Neuroendocrine effects of chronic neuroleptic therapy in male psychiatric patients

(1) Hypogonadism with impotence, decreased libido and oligospermia is known to occur in patients with prolactin (PRL) secreting tumors and in patients receiving neuroleptics. The present study deals with male psychiatric patients under chronic treatment with neuroleptics. (2) Testosterone levels were within the normal range. (3) Prolactin levels were only elevated in patients also receiving anticholinergic agents. (4) A significant inverse relationship was found between the PRL and testosterone levels. (5) Human chorionic gonadotrophin (HCG) produced a net increase in prolactin and testosterone. (6) The same treatment did not affect the prolactin levels when the patients were treated with bromocriptine (7.5 mg b.d). a dopamine agonist. (7) Bromocriptine did not affect the PRL and testosterone levels.     

Regional differences in chronic neuroleptic effects on extracellular dopamine activity.

The extracellular levels of dopamine (DA) and DA metabolites in the caudate-putamen (CPu) and the nucleus accumbens (NA) of rats following administration of haloperidol (HAL) decanoate and fluphenazine (FLU) decanoate for 8 months were assessed using intracranial microdialysis 1 month after final injection. Both HAL- and FLU-treated animals showed persisting plasma neuroleptic levels at time of sacrifice. Extracellular basal levels of homovanillic acid (HVA) in the CPu were significantly elevated in the FLU-treated animals, while basal levels of 3,4-dihydroxyphenylacetic acid (DOPAC) in the CPu were significantly elevated in the HAL-treated animals. Basal levels of DA and the serotonin metabolite, 5-hydroxyindoleacetic acid (5HIAA) in the CPu were not significantly different between groups. No significant between-group differences were found for basal levels of any of the analytes in the NA. Neuroleptic-treated animals showed an enhanced response to direct infusion through the dialysis probe of amphetamine (1 microM) and nomifensine (10 microM) in the CPu but not the NA. These results suggest that chronic neuroleptic treatment produces enhanced extracellular DA activity in nigrostriatal, but not mesolimbic DA pathways.     

Behavioural effects of chronic treatment with apomorphine in combination with neuroleptic drugs

Groups of male Wistar rats were injected with either apomorphine alone twice daily for one week or with apomorphine in combination with chlorpromazine or thioridazine. The neuroleptics were administered once daily so that it was possible to assess their duration of effect on the apomorphine responses. Other groups were injected with saline (controls) chlorpromazine or thioridazine. The nature and time of onset and duration of the stereotyped response following apomorphine injection was determined twice daily. In addition, the behaviour of the rats on the hole board apparatus was also assessed after seven days of drug treatment. Apomorphine was found to induce either a "sniffing/burrowing" or a "fighting" stereotypy. Chlorpromazine increased the latency and reduced the duration of both types of stereotypy. In contrast thioridazine only increased the latency and reduced the duration of response the "fighting" group. On the hole board apparatus, both neuroleptics reduced the ambulation and rearing scores of the "fighting groups alone. It is suggested that the different types of stereotypy induced by chronic apomorphine administration, and their sensitivity to the two neuroleptics, are mediated by different types of dopamine receptors.     

Inositol has behavioral effects with adaptation after chronic administration

Summary Inositol is a simple dietary polyol that serves as a precursor in important second messenger systems. Inositol in pharmacological doses has been reported recently to be therapeutic in depression, panic disorder and obsessive compulsive disorder. We hereby report effects of inositol in the elevated plus maze model of anxiety. These results should allow development of new inositol analogs that could expand psychoactive drug development possibilities via second messenger manipulation.     

Electrocortical and behavioral effects of chronic immobility on word processing

Neuroelectrical and subjective effects of chronic motor deficits (severe immobility) on word processing were explored. A total of ten artificially ventilated patients with end-stage amyotrophic lateral sclerosis (ALS), seven patients with tetraplegia due to a high spinal cord injury (SCI), and nine matched controls were examined. Both ALS and SCI patients were almost completely paralyzed; eye, head, and face movements were intact in SCI but not in ALS patients. Event-related brain potentials (ERPs) were recorded during presentation of verbs with strong motor-action associations and nouns with strong visual associations. Subjects estimated the subjective strength of motor and visual associations for each word using a scale from 0 to 5. No between-group difference was found for subjectively rated motor associations. All patients reported much stronger visual associations for both nouns and verbs than healthy subjects. ERPs to both word classes revealed a left occipital negativity in SCI patients at a latency of 200-300 ms, and a marked decrease of the slow positive wave in the interval of 300-800 ms in the two patient groups. Both psychophysical and electrophysiological data suggest compensatory activation of visual information processing areas in severely paralyzed patients. The more pronounced effects in the SCI group as compared with the ALS group may be attributed to somatosensory deafferentation in SCI patients, while the sensory inflow in ALS remains relatively intact.     

