Autoantibodies against opioid or glutamate receptors are associated with changes in morphine reward and physical dependence in mice.

BACKGROUND: Possible interactions between nervous and immune systems during opioid addiction remain elusive. Recombinant mu-delta opioid receptors (MDOR) and the glutamate receptor 1 (GluR1) subunit of amino-3-hydroxy-5-methyl-4-isoxazole propionic acid glutamate receptors are involved in acute and chronic effects of morphine. Elevated levels of autoantibodies (aAbs) to these receptors were demonstrated in heroin human addicts and in animal models. This study characterized the role of aAbs to these receptors in behavioral modulations recruited during opioid tolerance and sensitization. METHODS AND FINDINGS: Male CD-1 mice, immunized with either MDOR or GluR1 peptide fragments (80 microg intraperitoneal (i.p.)), were examined for spontaneous behavior and response to morphine (5 mg/kg i.p.). Spontaneous home-cage activity, novelty-induced self-grooming and morphine-induced hyperactivity were higher in GluR1 mice compared to Vehicle subjects, whereas MDOR immunization was associated with an increased morphine-induced conditioned place preference. In response to escalating doses of morphine (from 10 to 60 mg/kg i.p., twice daily) and naloxone-precipitated withdrawal (1 mg/kg subcutaneous), GluR1 mice exhibited a more marked stereotyped sniffing behavior and less body tremors compared to Vehicle subjects, whereas less sniffing and teeth chattering were found in MDOR mice. The expected downregulation of mu receptor binding sites, induced by chronic morphine in vehicle subjects, was completely absent following MDOR immunization. CONCLUSIONS: These findings indicate an altered response to morphine-related reinforcing and aversive effects in MDOR mice and altered coping with the environment in GluR1 mice. Circulating aAbs to specific neuroreceptors may alter the response to opiates and play a role as determinants of vulnerability to opiate addiction.

MDMA-induced impairment in primates: antagonism by a selective norepinephrine or serotonin, but not by a dopamine/norepinephrine transport inhibitor.

Human MDMA (R,S-3,4-methylenedioxymethamphetamine) users display selective cognitive deficits after acute MDMA exposure, frequently attributed to serotonin deficits. We postulated that MDMA will compromise executive function in primates and that an inhibitor of the serotonin transporter (SERT) and the norepinephrine transporter (NET) but not the dopamine (DAT) transporter, will prevent impairment. The potencies of DAT/NET, NET and SERT inhibitors to block transport of [(3)H]MDMA and [(3)H]monoamines were compared in vitro. Subsequently, cynomolgus monkeys (Macaca fasicularis) were trained to stable performance in a reversal learning task. Effects of once-weekly oral or i.m. dose of MDMA (1.5 mg/kg, n = 4) on performance were monitored, alone or after pretreatment with inhibitors of the SERT, DAT or NET (prior to i.m. MDMA). 1) Drug potencies for blocking [(3)H]MDMA or [(3)H]monoamine transport were not consistent; 2) Oral MDMA increased error rates in a cognitive task for up to three days following exposure, whereas intramuscular MDMA prevented subjects from performing the cognitive task on the day of administration, but not on subsequent days; 3) The SERT inhibitor citalopram and the NET inhibitor desipramine, but not the DAT/NET inhibitor methylphenidate, reversed the effects of MDMA on task performance and mandibular movements induced by i.m. MDMA and 4) MDMA altered sleep latency. Oral MDMA impairs executive function in monkeys for several days, a finding of potential relevance to MDMA consumption by humans. Reversal of impaired executive function by a NET inhibitor implicates the NET and norepinephrine in MDMA-induced cognitive impairment and may be relevant to therapeutic strategies.

Involvement of adenosinergic receptor system in an animal model of tardive dyskinesia and associated behavioural, biochemical and neurochemical changes.

