Brain catecholamines: relation to defense reaction evoked by acute brainstem transection in cat.

The concentration of noradrenaline, but not serotonin, in the brainstem of cats is reduced 3 hours after the production of a defense reaction by supracollicular decerebration, even when movements and changes in blood pressure are abolished by transection of the spinal cord. After midcollicular decerebration, which does not elicit a defense reaction, noradrenaline concentrations do not change. The decrease in its concentration accompanying the defense reaction produtced by brain lesions probably reflects activity, in this behavior, of neturons containinig noradrenaline.

Methadone maintenance: plasma levels and therapeutic outcome.

Twenty-one opiate-dependent subjects were inducted into methadone maintenance treatment (MMT) in a closed metabolic ward. A daily dose of 30 mg of d, 1-methadone was given for 10 to 24 days followed by 60 mg/day for another 10 to 24 days. Analysis of plasma levels at 4-day intervals showed accumulation to a peak followed by a decrease to a lower level, indicative development of dispositional tolerance. The outcome of treatment was assessed after 21 to 43 mo (median, 33 mo). The best record of rehabilitation was obtained in subjects discharged with steady-state plasma concentrations above 200 ng/ml. Lower levels of plasma methadone were associated with higher frequency of urines containing illicit drugs and poorer psychosocial rehabilitation. This study indicates that a pharmacokinetically optimized dosage regimen would be useful in increasing the therapeutic effectiveness of MMT.

Disposition of methadone in methadone maintenance.

Six detoxified opiate addicts housed in a closed metabolic ward received methadone in stepwise increasing doses of 10, 20, 40, and 80 mg/day during 1 month. Four were given 14C-methadone at the lowest dose and again at the highest dose. Of the subjects receiving radiomethadone, 2 excreted the major part of the radioactivity in urine and 2 about equally in urine and feces. In addition to methadone, 7 metabolites were isolated and identified in urine and 3 metabolites in feces. About 75% of the urinary and fecal radioactive metabolites were unconjugated. Urinary excretion of methadone and its major N-monomethylated metabolite accounted for 17% to 57% of the given dose. The ratio of metabolite to parent drug increased in 5 of 6 subjects, and the urinary recovery of unchanged methadone decreased during the period. The results indicate that enhanced demethylation of methadone may occur during oral administration to man.

CSF and plasma beta-casomorphin-like opioid peptides in postpartum psychosis.

The authors measured opioid receptor-active components in the CSF of 11 women with postpartum psychosis, 11 healthy lactating women, and 16 healthy women who were not lactating. Activity that eluted with 0.2 M acetic acid 0.7-0.9 times the total volume of the column (fraction II activity) was significantly higher in the CSF of both healthy and psychotic women in the puerperium than in that of the lactating women. Very high levels of fraction II activity were seen in four psychotic patients. Material from these patients was further characterized by electrophoresis and high-performance liquid chromatography: The material migrated as bovine beta-casomorphin. Receptor-active material with the same characteristics was also found in the plasma of these four patients. The authors conclude that certain cases of postpartum psychosis are associated with the occurrence in plasma and CSF of unique opioid peptides probably related to bovine beta-casomorphin.

Chronic treatment with a classical neuroleptic alters excitatory amino acid and GABAergic neurotransmission in specific regions of the rat brain.

The purpose of the following experiments was to describe some of the neurochemical changes that occur in the basal ganglia of rats exposed chronically to a classical neuroleptic, fluphenazine, and to relate these changes to extrapyramidal motor dysfunction. For these studies a combination of behavioural, receptor autoradiographic and in situ hybridization methods were employed. Preliminary pharmacological studies on GABA receptors showed that incubation in Tris-acetate rather than Tris-citrate buffer increased the number of binding sites labelled by [3H]muscimol by over 120% without affecting binding affinity or selectivity. The results of experiments with fluphenazine showed that treatment for six months increased the frequency of vacuous chewing movements compared to controls. In the striatum, changes in GABA transmission were observed in fluphenazine-treated rats with increases in glutamate decarboxylase mRNA levels in the caudate nucleus, dorsal shell and core of the accumbens and decreases in [3H]muscimol binding in the caudate and dorsal shell regions. These data suggest that fluphenazine treatment increased GABA transmission in specific subregions of the caudate and accumbens nuclei. In addition, glutamate decarboxylase mRNA levels were elevated in the entopeduncular nucleus of fluphenazine-treated animals. Autoradiographic analysis of excitatory amino acid binding showed that fluphenazine exposure decreased [3H]alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid binding in entopeduncular nucleus and in the ventrolateral thalamic nucleus and decreased [3H]dizocilpine maleate binding in the medial geniculate nucleus. These experiments show that in addition to altering GABA transmission, chronic neuroleptic exposure alters excitatory amino acid transmission in specific regions of the basal ganglia-thalamocortical motor system. The neuroleptic dependent increases in glutamate decarboxylase mRNA levels in the entopeduncular nucleus may reflect changes in neurotransmission in the indirect pathway connecting the major input and output nuclei of the basal ganglia. Changes in some of these brain regions may be related to the occurrence of extrapyramidal motor disturbances.

