High Dose Of Apomorphine Research Articles

Repeated pre-trial and post-trial low and high dose apomorphine treatments induce comparable inhibitory/excitatory sensitization and conditioned drug effects

This investigation was undertaken to compare the sensitization/conditioned effects induced by apomorphine given pre-trial versus administered immediately post-trial or 15 min post-trial. We measured the effects on locomotor activity of 5 daily apomorphine treatments induced by an inhibitory low auto-receptor dose (0.05 mg/kg) and a stimulatory high postsynaptic dose (2.0 mg/kg). Three sets of four groups were used and each set of four groups was comprised of two vehicle and two apomorphine groups (0.05/2.0 apomorphine). The only difference among the three sets of four groups was when the treatments were administered relative to placement in the novel environment. One set received the treatment pre-test, another set was injected immediately after and the third set injected 15 min after 5 min test sessions in a novel environment. The repeated pre and immediate post-test apomorphine treatments induced locomotor sensitization over the 5 days of treatment. The low dose pre and immediate post-test treatments progressively decreased locomotion and the high dose pre and immediate post-test progressively increased locomotion. Critically, the tests for the immediate post-test groups were non-drug and for both the pre-test and immediate post-test groups, sensitization effects did not occur until the second test day. To control for non-associative apomorphine effects, the same apomorphine treatments were given post-test after a 15 minute delay and were found to be equivalent to vehicle. In a subsequent conditioning test, both the pre and immediate post-test low dose apomorphine groups showed conditioned behavioral inhibition and the pre and immediate post-test high dose apomorphine groups showed conditioned behavioral stimulation. We propose that the inhibitory low dose apomorphine decreased the salience/incentive of the novel environment association and thereby decreased the behavioral response and conversely that the high dose excitatory apomorphine treatment increased the salience/incentive value of the novel environment association and potentiated the behavioral response.

Neurochemical and behavioural effects of hypidone hydrochloride (YL-0919): a novel combined selective 5-HT reuptake inhibitor and partial 5-HT1A agonist.

Our previous studies revealed that hypidone hydrochloride (YL-0919), which acts as a selective 5-HT (serotonin) reuptake inhibitor (SSRI) and displays partial 5-HT1A receptor agonist properties, exerts a significant antidepressant effect in various animal models. The aim of present research was to further investigate the pharmacology of YL-0919. We first investigated the target profile of YL-0919 using [35 S]-GTPγS binding and microdialysis. To determine whether the 5-HT or noradrenergic systems are involved in the antidepressant-like effect of YL-0919, the 5-hydroxytryptophan (5-HTP)-induced head-twitch test and antagonism with a high dose of apomorphine were performed. Using the learned helplessness paradigm, the novelty suppressed feeding test, the Vogel-type conflict and elevated plus-maze test, we further verified the antidepressant-like and anxiolytic-like effects of YL-0919. The effects of YL-0919 on hippocampal long-term potentiation (LTP) and sexual behaviour were also evaluated. Data from the present study demonstrated that YL-0919 displays partial 5-HT1A receptor agonist properties, producing a greater impact on extracellular 5-HT levels than a conventional SSRI (fluoxetine), as well as significant antidepressant and anxiolytic effects. Furthermore, YL-0919 treatment rapidly influenced the synaptic plasticity (enhancing LTP) of rats. Finally, at doses close to those producing antidepressant-like effects, YL-0919 did not result in a marked inhibition of sexual function. These data suggest that YL-0919 is probably a fast-onset potent antidepressant with few side effects.

Post-trial dopaminergic modulation of conditioned catalepsy: A single apomorphine induced increase/decrease in dopaminergic activation immediately following a conditioned catalepsy response can reverse/enhance a haloperidol conditioned and sensitized catalepsy response