Tardive dyskinesia is a syndrome characterized by repetitive involuntary movements usually involving the mouth, face and tongue. It is considered as the late onset adverse effect of prolonged administration of typical neuroleptic drugs. Adenosine is now widely accepted as the major inhibitory neuromodulators in the central nervous system besides GABA. Both, agonists of adenosine A(1) and A(2) receptors and the antagonists of A(2A) receptors are known to protect against neuronal damage caused by toxins as well as they can also protect against the cell damage inflicted by reactive oxygen species. The present study investigated the effect of adenosine and A(2A) receptor antagonist, caffeine in an animal model of tardive dyskinesia by using different behavioural (orofacial dyskinetic movements, stereotypic rearing, locomotor activity, % retention), biochemical (lipid peroxidation, reduced glutathione levels, antioxidant enzyme levels (superoxide dismutase and catalase) and neurochemical (neurotransmitter levels) parameters. Chronic administration of haloperidol (1 mg/kg i.p. for 21 days) significantly increased vacuous chewing movements (VCMs), tongue protrusions, facial jerking in rats which was dose dependently inhibited by adenosine and caffeine. Chronic administration of haloperidol also resulted in an increased dopamine receptor sensitivity as evident by increased locomotor activity and stereotypic rearing after day 14. Chronic administration of haloperidol also decreased % retention time on elevated plus maze paradigm. Treatment with adenosine or caffeine reversed these behavioural changes. Besides, haloperidol also induced oxidative damage in all regions of brain which was prevented by caffeine and adenosine, especially in striatum. On chronic administration of haloperidol there was a decrease in dopamine and norepinephrine turnover which was dose-dependently reversed by treatment with adenosine or caffeine. When caffeine and adenosine were co-administered, there was no synergistic effect, possibly due to mutual antagonistic effects. The findings of the present study suggested the involvement of adenosinergic receptor system in the genesis of neuroleptic-induced tardive dyskinesia.

Role of nigral NFkappaB p50 and p65 subunit expression in haloperidol-induced neurotoxicity and stereotyped behavior in rats.

Long-term use of typical neuroleptics such as haloperidol may be limited by unwanted motor side effects like tardive dyskinesia (TD) characterized by repetitive involuntary movements, involving the mouth, face and tongue. TD generally persists after haloperidol withdrawal indicating long lasting changes in brain function that are no longer related to the presence of the drug. The precise mechanisms of the neuronal toxicity induced by haloperidol are poorly understood. Haloperidol has been shown to induce the expression of the transcription factor nuclear factor-kappaB (NFkappaB). NFkappaB resembles a heterodimer protein composed of a 50 and a 65 kDa subunits and the role of the NFkappaB subunits on haloperidol-induced toxicity remains still unknown. The aim of the present study is to investigate the role of the p65 and p50 subunits of NFkappaB on the toxicity induced by chronic haloperidol administration in an experimental model of TD. Rats were treated for 21 days with: haloperidol (1mg/kg), clozapine (1mg/kg) or saline. Apomorphine-induced stereotyped behavior was evaluated. Striatal expression of the dopamine transporter (DAT) and the nigral expression of the NFkappaB p65 and p50 subunits were measured by Western Blot. Haloperidol, but not clozapine, increased stereotyped behavior associated to a decreased striatal DAT expression (p<0.01). Haloperidol did not modify the nigral expression of the p65 subunit whereas clozapine decreased it (p<0.01). Both drugs induced a significant decrease in the nigral expression of the NFkappaB p50 (p<0.05 and p<0.01, respectively). The decrease in nigral expression of the p50 subunit may increase the vulnerability of the dopaminergic neurons to a possible neurotoxic effect of p65 subunits in the haloperidol-treated rats.

Acute toxicity and anticonvulsant activity of liposomes containing nimodipine on pilocarpine-induced seizures in mice.

