did not produce circling. Pretreatment with the PG synthetase inhibitor, indomethacin, caused the apo treated mice to circle at significantly higher rates than control animals. These results are the first report suggesting that within dopamine (DA)-mediated pathways PGs act at sites postsynaptic to the dopaminergic synapse.     

Pavlovian conditioning ofl-dopa induced movement

Using the unilateral 6-hydroxydopamine (6-OHDA) substantia nigra pars compacta (SNC) lesion rat model and a Pavlovian conditioning protocol, the present investigation determined that the contralateral rotation response induced by the antiparkinsonian dopaminergic drugl-dopa can become conditioned to exteroceptive test environment stimuli. Two non-drug conditioning tests indicated that contralateral rotation was elicited by the test environment without the presence ofl-dopa. This conditioned response had a rotation diameter profile that was qualitatively the same as thel-dopa induced contralateral rotation response. Additionally, drug tests with the combined dopaminergic receptor antagonists, SCH 23390 (0.1 mg/kg) and haloperidol (0.5 mg/kg), at doses sufficient to block spontaneous behavior andl-dopa (20 mg/kg)-induced rotation, revealed that the conditioned contralateral rotation response, unlikel-dopa-induced contralateral rotation, is not affected by D₁/D₂ receptor blockade. Thus, the conditoned stimuli of the test environment can elicit the contralateral rotation response even in animals rendered akinetic by D₁/D₂ antagonists. This activation of a conditioned dopaminergic drug response by the situational stimuli, independent of dopaminergic mechanisms, may, therefore, contribute to the untoward overstimulation clinical effects ofl-dopa through summation of conditioned and drug-induced effects. Furthermore, the use of conditioning procedures to elicit movement in akinetic animals may provide a new research methodology to investigate the phenomenon of paradoxical kinesia.     

Asymmetrical dissociation of learning between scopolamine and Wy 4036, a new benzodiazepine tranquilizer

Summary Hungry rats, trained to drink milk rapidly in a small test chamber, received a single electric shock 30 min after injections of either scopolamine, a new benzodiazepine tranquilizer (Wy 4036), or saline. One week later, subgroups were tested for conditioned suppression of the drinking response under all drug conditions, according to a factorial design. Conditioned suppression transferred from saline to both drugs, across the same drug, and from scopolamine to Wy 4036, but not from the drugs to saline or from Wy 4036 to scopolamine. All groups tested under Wy 4036 showed supernormal suppression. The pattern of asymmetrical transfer was explained by a hypothetical neural conditioning model. The supernormal suppression caused by Wy 4036 was attributed to enhanced retrieval of the memory of the shock experience.     

Effects of apomorphine on appetitive conditioning in 6-hydroxydopamine treated rat pups

Rat pups were treated on postnatal day 5 either with the combination of desmethylimipramine (DMI) and 6-hydroxydopamine (6-OHDA) to produce depletion of brain dopamine, or with control injection of saline. Two days later they were presented a novel anise odor paired with intraoral baby formula, and on the next day were tested for preference for the novel odor. Before conditioning and testing, animals were treated with either apomorphine (0.05 mg/kg) or isotonic saline. Performance of the conditioned appetitive response was impaired in dopamine depleted animals. In DMI/6-OHDA treated pups, apomorphine administration prior to conditioning produced an improvement in performance, but drug treatment prior to testing had no effect. In normal pups, apomorphine administration either before conditioning or testing produced impaired performance at testing.     

Automated analysis of stereotypic behavior induced by psychomotor stimulants

A newly developed rotation sensing device has been applied to the continuous monitoring of animal movement. Animals treated with morphine, amphetamine or apomorphine display different stereotypic movements which can be distinguished by the apparatus. Initial studies have indicated that the apparatus is able not only to identify but also to quantitate some measures of stereotypic behavior. For example, the number and direction of rotations (a measure of motor asymmetry), frequency of changes in movement direction (a measure of stereotypic movement) and periods of cessation of movement are affected differentially with acute morphine, apomorphine or amphetamine treatment. Moreover, using this apparatus, morphine was shown to increase the degree of rotational asymmetry of normal animals and of animals with unilateral lesions of the nigrostriatal pathway.     