Experimental tardive dyskinesia.

In ongoing studies of chronic administration of neuroleptics to monkeys (Cebus apella) and rats, the regional distribution of glutamic acid decarboxylase (GAD) and brain levels of homovanillic acid were examined. Reduction of GAD activity, a GABA-synthesizing enzyme, in three specific brain areas (substantia nigra, medial globus pallidus, and nucleus subthalamicus) was related to the development of neuroleptic induced dyskinesias; these reductions were not seen in treated animals who did not develop movement disorders. The neostriatal level of HVA was reduced in dyskinetic monkeys. Such animal models can be useful in the screening process for new antipsychotics and thus potentially aid in the prevention of drug-induced tardive dyskinesia.

Reduction of nigral glutamic acid decarboxylase in rats with neuroleptic-induced oral dyskinesia.

Following eight monthly haloperidol decanoate injections rats showed an increased rate of vacuous chewing movements (VCM's), which gradually disappeared within 4 drug-free months. Another single dose of non-decanoate haloperidol reinstated a second increase in VCM rate which was still significant after 2 months. The glutamic acid decarboxylase (GAD) activity in the substantia nigra of these chronically haloperidol-treated rats was lower than untreated controls. Furthermore, there was a significant negative correlation between individual VCM rates and nigral GAD activity. No corresponding changes occurred in other brain regions. The depression of nigral GAD may reflect a reduced tissue density of GABA-ergic axon terminals within the descending striato-nigral pathway.

A monitoring test for the liability of neuroleptic drugs to induce tardive dyskinesia.

Two Cebus apella monkeys with haloperidol-induced tardive dyskinesia have been studied. Substitution of chlorpromazine, thioridazine, clozapine, melperone, or fluphenazine for the daily haloperidol administration temporarily reduced the signs of tardive dyskinesia. In a monkey with low-grade symptoms, persisting for more than 100 days after withdrawal of haloperidol, neuroleptic drugs induced a typical sequence of events: first the dyskinetic movements were abolished, but 1--3 days after administration of a single dose of a neuroleptic drug there was a rebound worsening of symptoms. It was noticed that this aggravation of symptoms corresponded in magnitude and duration to the approximate liability of each compound to induce tardive dyskinesia in man. It is therefore suggested that this animal model could be used to monitor neurological side effects in neuroleptic drugs.

Haloperidol-induced tardive dyskinesia in monkeys.

In three cebus monkeys the chronic daily administration of haloperidol (0.5 mg/kg/day orally) created sedation and parkinsonism during the first 5-7 weeks. Later the animals developed signs reminiscent of acute dystonia, as seen in the clinic during treatment with neuroleptics. These signs were dose-dependent and in extreme cases included widespread tonic and clonic seizures. After 3 and 12 months, respectively, two of the cebus monkeys developed buccolingual signs (grimacing and tongue protrusion), similar to tardive dyskinesia in the clinic. The tardive dyskinesia symptoms were reduced in a dose-dependent manner after each haloperidol administration, being most pronounced in the morning before haloperidol was given. Biperiden reduced acute dystonia but reinstated signs of tardive dyskinesia, which had been abolished by haloperidol. It is suggested that cebus monkeys may provide a useful animal model for the study of neurologic long-term complications from neuroleptic drugs.

Chronic neuroleptic effects on spatial reversal learning in monkeys.