Nimodipine has been shown to have an inhibitory action on seizures and brain damage in rodents. However, the pharmaceutical applicability of this drug is limited by its low solubility in gastrointestinal fluids and high first-pass effect in the liver, which leads to low bioavailability. These difficulties can be overcome through the use of liposomes. The aim of the present study is to evaluate the toxicity and anticonvulsant activity of liposomes containing nimodipine (NMD-Lipo) on pilocarpine-induced seizures. NMD-Lipo was prepared using the lipid-film hydration method. Central nervous system toxicity of NMD-Lipo was assessed by Hippocratic screening. Systemic toxicity was evaluated by analyses of biochemical and hematological parameters and by observing possible signs of toxicity. The possible anticonvulsant activity was tested by the pilocarpine model. The administration of the NMD-Lipo at doses of 0.1, 1, and 10 mg/kg caused no toxicity in animals. Furthermore, NMD-Lipo prevented the installation of 100% of the pilocarpine-induced seizures and prevented the death of 100% of the mice treated with pilocarpine. These data shown that NMD-Lipo has an anticonvulsant activity significantly superior to free NMD, suggesting that the liposomes promoted a drug controlled release by improving its bioavailability and consequently increasing its pharmacological activity.

The physiological consequences of crib-biting in horses in response to an ACTH challenge test.

Stereotypies are repetitive and relatively invariant patterns of behavior, which are observed in a wide range of species in captivity. Stereotypic behavior occurs when environmental demands produce a physiological response that, if sustained for an extended period, exceeds the natural physiological regulatory capacity of the organism, particularly in situations that include unpredictability and uncontrollability. One hypothesis is that stereotypic behavior functions to cope with stressful environments, but the existing evidence is contradictory. To address the coping hypothesis of stereotypies, we triggered physiological reactions in 22 horses affected by stereotypic behavior (crib-biters) and 21 non-crib-biters (controls), using an ACTH challenge test. Following administration of an ACTH injection, we measured saliva cortisol every 30 min and heart rate (HR) continuously for a period of 3h. We did not find any differences in HR or HR variability between the two groups, but crib-biters (Group CB) had significantly higher cortisol responses than controls (Group C; mean ± SD: CB, 5.84 ± 2.62 ng/ml, C, 4.76 ± 3.04 ng/ml). Moreover, crib-biters that did not perform the stereotypic behavior during the 3-hour test period (Group B) had significantly higher cortisol levels than controls, which was not the case of crib-biters showing stereotypic behavior (Group A) (B, 6.44 ± 2.38 ng/ml A, 5.58 ± 2.69 ng/ml). Our results suggest that crib-biting is a coping strategy that helps stereotypic individuals to reduce cortisol levels caused by stressful situations. We conclude that preventing stereotypic horses from crib-biting could be an inappropriate strategy to control this abnormal behavior, as it prevents individuals from coping with situations that they perceive as stressful.

Differential effects of dopamine D-1 and D-2 receptor agonists on EEG activity and behaviour in the rabbit.

SKF 38393, a selective agonist for dopamine D-1 receptors, LY 171555, a selective agonist for D-2 receptors and apomorphine, an agonist for both receptor sites, all induced activation of the electrical activity of the brain (EEG) in the rabbit. While SKF 38393 induced EEG changes without concomitant signs of stereotyped behaviour, the injection of both LY 171555 and apomorphine also elicited marked behavioural effects, mostly stereotyped mouth and head movements. The EEG effects of SKF 38393 were prevented by SCH 23390 (0.003 mg/kg i.v.), but not by (-)-sulpiride (6.2-25 mg/kg i.v.). Haloperidol attenuated the effects induced by SKF 38393 only at a dose (1 mg/kg) that induced EEG changes of its own. Similarly, effects of apomorphine on both EEG and behaviour were prevented by SCH 23390 and to a lesser extent by haloperidol, but not influenced by (-)-sulpiride. Different patterns of interactions were observed when D-2 receptors were selectively stimulated by LY 171555. Behavioural effects induced by LY 171555 were fully inhibited by both (-)-sulpiride (6.2-12.5 mg/kg i.v.) and haloperidol (0.1-0.3 mg/kg i.v.). The drug SCH 23390 attenuated some behavioural components at 0.3 mg/kg (i.v.), a dose at least 100-fold that effective on the EEG effects induced by SKF 38393. However, all these antagonists exerted weak or no effects on EEG activation induced by LY 171555 and did not restore the control patterns at any doses examined.(ABSTRACT TRUNCATED AT 250 WORDS)

Roles of dopamine and 5-hydroxytryptamine in stereotyped and non-stereotyped behaviour.