Antagonism of apomorphine-induced yawning by SCH 23390: Evidence against the autoreceptor hypothesis

The ability of apomorphine to induce yawning (YWG) in normal and reserpinized rats and its interaction with SCH 23390, a potent and specific D-1 receptor antagonist, was studied. Apomorphine was more potent in inducing YWG in reserpine-pretreated as compared to control rats. SCH 23390, in low doses (0.05 mg/kg SC), was able to significantly reduce the YWG evoked by apomorphine both in control and in reserpine-pretreated rats. The results indicate that D-1 receptors contribute to YWG elicited by apomorphine and contradict the idea that this effect is mediated by DA autoreceptors.     

Blockade of conditioned taste aversion by scopolamine and N-methyl scopolamine: associative conditioning,not amnesia

The anticholinergic, scopolamine, consistently disrupts one-trial passive avoidance conditioning but the effects of such drugs on one-trial conditioned taste aversion (CTA) are variable and contradictory. In the present study, treatment of rats with scopolamine impaired the suppression of sucrose intake by post-ingestion administration of lithium chloride (LiCl) in a two-bottle choice test. A similar effect was obtained by using N-methyl scopolamine which penetrates the brain only to a limited degree on acute administration. The blockade of CTA could be prevented in three ways: (i) by exposing the rats to sucrose only on the training day, (ii) by pre-exposing the rats to both sucrose and scopolamine, and (iii) by using a less palatable sucrose/ascorbate mixture. The results demonstrate that the effect of scopolamine on taste aversion is not mediated by the central nervous system, and can be modified by altering the novelty and relative salience of the taste conditioned stimulus. These experiments suggest that conditioned associations between taste and LiCl, and scopolamine and LiCl may underlie the blockade of CTA by scopolamine.     

Conditioning of behavioural effects produced by an intermediate dose of apomorphine: hypokinesia,ptosis and stereotypies

Summary Apomorphine, in an intermediate dose (0.18 mg/ kg s.c.) decreased dopamine turnover and produced signs generally attributed to a decrease in dopaminergic neurotransmission, e.g. ptosis and yawning, as well as signs of an increased stimulation of dopamine receptors in dopaminoceptive target neurones, e.g. stereotyped sniffing. In contrast, the former signs were exclusively observed after smaller doses and the latter after larger doses of apomorphine. Since it had been shown in previous studies that these signs, except yawning, could be conditioned in association with discriminative stimuli in the environment, the present study using conditioning experiments with this intermediate dose aimed at determining, 1. the time course of each conditioned response, 2. the interaction of conditioned and unconditioned responses, and 3. the conditions under which hypokinesia occurred. In each series, conditioned animals were compared with pseudoconditioned controls. Rats were conditioned for 8 days with apomorphine, and on day 9, treated with saline in presence of the conditional stimuli (a test cage in combination with acoustic and olfactory stimuli). In contrast to pseudoconditioned controls, ptosis and stereotyped behaviour were observed in conditioned rats, sometimes occurring alternatingly. These signs closely resembled the direct, unconditioned pharmacological effects. In addition, akinesia occurred after conditioning, although it was never manifest as a pure drug response, nor during the conditioning period. In contrast, yawning was observed in pseudoconditioned as well as in conditioned rats, although slightly more frequently in the former animals. Subsequently, the rats were again conditioned (or pseudoconditioned) on days 10–14 with apomorphine and both groups tested with the same dose (0.18 mg/kg) of apomorphine in the presence of the conditional stimuli. Both ptosis and stereotypies were significantly enhanced in conditioned animals, indicating synergistic interactions between conditioned and direct, pharmacological behavioural effects. In all cases the conditioned effects lasted for about 30 min.The results show that, after conditioning with an intermediate dose of apomorphine, both signs typical of a low dose of apomorphine and those characteristic of a large dose can be conditioned and sometimes occur alternately. Send offprint requests to K. Kuschinsky     

Apomorphine-induced facilitation of intracranial self-stimulation following dopamine denervation of the nucleus accumbens