Cebus apella monkeys were chronically administered the antipsychotic drug fluphenazine decanoate for periods ranging from 3.5 to 5.5 years. In the present study, four of these monkeys and two controls were tested for cognitive abilities on a spatial learning task, which consisted of an original discrimination and four reversals of that discrimination. No effect of fluphenazine administration was seen in the rate of learning the original discrimination, but the carryover of learning across discrimination reversals was significantly reduced by fluphenazine. After overtraining on the original discrimination, the controls showed the normal difficulty in learning the first reversal. The fluphenazine-treated monkeys showed no such disruption. On subsequent reversals, the controls showed continually improving performance, so that on the third and fourth reversals they had near-perfect scores. On the other hand, the fluphenazine-treated monkeys showed no change over the four reversals. Unlike normal monkeys, their learning did not improve with practice. Although simple forms of learning seem to be relatively unaffected by chronic fluphenazine administration, more complex learning is disrupted.

Oral dyskinesia in rats following brain lesions and neuroleptic drug administration.

After 10-12 weeks of chronic haloperidol administration rats with frontal cortex ablations or lesions induced by intracerebroventricular infection of 6-hydroxydopamine developed vacuous chewing behavior at a fairly stable frequency (bifrontal ablations had 15-20, 6-hydroxy-dopamine lesioned rats 7-12 chewing movements/min). This behavior persisted for 10 weeks after the last injection of haloperidol decanoate. However, rats with frontal cortex lesions developed a low rate of vacuous chewings (4-8 chewings/min) even without haloperidol administration. Bilateral intrastriatal injections of kainic acid in combination with chronic haloperidol administration did not cause chewing movements in excess of unlesioned haloperidol-treated controls. Pharmacological tests of this animal model for tardive dyskinesia (TD) revealed similarities to human TD, but also differences. Dopamine agonists (apomorphine) and antagonists (haloperidol) both lowered chewing behavior analogous to reported effects on TD and so did gabaculine. The cholinergic drugs physostigmine and pilocarpine, however, increased chewing in rats, while anticholinergics (atropine) reduced it, in contrast to reported effects on human TD.

High frequency oral movements induced by long-term administration of amperozide but not FG5803 in rats.

Long-term studies of antipsychotic-induced oral movements may serve as a rat model of acute and tardive movement disorders. Vacuous chewing movements (VCM), tongue protrusions (TP), and jaw tremors (TR) were studied in rats during acute and chronic administration of two potential antipsychotics, amperozide and FG5803. Comparisons were made with haloperidol and vehicle. Single intraperitoneal injections of amperozide (0.2, 1, or 5 mg/kg) or FG5803 (1.2, 6, or 30 mg/kg) were without effect on oral behaviors. During long-term drug administration, withdrawal and readministration, endpoint analysis was focused on changes in supranormal oral movements. The maximal mean control frequencies found at 29 sessions during 14 months experiment +2 standard deviations were used to define the upper limit of the normal range. FG5803 (1.2, 6, or 30 mg/kg per day) administered via the drinking water for 12 months, did not produce significant deviations from this normal range with respect to VCM, TP, or TR, and this drug was not studied further. Rats receiving amperozide (0.2, 1, or 5 mg/kg per day) showed dose-related increases in oral movements over the year. The changes began after 3 months of treatment with amperozide 1 and 5 mg/kg per day, but became statistically significant only during the second half of the treatment year. Amperozide 0.2 mg/kg per day did not produce significant changes in oral movements during administration for a year, but drug withdrawal resulted in a significant rise in TP behavior. Haloperidol (1 mg/kg per day) produced increases in supranormal oral movements which tended to level out after 9 months. In all groups with significant elevations (i.e. haloperidol and amperozide 1 and 5 mg/kg per day), there was a persistence of such movements during a month of drug withdrawal. During treatment with amperozide (1 or 5 mg/kg per day), some rats developed a high frequency chewing behavior up to 175 VCMs/min. It is concluded that long-term treatment with amperozide, but not FG5803, produced a tardive pattern of supranormal oral movements. The importance of these findings for the clinical future of amperozide is difficult to predict, due to the unexpected finding of high-frequency chewing, which has not been noticed before during extensive studies of classical neuroleptics.

Intranigral infusion of enkephalins elicits dyskinetic biting in rats.