The roles of dopamine (DA) and 5-hydroxytryptamine (5-HT) in stereotyped and non-stereotyped components of the classical behavioural syndromes induced by 5-HT and DA were investigated by studying (a) behavioural interactions between the DA agonist apomorphine and the 5-HT agonist 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) and (b) the effects of depletion of 5-HT on the behavioural responses to amphetamine and p-chloroamphetamine. In agreement with evidence [Andrews, Fernando and Curzon (1982) Neuropharmacology 21:63-68] that non-stereotyped (i.e. body shakes and hind limb abduction) and stereotyped (i.e. head weaving and reciprocal forepaw treading) behaviour induced by d-amphetamine (25 mg/kg, i.p.) were inhibited and enhanced respectively by DA, apomorphine inhibited two non-stereotyped behavioural responses induced by 5-MeODMT (hind limb abduction and Straub tail) but enhanced reciprocal forepaw treading. However, head weaving was inhibited. Evidence indicated that behaviour induced by DA (whether stereotyped or not) was inhibited by 5-HT. Thus, the induction by apomorphine of sniffing and mouth movements was enhanced when the synthesis of 5-HT was inhibited. Also, p-chloroamphetamine caused sniffing and mouth movements only when 5-HT synthesis was inhibited. Under the latter conditions, while most classical behavioural responses associated with 5-HT did not occur, hind limb abduction persisted. Similarly, amphetamine (25 mg/kg) caused hind limb abduction and forepaw treading even when 5-HT was almost completely depleted. These results may indicate that the amine releasers have some direct 5-HT agonist properties. Results in general indicate the multiplicity of behavioural interactions between DA and 5-HT.

Dopaminergic behaviors and signal transduction mediated through adenylate cyclase and phospholipase C pathways.

We determined the relative effects of chemical receptor inactivation on dopaminergic signaling through adenylate cyclase and phospholipase C pathways and evaluated the behavioral implications of such receptor manipulations. Groups of rats were given intraperitoneal injections of 10 mg/kg N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), a reagent that differentially inactivates neurotransmitter receptors. Control and treated animals were used to assess dopaminergic-mediated behaviors or brain tissues were prepared from the animals and used to assay D1-like receptor binding and agonist-stimulated second messenger formation. EEDQ decreased by 75% the number of D1-like binding sites and completely abolished dopamine-stimulated cyclic AMP formation in striatal membranes. Conversely, dopamine-stimulated phosphoinositide hydrolysis was insensitive to inactivation by EEDQ as examined over different durations of EEDQ treatment, in different brain regions, or with different concentrations of the D1-like receptor agonist SKF38393. EEDQ-pretreated animals lost their stereotypic response to apomorphine but showed increased vacuous jaw movements in response to apomorphine or SKF38393. Basal catalepsy was increased and SCH23390 was unable to further enhance catalepsy beyond the basal levels in the lesioned animals. In naive animals, SCH23390 catalepsy was reversed by apomorphine, and apomorphine stereotypy was reversed by SCH23390. Taken together, the present results imply that the dopamine-sensitive phospholipase C system mediates a subset of dopaminergic behaviors, notably vacuous jaw movements, in contrast to stereotypy and catalepsy which appear to be respectively mediated through stimulation and inhibition of the adenylate cyclase-coupled dopaminergic system.

Oral stereotypy induced by amphetamine microinjection into striatum: an anatomical mapping study.