Haloperidol can induce catalepsy and this drug effect can be conditioned as well as sensitized to contextual cues. We used a paired/unpaired Pavlovian conditioning protocol to establish haloperidol catalepsy conditioned and sensitized responses. Groups of rats were given 10 daily catalepsy tests following administration of vehicle (n=24) or haloperidol (1.0mg/kg) either paired (n=18) or unpaired (n=18) to testing. Subsequently, testing for conditioning was conducted and conditioning and sensitization of catalepsy were observed selectively in the paired group. Immediately following a second test for catalepsy conditioning, the groups were subdivided into 4 vehicle groups, 3 unpaired haloperidol groups and 3 paired haloperidol groups and were given one of three post-trial treatments (vehicle, 0.05mg/kg or 2.0mg/kg apomorphine). One day later the conditioned catalepsy test 3 was carried out and on the next day, a haloperidol challenge test was performed. The post-trial apomorphine treatments had major effects on the paired groups upon both conditioning and the haloperidol challenge test. The low dose apomorphine post-trial treatment enhanced both the conditioned and the haloperidol sensitized catalepsy responses. The high dose apomorphine post-trial treatment eliminated conditioned catalepsy and eliminated the initial acute catalepsy response to haloperidol that was induced in the vehicle control groups. These results demonstrate the sensitivity of conditioned drug cues to modification by increases/decreases in activity of the dopamine system in the immediate post-trial interval after a conditioning trial. This demonstration that post-trial dopaminergic drug treatments can modify conditioned drug behavior has broad implications for conditioned drug effects.

TAAR1-dependent effects of apomorphine in mice.

G protein-coupled trace amine-associated receptor 1 (TAAR1) is expressed in several brain regions and modulates dopaminergic activity partially by affecting D2 dopamine receptor function. In vitro, the nonselective dopamine agonist apomorphine can activate mouse and rat TAAR1. The aim of the present study was to evaluate whether apomorphine activity at the rodent TAAR1 observed in in vitro studies contributes to its behavioral manifestation in mice. For this purpose, we compared the behavioral effects of a wide range of apomorphine doses in wild type (WT) and TAAR1 knockout (TAAR1-KO) mice. Apomorphine-induced locomotor responses (0.01-4.0mg/kg) were tested in locomotor activity boxes, and stereotypic behavior at 5mg/kg was tested by ethological methods. A gnawing test was used to analyze the effects of the highest dose of apomorphine (10mg/kg). No statistically significant differences were observed between TAAR1-KO and WT mice following inhibitory pre-synaptic low doses of apomorphine. At higher doses (2.0-5.0mg/kg), apomorphine-induced climbing behavior was significantly reduced in TAAR1 mutants relative to WT controls. Moreover, the lack of TAAR1 receptors decreased certain types of stereotypies (as reflected in by measures of the global stereotypy score, licking but not sniffing or gnawing) that were induced by high doses of apomorphine. These data indicate that apomorphine activity at TAAR1 contributes to some behavioral manifestations, particularly climbing, in rodents following high doses of this drug. The contribution of TAAR1 to apomorphine-induced climbing in rodents should be considered when apomorphine is used as a screening tool in the search for potential antipsychotics.

Drug memory substitution during re-consolidation: A single inhibitory autoreceptor apomorphine treatment given during psychostimulant memory re-consolidation replaces psychostimulant conditioning with conditioned inhibition and reverses psychostimulant sensitization

Psychostimulant conditioning and sensitization effects have proven to be difficult to eliminate using behavioral methods. We used a low autoreceptor dose of apomorphine in counter-conditioning and memory re-consolidation protocols to modify conditioned and sensitized responses induced by a high dose of apomorphine. Rats received five daily treatments of apomorphine (2.0mg/kg) and were tested in an arena for 30min to induce conditioning and sensitization. Conditioning was validated in a brief 5min non-drug conditioning test and sensitization by a 2.0 apomorphine challenge test. Next, the counter-conditioning and memory re-consolidation protocols were initiated. In counter-conditioning, vehicle or 0.05mg/kg apomorphine was given either 15min or immediately before a 5min arena test. In the memory re-consolidation protocol, the vehicle and 0.05 apomorphine treatments were administered post-trial either immediately after or 15min after the 5min arena test. Effects were assessed with a 5min saline conditioning test and a second 2.0mg/kg apomorphine challenge test. The counter-conditioning protocol induced hypolocomotion and but did not induce a conditioned hypo-locomotion and did not alter the sensitized response. The 15min post-trial treatment did not affect either the conditioned or the sensitized responses. The immediate post-trial treatment eliminated sensitization and induced a conditioned hypoactivity response. These results highlight the memory re-consolidation period as a critical target for drug memory substitution and suggest the potential utility of the pharmacological inhibition of dopamine activity given as a therapeutic drug memory replacement during addictive drug memory re-consolidation.