Two groups of rats were trained to lever press for intracranial self-stimulation (ICSS) from electrodes aimed at the posterior lateral hypothalamus or at the region of the locus coeruleus. Following stabilization of baseline responding using descending rate/intensity functions, bilateral 6-hydroxydopamine (6-OHDA) lesions to the nucleus accumbens (N.Acc.) were performed. Subsequent injections of apomorphine (SC) resulted in significant increases in self-stimulation in both lesion groups and significant decreases in self-stimulation in both groups of sham operated animals. These results indicate that the destruction of the dopaminergic terminals in the nucleus accumbens results in a "supersensitive" enhancement of the ICSS stimulating properties of apomorphine regardless of the electrode placement. Both lesion groups also showed a pronounced increase in locomotor activity in photocell cages following treatment with the same dose of apomorphine. These results complement previous work showing that dopamine destruction affects ICSS regardless of electrode placement and support the hypothesis that the midbrain dopamine systems have a general response enabling role in reinforced behavior.     

Supersensitivity to apomorphine in experimentally induced hypokinesia and drug-induced modifications of the apomorphine response

The development and degree of supersensitivity to the locomotor stimulant effect of apomorphine were studied in rats which had been rendered hypokinetic by bilateral injections of 6-hydroxydopamine into the anterolateral hypothalamus. Up to 2 days after surgery the effect of apomorphine was comparable in lesioned and normal rats, indicating that dopaminergic supersensitivity did not develop over this short period. As the duration between the 6-hydroxydopamine injections and time of testing with apomorphine increased, the animals became progressively more sensitive to the stimulant effects of apomorphine. Pretreatment with butaclamol reduced the effect of apomorphine in a dose-dependent manner. A high dose of clozapine also antagonized the effect of apomorphine, but a low dose potentiated it. No inhibition was observed following administration of the -adrenergic antagonist, phenoxybenzamine, or the -adrenergic antagonist, propranolol. The 5HT antagonist methysergide and the anticholinergic drug, scopolamine potentiated the effects of apomorphine. These studies suggest that the apomorphine-induced ambulation in hypokinetic rats is primarily mediated through dopaminergic mechanisms but both serotonergic and cholinergic mechanisms exert modulating influences.     

Differential effects of apomorphine in 6-hydroxydopamine-treated and aged rats

Effects of dopamine depletion and old age were tested on the ability of rats to discriminate the interoceptive cue produced by IP administered apomorphine. In Experiment 1, rats were administered IC injections of 6-hydroxydopamine or its vehicle at 5 days of age. Administration of this dopamine neurotoxin resulted in significant depletion of whole-brain dopamine to 27.2% of controls as indicated when the brains of littermate rats, killed at 35 days of age, were analyzed by high-pressure liquid chromatography. Although this dopamine depletion was significant, toxintreated rats learned to discriminate 0.16 mg/kg apomorphine from saline at the same rate as control rats. However, the dose-response curve for apomorphine discrimination after doses of 0.04–0.24 mg/kg suggested hypersensitivity to the dopamine agonist in toxin-treated rats. In Experiment 2, senescent rats were similarly trained to discriminate apomorphine in the two-lever food-motivated operant task. Dose-response testing indicated hypersensitivity similar to that found in 6-OHDA-treated rats. This increased behavioral responsiveness of aged rats to dopamine agonists is discussed in relation to receptor supersensitivity, metabolic rates, and blood-brain barrier permeability.     