The ventrolateral striatum has been shown to specifically contribute to expression of psychostimulant-induced orofacial stereotypies. Adult male Sprague-Dawley rats were implanted with bilateral cannulae directed at one of eight striatal subareas, and were injected with saline or amphetamine (20 micrograms/0.5 microliter/side) in a counterbalanced order. Behaviors were observed and scored using a time-sampling procedure. In the middle ventrolateral striatum, amphetamine injections produced intense stereotypy, primarily consisting of bar biting, non-injurious self-biting and repetitive paw-to-mouth movements, while having no effect on locomotion or rearing. Amphetamine injections 2 mm medial or 1 mm dorsal produced no oral stereotypy, while injections 1 mm rostral or caudal to the effective site produced only low levels of stereotypy. Injections into the surrounding sites, particularly in the ventromedial region, also had stimulatory effects on locomotion and rearing. In a separate experiment, animals were given either unilateral or bilateral injection of amphetamine into the ventrolateral striatum. The unilateral injection produced stereotypy half as intense as that observed with bilateral injections. These results suggest that the ventrolateral striatum is a discrete neuroanatomical region which is primarily responsible for expression of psychostimulant-induced orofacial stereotypies, and which is likely to be the striatal region controlling normal oral motor function. Further investigation of this area may provide valuable insights concerning the etiology and treatment of orofacial dyskinesias associated with basal ganglia dysfunction.

The angiotensin converting enzyme inhibitors captopril and enalapril inhibit apomorphine-induced oral stereotypy in the rat.

The possible functional interaction between angiotensin and dopamine mechanisms in the rat was investigated by examining the effects of the angiotensin converting enzyme inhibitors captopril and enalapril on apomorphine-induced stereotypy. Apomorphine-induced behaviour was observed, and recorded using a keypad linked to a microcomputer. In agreement with previous findings, low doses of apomorphine induced a syndrome of vacuous mouth movements, penile grooming, yawning and immobility whereas at higher doses the yawning syndrome disappeared to be replaced with sniffing, licking and gnawing. Two antagonism studies were carried out. In the first the effects of captopril on apomorphine-induced behaviour were compared with those of the classical neuroleptic haloperidol, and in the second dose-response curves for the effects of captopril and enalapril on apomorphine-induced behaviour were determined. Captopril had no effect on the apomorphine-induced yawning syndrome whereas this was blocked by haloperidol. In contrast, both captopril and haloperidol blocked oral stereotypy (licking and gnawing) induced by apomorphine but had no effect on sniffing induced by the dopamine agonist. Selective blockade of apomorphine-induced oral stereotypy by angiotensin converting enzyme inhibition was confirmed in the second study in which both captopril and enalapril were observed to antagonize apomorphine-induced gnawing. The inhibition of apomorphine-induced gnawing by enalapril correlated with inhibition of brain angiotensin converting enzyme, but not lung angiotensin converting enzyme, by the drug as assessed by ex vivo penetration studies. These data suggest that angiotensin converting enzyme inhibition modulates the expression of apomorphine-induced oral stereotypy, a response that is thought to be mediated by postsynaptic dopamine receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of D1 and D2 dopamine receptors in oral stereotypy induced by dopaminergic stimulation of the ventrolateral striatum.

Microinjection of amphetamine into the ventrolateral region of the striatum results in compulsive and intense oral stereotypies in the rat. Although these stereotyped behaviors are known to be a direct result of excessive stimulation of the striatal dopamine neurons, the relative roles of the D1 and D2 receptors in oral stereotypies are not clearly understood. It is reported here that microinjection of the selective D1 agonist, SKF 38393 (0, 0.3, 3.0, 30.0 micrograms in 0.5 microliters vehicle) into the ventrolateral striatum resulted in no observable changes in behavior during the 30-min test period. However, it was observed that intense self-biting emerged 3-4 h following injection. Examination of histology from these animals revealed extensive tissue damage and the delayed onset of biting was hypothesized to result from a neurotoxic effect of SKF 38393. Infusion of quinpirole (0, 0.3, 3.0, 30.0 micrograms in 0.5 microliter vehicle), a selective D2 agonist, resulted in a dose-dependent increase in orofacial behaviors such as licking, wood-chip eating, head-down sniffing and mouth movements. Intense oral stereotypies such as biting or gnawing were not observed following treatment with quinpirole. Infusion of the mixed agonist dopamine (0, 2.0, 10.0, 20.0 micrograms in 0.5 microliter vehicle) into the ventrolateral striatum was found to elicit intense oral stereotypy. This behavior consisted almost exclusively of self-biting similar to that observed following amphetamine microinjection into this region. Haloperidol, when given as either a systemic (0.2 mg/kg) or intra-ventrolateral striatum (2.5 micrograms/0.5 microliter) pretreatment, effectively blocked oral stereotypies induced by amphetamine microinjection into the ventrolateral striatum. Pretreatment with either the D1 antagonist SCH 23390 (0, 0.01, 0.1 mg/kg, i.p.) or the D2 antagonist raclopride (0, 0.05, 0.50, 1.0 mg/kg, i.p.) antagonized amphetamine-induced oral stereotypy in a dose-dependent manner. These findings demonstrate that within the striatal site specifically implicated in oral behavior, concurrent stimulation of both receptor subtypes is necessary for the expression of intense oral stereotypies.