Clinical effects of an intravenous apomorphine protocol in Parkinson disease

protocol of apomorphine produces detectable biological effect (increased growth hormone concentration) but negligible clinical effect (tapping speed and expert rated of parkinsonism) • We do not have much power to detect a difference in tapping scores in 8 subjects, however the difference likely does not exceed 5 taps/min • Although this dose produces reliable increases of GH in PD and controls, a higher dose of apomorphine, or a larger sample size, may be needed to detect significant motor improvement in PD. • The results suggest there are advantages and disadvantages to this dosing schedule: • Disadvantage: minimal effect in the clinical assay • Advantages: • well tolerated • detectable effect on hypothalamic DA receptors • imaging changes with this protocol could be interpreted as directly drug-induced rather than as indirect effects of a change in PD motor function or patient comfort • Moderately severe PD (modified UPDRS, apo day 22.1 + 6.3; saline day 21.7 + 7.7, mean + SD) • No significant differences between post infusion drug and saline UPDRS scores (apo: 21.7 + 7.7; saline 24.0 + 2.2) • No significant improvement in tapping speed with apomorphine (apo 2.2 + 7.2 clicks/min; saline 2.3 + 5.0 [95% C.I. for difference = -5.1 to +4.9]) • GH level was significantly higher after apomorphine than after saline (apo: 1.43 + 2.1 ng/mL; saline: 0.27 + 0.5, p = 0.04; see graph)

Behavioral sensitization to dopaminergic inhibitory and stimulatory effects induced by low vs. high dose apomorphine treatments: An unconventional dose and response reversal sensitization challenge test reveals sensitization mechanisms

Low dose apomorphine treatments preferentially activate dopamine autoreceptors and inhibit dopamine neurons as well as behavior. In contrast, high doses of apomorphine induce locomotor stimulation by activating dopamine postsynaptic receptors. We compared the effects of low (0.05 mg/kg) vs. high (2.0 mg/kg) repeated apomorphine treatments (5) using paired/unpaired protocols upon the development of Pavlovian conditioned drug responses and upon drug sensitization effects. In addition to the conventional challenge test for sensitization, we also conducted a treatment reversal sensitization test in which low dose groups received the high dose treatment and vice versa. The high dose treatment produced the expected Pavlovian conditioned locomotor stimulant response as well as a sensitization effect in the high dose challenge test; but in the low dose challenge test, the effect was desensitization. The low dose apomorphine regimen induced an inhibitory sensitization effect in the low dose challenge test. In the high dose reversal challenge test, there was a sensitization effect to the locomotor stimulant effect. The low dose apomorphine treatments, however, did not produce a Pavlovian conditioned locomotor inhibitory effect. Surprisingly, the dose reversal challenge test revealed context-independent as well as context-specific sensitization/desensitization effects. These findings demonstrate that Pavlovian drug conditioned effects and drug sensitization effects are independent phenomena and that sensitization effects are not response specific. Moreover, context-specific vs. context-independent sensitization effects were protocol dependent but not drug dose dependent.

Biphasic effect of apomorphine, an anti-parkinsonian drug, on bladder function in rats

The effects of anti-parkinsonian drugs on bladder function have been controversial; namely, some aggravated while others alleviated bladder dysfunction in patients with Parkinson disease. These studies, however, did not consider the dose- and time-dependent effects. Therefore, we investigated these effects of apomorphine, an anti-parkinsonian drug and a nonselective dopamine receptor agonist, on the bladder function using normal conscious rats. Consecutive cycles of micturition were analyzed for 30-min periods before and after (over a 4-h period) s.c. administration of a single dose of 0.01 (low), 0.05 (medium), 0.5 (high) mg/kg of apomorphine or saline to the rats. Apomorphine administration produced various effects in relevant urodynamic parameters, although the monitored parameters remained unchanged in saline-administered rats. During filling, low-dose apomorphine induced initial decreases in voiding frequency (VF; defined as the number of voidings during a 15-min period). However, medium- and high-dose apomorphine dose-dependently induced initial increases in VF, and was followed by decreases in VF. These doses also induced initial increase in threshold pressure. During voiding, low-dose apomorphine induced initial increases in micturition volume (MV), which reflected an increase in bladder capacity (BC). However, medium- and high-dose apomorphine dose-dependently induced initial decreases in MV, and was followed by increases in MV. These doses also dose-dependently induced an initial increase in maximum bladder contraction pressure during the early phase after administration. The present study demonstrated that apomorphine displayed a dose- and time-dependent biphasic effect on the normal bladder filling function. These pharmacodynamic characteristics of apomorphine could be applicable to other anti-parkinsonian drugs such as levodopa and nonselective dopamine receptor agonists, and may account for the previous reported conflicting effects of anti-parkinsonian drugs on bladder dysfunction in patients with Parkinson disease, although it needs to be evaluated in disease status.