Leu- and Metenkephalin (Lenk and Menk) and their more stable analogues D-Ala-Leu- and D-Ala-Metenkephalin (DALenk and DAMenk) as well as D-Ala-D-Leu- and D-Ala-D-Metenkephalin (DADLenk and DADMenk) were infused bilaterally into substantia nigra in awake rats and oral movements were recorded for 90 min. DADLenk and DADMenk elicited dose-dependent biting dyskinesias with a chewing rate of about 90 jaw movements/min. DALenk produced a similar but weaker effect, whereas DAMenk, Lenk and Menk were ineffective in the doses given. These findings suggest a possible enkephalinergic mechanism underlying neuroleptic-induced tardive dyskinesias.

(-)-OSU 6162 inhibits levodopa-induced dyskinesias in a monkey model of Parkinson's disease.

We have studied the effects of two D2 dopamine receptor-selective compounds, (-)-OSU 6162 and raclopride, on levodopa-induced dyskinesias in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned common marmosets (Callithrix jacchus). Three monkeys developed a severe parkinsonian syndrome following administration of MPTP. In response to daily levodopa treatment the animals developed reproducible and idiosyncratic peak-dose dyskinesias. Pretreatment with (-)-OSU 6162 and raclopride, in doses increased by multiples of three, both dose-dependently relieved the levodopa-induced dyskinesias. However, in contrast to when raclopride pretreatment was given, (-)-OSU 6162 pretreatment did not induce akinesia. Our investigation suggests that (-)-OSU 6162 may be useful an an adjuvant treatment to levodopa in advanced Parkinson's disease to selectively combat levodopa-induced dyskinesias without affecting the antiparkinsonian response.

Neuroleptics differentially modulate central dopamine D1-receptor binding.

The effect of the classical neuroleptic, fluphenazine, on dopamine D1-receptor binding was examined in different regions of the basal ganglia. Whereas exposure to fluphenazine for 18 months reduced [125I]SCH-23982 binding to D1-receptors in the caudate putamen, nucleus accumbens and olfactory tubercle, binding in the entopeduncular nucleus was enhanced after fluphenazine treatment. Competition studies indicated that the region-dependent changes in [125I]SCH-23982 binding after fluphenazine exposure were not due to differences in the affinity of fluphenazine or other dopamine ligands for D1-binding sites. These data suggest that in addition to modulating striatal function, classical neuroleptics may also alter neurotransmission in the basal ganglia by enhancing dopamine receptor binding in the entopeduncular nucleus.

Intranigral stimulation of oral movements by [Pro9] substance P, a neurokinin-1 receptor agonist, is enhanced in chronically neuroleptic-treated rats.

Bilateral intranigral infusions of three different peptide agonists were made in rats exposed to fluphenazine decanoate, 30 mg/kg/month (FLU) or vehicle (CON) for seven months. Oral movements were monitored repeatedly during the neuroleptic pretreatment period, as well as before the intranigral infusion and during a 90-min period postinfusion. The FLU group had an increased frequency of vacuous chewing movements (VCM) during the pretreatment period in comparison to controls. Intranigral infusion of the neurokinin-1 (NK1) receptor agonist, [Pro9]Substance P (2.5 nmol on each side), 5-7 weeks after the last FLU injection, caused a significant increase of VCM in both pretreatment groups, lasting 7 min after the infusion. The VCM response to [Pro9]Substance P in the FLU group was significantly higher than in the CON group. A NK2 agonist [Lys5, MeLeu9, Nle10]Neurokinin A(4-10) (2.5 nmol) failed to produce significant changes in oral activity. A Leu-enkephalin analogue [D-Ala2,D-Leu5]enkephalin (3.8 nmol) induced a massive biting behavior in both FLU and CON rats. Using VCM as a behavioral assay, an increased nigral sensitivity to a NK1 agonist is demonstrated in rats chronically exposed to neuroleptics. No corresponding alterations could be ascribed for the NK2 receptor agonist or the Leu-enkephalin analogue.

Motor effects of (-)-OSU6162 in primates with unilateral 6-hydroxydopamine lesions.