Chronic treatment with clozapine, unlike haloperidol, does not induce changes in striatal D-2 receptor function in the rat.

Comparison has been made of the effects on brain dopamine function of chronic administration of haloperidol or clozapine to rats for up to 12 months. In rats treated for 1-12 months with haloperidol (1.4-1.6 mg/kg/day), purposeless chewing jaw movements emerged. These movements were only observed after 12 months' treatment with clozapine (24-27 mg/kg/day). Apomorphine-induced (0.125-0.25 mg/kg) stereotyped behaviour was inhibited during 12 months treatment with haloperidol. Clozapine treatment was without effect. After 12 months, stereotypy induced by higher doses of apomorphine (0.5-1.0 mg/kg) was enhanced in haloperidol, but not clozapine, treated rats. Bmax for striatal 3H-spiperone binding was elevated throughout 12 months of haloperidol administration, but was not altered by clozapine treatment. Bmax for striatal 3H-NPA binding was only elevated after 12 months of haloperidol treatment; clozapine treatment was without effect. Bmax for 3H-piflutixol binding was not altered by haloperidol treatment, but was increased after 9 and 12 months of clozapine treatment. Dopamine (50 microM)-stimulated adenylate cyclase activity was inhibited after 1 month's haloperidol treatment but normal thereafter. Adenylate cyclase activity was not altered by chronic clozapine treatment. Striatal acetylcholine content was increased after 3 and 12 months of haloperidol or clozapine intake. These findings indicate that the chronic administration of the atypical neuroleptic clozapine does not produce changes in brain dopamine function which mirror those of the typical neuroleptic haloperidol. In particular, chronic administration of clozapine, unlike haloperidol, does not appear to induce striatal D-2 receptor supersensitivity. Unexpectedly, clozapine treatment, unlike haloperidol, altered D-1 receptor function.

Alpha 1- and alpha 2-adrenoreceptor antagonists differentially influence locomotor and stereotyped behaviour induced by d-amphetamine and apomorphine in the rat.

The importance of dopamine (DA) in mediating locomotor, exploratory and stereotyped behaviour in rodents is well established. Evidence also indicates a modulatory role for noradrenaline (NA) although, due to nonspecificity. of previously available agents, a precise role remains undefined. The effects of the specific and selective alpha-adrenoreceptor antagonists idazoxan (alpha 2) and prazosin (alpha 1) on behaviour induced by amphetamine and apomorphine have been investigated in the rat. d-Amphetamine (2 mg/kg) induced hyperactive locomotion and exploration. Pretreatment with prazosin (1 mg/kg) markedly reduced these responses. In contrast, pretreatment with idazoxan (20 mg/kg) only marginally altered d-amphetamine hyperactivity. Apomorphine (0.5 mg/kg) induced biphasic locomotor and exploratory activity. Neither alpha-antagonist affected the initial burst of activity (60 min), although prazosin inhibited whereas idazoxan potentiated the secondary phase (90-180 min). At higher dosage, amphetamine (6 mg/kg) and apomorphine (2 mg/kg) induced stereotyped behaviours. Prazosin pretreatment enhanced stereotyped gnawing and decreased sniffing and locomotion, whereas idazoxan increased locomotion and decreased amphetamine-induced mouth movements. These data indicate that DA-induced locomotor and stereotyped behaviours are differentially influenced (in opposite directions) by both alpha1- and alpha 2-adrenoreceptor antagonists. NA may thus modulate the expression and character of behaviour by influencing DA function in certain brain areas.