Foot-Tapping Rate as an Objective Outcome Measure for Parkinson Disease Clinical Trials

To explore foot-tapping rate as a reliable and a valid measure of motor function in Parkinson disease (PD). We present data from a randomized, single-blind, outpatient study and a randomized, double-blind, placebo-controlled, crossover, inpatient study. Fifty PD subjects completed the outpatient study. A Unified Parkinson Disease Rating Scale motor score was determined for each subject. Subsequently, finger tapping, alternate (between 2 pedals) and repetitive (on 1 pedal) foot-tapping rates, and gait were measured. Thirteen PD subjects completed the inpatient study. Each subject received a daily infusion of high-dose apomorphine (APO), low-dose APO, and placebo in random order over 3 days. In this subanalysis, we compared variance and reliability of the finger- and the foot-tapping techniques during the placebo day and compared the validity of these outcome measures to detect improvement in parkinsonism during high-dose APO infusion. Alternate foot tapping was reliable (interclass correlation on the placebo inpatient day, 84%). Only foot tapping detected improvement in parkinsonism with high-dose APO treatment (a measure of validity). In the outpatient study, there was a significant correlation between alternate and repetitive tapping with finger tapping (R2 = 0.28 and 0.23, respectively) and Unified Parkinson Disease Rating Scale motor score (R2 = 0.09 and 0.08), but only alternate tapping correlated with gait (R2 = 0.16). Alternate foot tapping was equally reliable but more valid than finger tapping. Alternate foot tapping correlated better did existing PD outcome measures than did repetitive foot tapping. Foot tapping may be a useful outcome measure for determination of dopaminergic medication effect in PD clinical trials.

Sept4, a Component of Presynaptic Scaffold and Lewy Bodies, Is Required for the Suppression of α-Synuclein Neurotoxicity

In Parkinson disease (PD), alpha-synuclein aggregates called Lewy bodies often involve and sequester Septin4 (Sept4), a polymerizing scaffold protein. However, the pathophysiological significance of this phenomenon is unclear. Here, we show the physiological association of Sept4 with alpha-synuclein, the dopamine transporter, and other presynaptic proteins in dopaminergic neurons; mice lacking Sept4 exhibit diminished dopaminergic neurotransmission due to scarcity of these presynaptic proteins. These data demonstrate an important role for septin scaffolds in the brain. In transgenic mice that express human alpha-synuclein(A53T) (a mutant protein responsible for familial PD), loss of Sept4 significantly enhances neuropathology and locomotor deterioration. In this PD model, insoluble deposits of Ser129-phosphorylated alpha-synuclein(A53T) are negatively correlated with the dosage of Sept4. In vitro, direct association with Sept4 protects alpha-synuclein against self-aggregation and Ser129 phosphorylation. Taken together, these data show that Sept4 may be involved in PD as a dual susceptibility factor, as its insufficiency can diminish dopaminergic neurotransmission and enhance alpha-synuclein neurotoxicity.