Drinking behaviour and brain dopamine: Antagonistic effect of two neuroleptic drugs (Pimozide and Spiramide) upon amphetamine- or apomorphine-induced hypodipsia

Hypodipsia produced by injection of d-amphetamine (2.0 mg/kg) or apomorphine (0.8 mg/kg) in rats, was partially antagonized by two DA-specific neuroleptic drugs, Pimozide and Spiramide, respectively. Pimozide revealed a maximal amphetamine-antagonistic effect at dose levels between 0.1–0.4 mg/kg. Hypodipsia could also be produced by Pimozide alone in doses greater than 1.0 mg/kg. Pretreatment of the apomorphine-induced hypodipsia with 0.05 mg/kg Spiramide also reliably counteracted drinking deficits.The interaction of water deprivation combined with the presence or absence of food in the test situation was also examined, but no effect was found.The possibility that perseverative rearing on the hind legs under d-amphetamine might interfere with drinking was tested with high vs. low drinking-tubes in the Pimozide-amphetamine experiments. There was evidence for a slight initial effect of drinking position, but the general form of the dose-response curve was not greatly altered.It was concluded that dopamine effects cannot easily be excluded from a role in the control of drinking, and that the primary role often accorded norepinephrine in relation to amphetamine effects should be re-examined with respect to the specific behavioural functions which are altered.     

Behavioural supersensitivity to apomorphine following cerebral dopaminergic denervation by 6-hydroxydopamine

Intraventricular injections of 6-hydroxydopamine that induce a marked and long lasting depletion of cerebral dopamine as well as noradrenaline, greatly enhanced the stimulation of locomotor activity of mice produced by the injection of apomorphine. Dose-response relationships indicated that the maximal response to apomorphine was greatly increased but that there was no apparent change in the ED50 from the response in vehicle-treated mice. 6-Hydroxydopamine treated mice were also considerably less susceptible to the cataleptic activity of pimozide and it is suggested that cerebral dopaminergic denervation may result in an increased number of available post-synaptic dopamine receptors.     

Behavioral sensitization: Characterization of enduring changes in rotational behavior produced by intermittent injections of amphetamine in male and female rats

Factors influencing the behavioral sensitization (reverse tolerance) produced by intermittent amphetamine (AMPH) injections were studied by quantifying rotational behavior in rats that had a unilateral 6-hydroxydopamine lesion of the substantia nigra. The results indicate that (1) a single injection of a low dose of AMPH enhances rotational behavior induced by a second injection of AMPH for up to 12 weeks; (2) multiple, weekly injections of AMPH produce a progressive enhancement in rotational behavior, over-and-above that produced by a single injection; (3) female rats show more robust sensitization than males following single or multiple injections of AMPH; (4) this sex difference may be due to the suppression of sensitization by an androgen, because removal of testicular hormones potentiates sensitization; (5) the long-lasting sensitization of rotational behavior produced by infrequent injections of AMPH is not due to drug-environment conditioning effects, but perhaps to a persistent AMPH-induced change(s) in brain catecholamine systems; and (6) a simple change in DA receptors is probably no involved, because the sensitization produced by infrequent injections of AMPH does not influence the rotation produced by a subsequent injection of apomorphine. The results illustrate an intriguing example of neuroplasticity that may have clinical relevance.     

A comparison of the effects of muscarinic and nicotinic anticholinergic drugs on habituation and fear conditioning in rats

Comparisons were made between the effects of scopolamine and mecamylamine in two behavioral paradigms that have been found to be sensitive to cholinergic disruption by antimuscarinic compounds (i.e., habituation and fear conditioning). In the habituation paradigm, water deprived rats were exposed to a novel environmental chamber under either scopolamine, methscopolamine, mecamylamine, hexamethonium or saline. Three days later all animals were returned to the same chamber which now contained a drinking tube. Time to complete 100 licks was used to assess habituation. Only the rats trained under scopolamine showed long drinking times (failed to habituate to the apparatus stimuli) thereby demonstrating the central muscarinic nature of the habituation process. In the fear conditioning paradigm, hungry rats, trained to drink milk in a test chamber, received a single electric shock 20 min after injections of either scopolamine, mecamylamine, hexamethonium or saline. Three days later subgroups were tested for conditioned suppression under either the same drug conditions or saline. Conditioned suppression was found in all groups except those trained under scopolamine or mecamylamine and tested under saline. Apparently the processes underlying this asymmetrical dissociation are not predominantly nicotinic or muscarinic in nature.In conducting the research described in this report, the investigators adhered to the Guide for Laboratory Animal Facilities and Care as promulgated by the Committee on the Guide for Laboratory Animal Resources, National Academy of Sciences-National Research Council.     