Vacuous jaw movements induced by sub-chronic administration of haloperidol: interactions with scopolamine.

The present series of experiments was conducted to investigate the vacuous jaw movements induced by sub-chronic administration of haloperidol (HP). In the first experiment, daily injection of 0.4 mg/kg HP for 10 days increased vacuous jaw movements and decreased rearing behavior. The second and third experiments investigated the interaction between the effects of HP and the anticholinergic drug scopolamine. Co-administration of 0.5 mg/kg scopolamine with 0.4 mg/kg HP for 9 days reduced vacuous jaw movements and increased rearing responses relative to rats that received HP alone. Co-administration of HP with 0.25 mg/kg scopolamine for 9 days increased rearing relative to rats that received HP alone, but there was no effect of the lower dose of scopolamine on vacuous jaw movements. Administration of 0.5 mg/kg scopolamine plus 0.4 mg/kg HP on days 11-14 to rats that had received HP alone for 10 days reversed the effect of HP on rearing, but not on vacuous jaw movements. Rats that had received HP plus scopolamine for 10 days showed dramatic increases in vacuous jaw movements when scopolamine was withdrawn. Because vacuous jaw movements are produced within the first few days of administration, reduced by administration of scopolamine, and exacerbated by withdrawal of scopolamine, the pharmacological characteristics of these movements do not appear to bear a close relation to those of tardive dyskinesia in humans. The present results are consistent with the hypothesis that vacuous jaw movements in rats share some characteristics with Parkinsonian symptoms.

Continuous low-level apomorphine administration induces motor abnormalities and hallucinogen-like behaviors.

Continuous low-level (0.825 mg/kg/h for 20 h) administration of AP through SC in-dwelling silicone reservoirs in the rat induced behavioral and biochemical changes that were similar to those induced by low levels (0.1 mg/kg) of acutely administered AP (decreased behavioral activity and decreased dopamine metabolism in the striatum). With longer periods of continuous AP exposure (40 h or more) the activity-depressing effects of low-level AP diminished. Concurrently a novel behavioral syndrome emerged characterized by limb flicks, body shakes, sudden orienting responses, and motor abnormalities, such as tremors of the jaw muscles, chewing movements, prominent tongue extensions, and body 'tics'. This behavioral syndrome became more apparent following cessation of drug treatment. These novel behavioral changes, which were accompanied by increased behavioral responsiveness to acutely administered AP and amphetamine, were correlated with increased levels of dopamine, homovanillic acid, and 3,4-dihydroxyphenylacetic acid in the striatum but not the nucleus accumbens. This novel behavioral syndrome appears to reflect a rebound increase in dopaminergic mechanisms in striatum following their chronic suppression by low levels of AP.

The NK-3 tachykinin agonist senktide elicits yawning and chewing mouth movements following subcutaneous administration in the rat. Evidence for cholinergic mediation.

The selective NK-3 tachykinin receptor agonist senktide elicited yawning, chewing mouth movements and sexual arousal following subcutaneous administration (0.1-1.0 mg/kg) in the rat. These responses were not significantly affected by the dopamine antagonist haloperidol (0.03 mg/kg) or by 6-hydroxydopamine lesions of the nigrostriatal projection. In contrast, the behaviours were markedly attenuated by the peripheral and central muscarinic antagonist scopolamine (1 mg/kg), but not by the peripheral muscarinic antagonist N-methylscopolamine (1 mg/kg). These findings suggest that stimulation of NK-3 receptors produces yawning, chewing and sexual arousal by directly activating central cholinergic neurons.

Chronic neuroleptic-induced mouth movements in the rat: suppression by CCK and selective dopamine D1 and D2 receptor antagonists.