Differential effects of μ-opioid, δ-opioid and κ-opioid receptor agonists on dopamine receptor agonist-induced climbing behavior in mice

Interactions between the dopaminergic system and opioids have not been adequately clarified. The present study was designed to investigate the effects of micro-opioid (morphine), delta-opioid (SNC80) and kappa-opioid (U50 488H) receptor agonists on dopamine receptor agonist-induced climbing behavior in mice. Apomorphine (dopamine-receptor agonist) increased stereotyped climbing behavior, unlike methamphetamine, morphine, U-50 488H and (+/-)7-hydroxy-N,N-di-n-propyl-2-aminotetralin hydrobromide (D2-like receptor agonist). Furthermore, SKF81297 (D1 receptor agonist) and SNC80 caused climbing behavior. In addition, while morphine (20 mg/kg), but not U50 488H or SNC80, significantly attenuated high-dose apomorphine (2.0 mg/kg)-induced climbing behavior, it significantly potentiated low-dose apomorphine (0.5 mg/kg)-induced climbing behavior. These results suggest that morphine may have dual effects on the behavioral effects induced by apomorphine. Furthermore, we interestingly showed that the combination of apomorphine or SKF81297 and SNC80 enhanced frequent nonstereotypic climbing behavior, suggesting that delta/D1 interactions may play a prominent role in the expression of certain types of behavior in mice. Thus, micro-opioid, delta-opioid and kappa-opioid receptor agonists induce possible differential effects on the dopaminergic system in mice.

Behavioral effects of dopaminergic agonists in transgenic mice overexpressing human wildtype α-synuclein

Overexpression of α-synuclein causes familial Parkinson’s disease and abnormal aggregates of the protein are present in sporadic cases of the disease. We have examined the behavioral effects of direct and indirect dopaminergic agonists in transgenic mice expressing human α-synuclein under the Thy-1 promoter (Thy1-aSyn, alpha-synuclein overexpressor), which exhibit progressive impairments in behavioral tests sensitive to nigrostriatal dopamine dysfunction. Male Thy1-aSyn and wild-type mice received vehicle, benserazide/ l-DOPA (25 mg/kg, i.p.), high (2 mg/kg, s.c.) and low doses (0.125, 0.25, 0.5 mg/kg, s.c.) of apomorphine, and amphetamine (5 mg/kg, i.p.), beginning at 3 months of age, and were tested on the challenging beam, spontaneous activity, pole test, and gait. l-DOPA had a paradoxical effect and worsened the deficits in Thy1-aSyn mice compared with controls, whereas the high dose of apomorphine only produced few deficits above those already present in Thy1-aSyn. In contrast to wild-type mice, Thy1-aSyn mice did not show amphetamine-induced stereotypies. The results indicate that chronic overexpression of α-synuclein led to abnormal pharmacological responses in mice.

THE ROLE OF DOPAMINE IN REINFORCEMENT: CHANGES IN REINFORCEMENT SENSITIVITY INDUCED BY D1-TYPE, D2-TYPE, AND NONSELECTIVE DOPAMINE RECEPTOR AGONISTS

Dose-dependent changes in sensitivity to reinforcement were found when rats were treated with low, moderate, and high doses of the partial dopamine D1-type receptor agonist SKF38393 and with the nonselective dopamine agonist apomorphine, but did not change when rats were treated with similar doses of the selective dopamine D2-type receptor agonist quinpirole. Estimates of bias did not differ significantly across exposure to SKF38393 or quinpirole, but did change significantly at the high dose of apomorphine. Estimates of goodness of fit (r2) did not change significantly during quinpirole exposure. Poor goodness of fit was obtained for the high doses of SKF38393 and apomorphine. Decrements in absolute rates of responding were observed at the high dose of quinpirole and at the moderate and high doses of SKF38393 and apomorphine. Changes in r2 and absolute responding may be due to increases in stereotyped behavior during SKF38393 and apomorphine exposure that, in contrast to quinpirole, were distant from the response lever. The present data provide evidence that sensitivity to reward is affected more strongly by dopamine D1-like receptors rather than D2-like receptors, consistent with evidence from other studies investigating consummatory dopamine behavior and the tonic/phasic dopamine hypothesis.