The effects of the novel compound, (-)-OSU6162 ((S)-(-)-3-methylsulfonylphenyl-1-propylpiperidine), on rotational behavior induced by dopamine receptor agonists was investigated in common marmosets (Callithrix jacchus) with unilateral 6-hydroxydopamine lesions. (-)-OSU6162 per se displayed no effect on the animals' behavior. On the other hand, pretreatment with (-)-OSU6162 attenuated rotational behavior induced by apomorphine (apomorphini hydrochloridum), L-DOPA (3,4-dihydroxyphenylalanine), and the dopamine D2 receptor agonist, quinpirole (trans-(-)-4aR-4,4a, 5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolol[3,4-g]quinoline hydrochloride), without inducing motor impairment such as akinesia or dystonia. In addition, treatment with (-)-OSU6162 for 5 consecutive days almost completely abolished the rotational behavior provoked by apomorphine and produced a transient subsensitization of such apomorphine-induced effects after it was discontinued. Moreover, pretreatment with (-)-OSU6162 in two monkeys augmented the rotational behavior elicited by the dopamine D1 receptor agonists, SKF-81297 (R(+)-6-chloro-7,8,dihydroxy-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine hydrobromide) and A-77636 ((-)-(1R, 3S)-3-adamantyl-1-(aminomethyl)-3,4-dihydro-5, 6-dihydroxy-1H-2-benzopyran hydrochloride). The findings indicate that (-)-OSU6162 can exert indirect state-dependent effects that differentially affect dopamine D1 and dopamine D2 receptor agonist-induced behavior.

A Swedish drug abuse warning network.

During the period June 1971-December 1976 a total of 592 consecutive admissions to a Drug Addiction Clinic were asked which drugs they had been taking since their first contact with the illegal drug market. Nine drugs belonging to the opiate group, five different amphetamines, five hallucinogens, cocaine and cannabis were mentioned and the patients were asked to specify which year or years they had self-administered any of the drugs mentioned. No attempts were made to quantify the individual drug consumption. The amphetamines and cannabis dominated in the mid sixties, but from then on recorded used of these drugs declined. From 1965 there was a constant increase in the reported use of opiates up to a maximum of 55 per cent of the patients in 1976. The opiates seem to have been introduced on to the market in the order of increasing potency. Morphine base replaced raw opium in the early seventies but was later succeeded by heroin. Hallucinogens, except for a short period around 1969 when 11 per cent of our patients mentioned them, never seemed to reach important levels. A small but growing proportion of our patients have mentioned use of cocaine in the seventies.

The Swedish methadone maintenance program: a controlled study.

Thirty-four drug addicts, aged 20 - 24 years, with a history of 4 - 8 years of intravenous heroin abuse, were randomly assigned either to a methadone maintenance treatment (MMT) (17) or to an untreated group (17). The untreated controls could not apply for entrance to the program until two years later. It was found that after two years 12 MMT patients had abandoned their drug habits and begun work, whereas 5 had recurrent drug abuse problems. Of the controls, one was drug-free and gainfully employed, 12 were continuously abusing heroin (3 of these had incurred potentially fatal diseases in consequence), 2 were in prison and 2 had diet. Two to seven years after their first visit to the Psychiatric Research Center 8 of the original control group have been accepted into the program. At present 19 (out of 25 admitted) are gainfully employed and no longer abusing drugs. Among the remaining controls 4 are dead, 3 are in prison, one in spite of a serious heart condition abuses heroin and one is drug-free. The rehabilitation rate was thus 76 per cent in the program as compared to 6 per cent among the control group. In addition, MMT obviously reduced the high morbidity and mortality rates found in a selection of heroin addicts who fulfilled the admittance criteria of the Swedish program.

Effects of buprenorphine in heroin addicts.

Twelve heroin addicts on the 8th day after withdrawal, and 8 healthy volunteers were given a single i.m. injection of buprenorphine 0.6 mg and their subjective response rated on 10 psychological variables. Pre-injection rating differed significantly between addicts and controls on 7 variables out of 10. Following buprenorphine more subjective changes were noted in the control group which became more calm, depressed, more aware of the environment, sleepy, tired, intoxicated, dizzy and nauseated. The drug addicts reported changes only in 2 variables (less tense and dysphoric) but otherwise showed no significant changes. These findings support the notion that buprenorphine induces low or normalizing effects in heroin addicts. This drug might thus be suitable for maintenance therapy in opiate addiction.