Fluphenazine decanoate (25 mg/kg IM every 3 weeks x 6) resulted in spontaneous vacuous chewing mouth movements and jaw tremor in male Sprague-Dawley rats. These movements could be suppressed by the selective D1 or D2 dopamine antagonists SCH 23390 (0.5 mg/kg) and raclopride (0.5 mg/kg), respectively, and by CCK-8S (50 micrograms/kg). Fluphenazine-induced mouth movements were unaffected by the selective CCK antagonist MK-329, and by a dose of physostigmine (50 micrograms/kg) sufficient to stimulate mouth movements in placebo treated rats. Scopolamine (0.1 mg/kg) suppressed spontaneous mouth movements in placebo-treated rats, but the effect on fluphenazine-induced mouth movements was not significant. A higher dose of scopolamine (0.5 mg/kg) did suppress the neuroleptic-induced mouth movements, but also induced hyperactivity, characterized by increased sniffing and grooming. These findings indicate that mouth movements resulting from the chronic administration of neuroleptics to the rat may serve as a useful pharmacological model of tardive dyskinesia in the human, and suggest that a relative increase of D1 activity as well as impaired CCK function may contribute to the pathogenesis of this disorder.

Persistent vacuous chewing in rats following neuroleptic treatment: relationship to dopaminergic and cholinergic function.

In order to relate the effects of pharmacological intervention to neuroleptic induced increases in oral activity rats were treated continuously (7 mg/kg per week) or discontinuously (7 mg/kg per week or 2 mg/kg per week) with haloperidol for 6 months. Only the two intermittently treated groups developed persisting increases in vacuous chewing movements (VCM) following drug withdrawal. Opposed to control animals and continuously treated rats, the discontinuously treated groups demonstrated significant elevation in mouth movements following stimulation with the dopamine (DA) D1 receptor agonist SK&F 38393 (23 mg/kg), whereas they did not response to an acute challenge with the selective DA D1 receptor antagonist NNC-756 (0.1 mg/kg). The DA D2 receptor antagonist raclopride (1 mg/kg) provoked a general fall in VCM; however, this was only significant in rats treated intermittently with haloperidol 7 mg/kg per week and in control rats. Intermittent neuroleptic treatment also increased apomorphine-induced stereotypy. The effect of challenge with the anticholinergic drug scopolamine (0.25 mg/kg) was not related to oral activity; furthermore, the finding of severe agitation in rats tested with the latter drug points to caution in the interpretation of rating of rats treated with anticholinergics. These results support that intermittent ingestion of neuroleptic drugs lead to long-lasting increases in VCM. They also suggest a relation of persisting elevated oral activity to supersensitivity to DA receptor agonists, as opposed to subsensitivity to D1 receptor antagonists.

Effect of chronic trifluoperazine administration and subsequent withdrawal on the production and persistence of perioral behaviours in two rat strains.

The effect of chronic administration of trifluoperazine on the perioral movement profile of Wistar and Sprague-Dawley rats was examined. Perioral movements were characterised by visual observations, coupled with electromyographic recording from the masseter muscle. In drug-naive animals from both strains the spectrum of perioral behaviours was essentially identical, primarily consisting of purposeless chewing, accompanied by occasional bursts of facial tremor and teeth chattering, with occasional yawning. Each burst of facial tremor was accompanied by a transient increase in the rate of purposeless chewing. Wistar rats exhibited a higher level of spontaneous purposeless chewing compared to Sprague-Dawley rats. In both strains, chronic administration of trifluoperazine (5 mg/kg per day, PO) for 5 months induced an increase in perioral behaviour, which primarily consisted of enhanced purposeless chewing. In Wistar rats the drug-induced increase in purposeless chewing was accompanied by an increase in the incidence of yawning, with no change in the incidence of either facial tremor or teeth chattering. In contrast, Sprague-Dawley rats displayed a drug-induced increase in purposeless chewing, accompanied by an increase in the incidence of facial tremor and teeth chattering, but not yawning. In Wistar rats withdrawal of trifluoperazine diminished but did not reverse the drug-induced increase in purposeless chewing. Drug withdrawal also precipitated a transient increase in the incidence of facial tremor and teeth chattering, but had no effect on yawning. In Wistar rats, the level of purposeless chewing and the incidence of yawning remained elevated above control levels for at least 13 weeks after drug withdrawal.(ABSTRACT TRUNCATED AT 250 WORDS)