Preclinical pharmacology of F-98214-TA, a novel potent serotonin and norepinephrine uptake inhibitor with antidepressant and anxiolytic properties

Serotonin (5-HT) and norepinephrine (NE) re-uptake inhibitors (SNRIs) have been proposed to have a higher efficacy and/or faster onset of action than previously available antidepressants. We examined in biochemical, electrophysiological and behavioural assays the antidepressant properties of (S)-(-)-4-[(3-fluorophenoxy)-phenyl]methyl-piperidine (F-98214-TA), a compound that displays very high affinity for 5-HT and NE transporters. F-98214-TA potently inhibited the uptake of both 5-HT and NE into rat brain synaptosomes (IC50 = 1.9 and 11.2 nM, respectively) and decreased the electrical activity of dorsal raphe serotonergic neurones (ED50 = 530.3 microg/kg i.v.), an effect completely abolished by the 5-HT(1A) antagonist WAY100,635. In acute behavioural assays in mice, the orally administered compound potentiated the 5-hydroxy-tryptophan (5-HTP)-induced syndrome [minimal effective dose (MED) = 10 mg/kg], antagonized the hypothermia induced by a high dose of apomorphine (ED50 = 2 mg/kg) and reduced the immobility in the tail suspension test (MED = 10 mg/kg). Moreover, it also decreased the immobility in the forced swimming test in mice and rats (30 mg/kg, p.o.). Chronic administration of F-98214-TA (14 days, 30 mg kg(-1) day(-1), p.o.) attenuated the hyperactivity induced by olfactory bulbectomy in rats, confirming its antidepressant-like properties. Interestingly, the same dosage regimen significantly increased the social interaction time in rats, suggesting an additional potential anxiolytic activity. In most assays the compound was more potent than fluoxetine, venlafaxine and desipramine. F-98214-TA is a novel SNRI that displays greater potency than other reference antidepressants in animal models predictive of antidepressant and anxiolytic activities.

P.2.157 Decreased platelet serotonin transporter inpatients with psychotic disorders

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 γ-endorphin (γE) or the non-opioid peptide Nα-acetyl-γ-endorphin (AcγE) in a dose of 100 pg. High doses of apomorphine (10 μg) or amphetamine (2 μg) injected into the nucleus accumbens resulted in hyperlocomotion. This response was blocked by pretreatment with γE but not with AcγE. This effect of γE 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 γE and AcγE 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.

SCD-HeFT

Neuropharmacological studies were conducted in mice with a number of hetero[2,1]benzothiazepine derivatives, analogues of tianeptine. Seven of the 12 compounds under study potentiated the actions of 5-hydroxytryptophan (5-HTP, 50 mg/kg i.p.) and/or antagonised the hypothermia induced by high doses of apomorphine. Moreover, some of them inhibited the head twitches induced by 5-HTP (250 mg/kg i.p.) and the stereotyped behaviour and/or climbing behaviour of low doses of apomorphine. These compounds also produced a slight inhibition of exploratory behaviour in the holeboard test. On the other hand, no significant muscle relaxant, anticonvulsant and anxiolytic activities were observed at any dose employed. Together, these data suggest that some of the compounds under study exert antidepressant and neuroleptic effects in mice with no muscle relaxant, anxiolytic and anticonvulsant activities.

Behavioral effects of dopamine agonists and antagonists in MPTP-lesioned D 3 receptor knockout mice

To test the modulatory role of D 3 receptors in normal and dopamine-depleted mice, D 3 receptor KO mice and wild-type (WT) littermates were administered saline, l-dopa/carbidopa (20/2 mg/kg ip), a preferential D 3>D 2 agonist S32504, a D1+D 2/D 3 agonist apomorphine, a selective D 3 antagonist S33084, or apomorphine with S33084 prior to and after administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We monitored lines crossed in a 55-min session, average number of rears, and average number of grooming bouts. MPTP treatment produced equivalent 70% losses of dopamine fibers in the caudate putamen (CPu) and nucleus accumbens (NAC) of WT and D 3 KO mice as compared to their control (vehicle injected) counterparts. D 3 receptors were absent in KO mice, and the number of D 3 receptors was unaffected by MPTP-induced loss of DA terminals in WT mice. The results support a lack of involvement of the D 3 receptor for D1:D2 receptor-mediated behavioral activity (synergy). First, S32504 inhibited all behaviors and to a similar degree in D 3 KO and WT mice. Second, S33084 at the higher concentration increased number of lines crossed in response to high dose apomorphine in both D 3 KO and WT mice. Third, in nonlesioned mice, apomorphine-induced gnawing stereotypies were inhibited by S33084 in both D 3 KO and WT mice. Interestingly, the inhibition of apomorphine-induced gnawing was not apparent in MPTP-lesioned mice, and this stereotypy was elevated in D 3 KO-MPTP-lesioned mice. Thus, the suppressive effects of S32504 could be via D2 autoreceptor inhibition of DA release, and D2 receptor blockade by S33084 leads to release of that inhibition. This may be more apparent in MPTP-lesioned partially DA denervated mice.