On the selectivity and specificity of the antagonism of apomorphine-induced suppression of exploration by sulpiride

Ten behavioural variables were recorded by means of an automatic holeboard apparatus. The behaviour of rats placed for the first time in the apparatus was recorded for 10 min. The suppression of this exploratory behaviour by the dopamine agonist apomorphine (0.01–0.1 mg/kg) was shown to bereversible in a surmountable fashion by the dopamine antagonist sulpiride (2 and 4 mg/kg). Suppression of exploration induced by clonidine (0.05 0.2 mg/kg) or diazepam (2 mg/kg) was not antagonised by sulpiride (10 and 50 mg/kg, respectively). The partial dopamine D1-agonist SKF 38393 (2–20 mg/kg) also suppressed exploration but neither sulpiride (20 mg/kg) nor the D1-antagonist SCH 23390 (0.02 mg/kg) could antagonise this effect. The data show that dopamine agonist induced suppression of exploration display pharmacological characteristics of a receptor-mediated response and the data support our previous suggestion that these receptors may be pharmacologically distinct from other dopamine D2-receptors.     

6-Hydroxydopamine and avoidance: Possible role of response suppression.

The intraventricular administration of 6-HD to rats pretreated with pargyline resulted in severe, long-lasting decreases in avoidance responding with little or no effect on escape responding. Despite the fact that the rats failed to avoid, they appeared to be able to discriminate the CS, as was evident from freezing behavior and other symptoms of an apparent fear reaction during the CS. The increase in freezing, a response that was incompatible with avoidance was seen during the first few test sessions after 6-HD treatment and seemed to be largely responsible for a gradual decline in avoidance responding during this same period. The role of CA depletion in the animal's response to aversive stimuli thus appears to be a significant aspect of the avoidance decrement that follows 6-HD administration.     

Apomorphine-induced yawning in rats is abolished by bilateral 6-hydroxydopamine lesions of the substantia nigra

Apomorphine-induced yawning was studied in male rats with bilateral 6-hydroxydopamine lesions of the substantia nigra. Apomorphine 10, 20 and 50 g/kg SC induced dose-dependent yawning in unoperated controls and animals with sham lesions. In the lesioned animals (in which the mean striatal dopamine depletion was 67%), the maximum yawning response rate was greatly attenuated with no evidence that the dose response curve was shifted in either direction. Furthermore, blockade of yawning in the lesioned animals was not simply due to suppression by other stereotyped behaviours, since there was no evidence of increased sniffing or chewing in these animals. These data provide further support for the hypothesis that apomorphine-induced yawning is mediated by dopamine autoreceptors and requires intact nigrostriatal projections.     

Influence of 6-hydroxydopamine on the behavioral effects induced by apomorphine or clonidine in rats

The aim of this paper is to examine if central chemical sympathectomy induced by two injections of 6-hydroxydopamine (6-OHDA) in a dose of 250 g intracerebroventricularly (k.c.v.) affects behavioral phenomena elicited by apomorphine (AP) (1 or 1.2 mg/kg i.p.) or clonidine (CL) (0.1 mg/kg, 5 or 1 g/kg i.p.).Experiments were carried out on male Wistar rats. The time of duration of several components of behavior and the degree of irritability of rats were measured. Moreover, open field and hole test were performed. The lower dose of AP did not affected behavior of rats. The higher dose increased the locomotor and exploratory activity of animals. 6-OHDA potentiated these effects of AP. CL (0.1 mg/kg) had a depressive effect on the rats' behavior, which was potentiated by 6-OHDA. CL (5 g/kg) had no effect on the rats' behavior, but in a dose of 1 g/kg caused excitatory behavior. This type of behavior was abolished by 6-OHDA. In conclusion, central chemical sympathectomy caused increased sensitivity of the central nervous system on AP. Excitatory behavioral effects of CL in low dosage may be connected with stimulation of central adrenergic receptors. Depressive behavioral effect of CL in high dosage is unspecific. Central chemical sympathectomy affects by different methods the reactivity of dopaminergic and noradrenergic neurons.