Neuropharmacological study of hetero[2,1]benzothiazepine derivatives analogues of tianeptine

Neuropharmacological studies were conducted in mice with a number of hetero[2,1]benzothiazepine derivatives, analogues of tianeptine. Seven of the 12 compounds under study potentiated the actions of 5-hydroxytryptophan (5-HTP, 50 mg/kg i.p.) and/or antagonised the hypothermia induced by high doses of apomorphine. Moreover, some of them inhibited the head twitches induced by 5-HTP (250 mg/kg i.p.) and the stereotyped behaviour and/or climbing behaviour of low doses of apomorphine. These compounds also produced a slight inhibition of exploratory behaviour in the holeboard test. On the other hand, no significant muscle relaxant, anticonvulsant and anxiolytic activities were observed at any dose employed. Together, these data suggest that some of the compounds under study exert antidepressant and neuroleptic effects in mice with no muscle relaxant, anxiolytic and anticonvulsant activities.

Nucleus accumbens dopamine and discriminated approach learning: interactive effects of 6-hydroxydopamine lesions and systemic apomorphine administration.

Although dopaminergic mechanisms have been implicated in incentive motivational processes, their role in appetitive conditioning remains poorly understood. To investigate the effects of dopamine (DA) depleting lesions of the nucleus accumbens and the direct acting dopamine receptor agonist apomorphine on the learning of discriminated appetitive approach behavior in a Pavlovian autoshaping paradigm. Rats received bilateral infusions of either phosphate-buffered saline (shams) or 6-hydroxydopamine (lesions) directly into the nucleus accumbens. Ten days later, rats were trained on an autoshaping task whereby a previously neutral light stimulus was paired with food reward. Presentation of another stimulus (CS-) was never followed by reward. Over 100 pairings subjects developed a conditioned response of approaching the reward-predictive stimulus (CS+). Prior to each autoshaping session subjects were administered either saline (1 ml/kg SC) or apomorphine (30 microg/kg; 100 microg/kg), in a between-subjects design. Lesioned subjects showed a delay in the acquisition of discriminated approach and were insensitive to a subsequent change in the contingency of the task whereby approaches to the CS+ now prevented food delivery. Low dose apomorphine profoundly impaired learning in both sham and lesioned subjects. Despite increasing the overall number of CS+ and CS- approaches, the higher dose of apomorphine allowed discriminated approach in sham-operated animals only. These data are compatible with the hypothesis that nucleus accumbens dopamine serves to energize rather than guide conditioned approach to appetitive cues. They also support the notion that DA inputs in this region confer flexibility of approach to cues predictive of reward.

Drug-induced rotation intensity in unilateral dopamine-depleted rats is not correlated with end point or qualitative measures of forelimb or hindlimb motor performance

The pharmacological induction of rotational (circling) behavior is widely used to assess the effects of lesions to the dopaminergic system and the success of treatment strategies in rat models of Parkinson’s disease. While the number of rotations under apomorphine, L-DOPA and amphetamine is related to the extent of dopamine depletion after unilateral 6-hydroxydopamine lesion of the nigrostriatal dopamine system, the relationship of the intensity of rotational behavior to the degree of impairment in motor behavior is unclear. The present study examined this question by correlating rotational behavior and motor abilities in a rat analogue for Parkinson’s disease produced by unilateral nigrostriatal bundle lesion with 6-hydroxydopamine. Ipsiversive and contraversive rotation was measured in the rats following systemic administration of low and high doses of apomorphine, the dopamine precursor L-DOPA, and amphetamine. The motor assessment included end point and qualitative measures of fore- and hindlimbs assessed in a skilled reaching task and a skilled ladder rung walking task. The intensity of drug-induced rotation did not correlate with the measures of motor performance. We conclude that independence of rotational behavior and motor performance argues that both the assessment of 6-hydroxydopamine behavioral deficits and potential treatments for the functional deficits require comprehensive assessment, including both measures of rotation and motor behavior.