Medical effects of abrupt neuroleptic withdrawal

Abrupt withdrawal of neuroleptics is often associated with symptoms such as headache, insomnia, nausea, and vomiting. Do these symptoms exceed base rates? Are prewithdrawal dosage and type of neuroleptic significant? Are the concurrent administration and/or withdrawal of AP drugs necessary for the production of these withdrawal symptoms? The literature in the area is reviewed to indicate current status of these issues. Also, prewithdrawal and postwithdrawal symptom data are presented from a withdrawal study of 56 chronic schizophrenic patients.Postwithdrawal symptom rates (38%) significantly exceeded base rates for the total group and for subgroups withdrawn from neuroleptics only and from neuroleptics and AP drugs. Other studies^2,3,5,8 have found incidences of 60% and higher. A relationship between neuroleptic dosage and withdrawal symptoms was not found, as was also the case in one prior study.³ We did not establish a relationship between neuroleptic type and withdrawal symptoms, but the studies^2,3,5,8 showing the highest incidences of withdrawal symptoms used particularly autonomic neuroleptics (especially aliphatics). Although nonautonomic neuroleptics (piperazines and butyrophenones) alone can lead to withdrawal symptoms, they appear to do so mostly when AP drugs are concomitantly being taken and are withdrawn. The clinical implications of these findings are discussed.     

Naloxone in chronic schizophrenic patients: neuroendocrine and behavioral effects

Naloxone produced improvement in abnormal thought content in medicated chronic schizophrenic patients, but not in drug-free patients. In contrast, drowsiness and increases in plasma prolactin concentrations were seen only in drug-free schizophrenic patients. Although growth hormone concentrations increased in drug-free and medicated schizophrenic patients, the time course was different in the two groups. Neuroleptics appear to alter naloxone's clinical and neuroendocrine effects in chronic schizophrenic patients.     

Neurotensin and neurotensin analogues modify the effects of chronic neuroleptic administration in the rat.

The effects of intracerebroventricular neurotensin and the neurotensin analogues neuromedin N and [D-Trp 11]neurotensin on the behavioural responses to chronic neuroleptic administration were investigated in the rat. Chronic (18 weeks) administration of a low dose (12.5 mg/kg, i.m., every 3 weeks) of fluphenazine decanoate alone failed to elicit the vacuous chewing mouth movements (VCMs) which have previously been reported following higher doses of this drug, but VCMs were seen in neuroleptic-treated animals following the additional administration of neurotensin. A higher dose of fluphenazine (25 mg/kg, i.m., every 3 weeks) greatly increased the VCM response, and this potentiation was suppressed to control levels by [D-Trp11]neurotensin, but unaffected by neuromedin N. These findings suggest that alterations in neurotensin may contribute to the deleterious extrapyramidal effects of long-term neuroleptic administration, and that [D-Trp11]neurotensin may attenuate these effects by blockade of neurotensin receptors within the central nervous system.     

Sensitization to the effects of tumor necrosis factor-alpha: neuroendocrine, central monoamine, and behavioral variations.

Consistent with the proposition that cytokines act as immunotransmitters between the immune system and the brain, systemic administration of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha; 1.0-4.0 microg) induced mild illness in CD-1 mice, increased plasma corticosterone concentrations, and altered central norepinephrine, dopamine, and serotonin turnover. The actions of TNF-alpha were subject to a time-dependent sensitization effect. After reexposure to a subeffective dose of the cytokine (1.0 microgram) 14-28 d after initial treatment, marked illness was evident (reduced consumption of a palatable substance and diminished activity and social exploration), coupled with an elevation of plasma corticosterone levels. In contrast, cytokine reexposure 1-7 d after initial treatment did not elicit illness, and at the 1 d interval the corticosterone response to the cytokine was reduced. The increase of norepinephrine release within the paraventricular nucleus of the hypothalamus, as reflected by elevated accumulation of 3-methoxy-4-hydroxyphenylglycol, was augmented at the longer reexposure intervals. In contrast, within the central amygdala and the prefrontal cortex TNF-alpha reexposure at the 1 d interval was associated with a pronounced sensitization-like effect, which was not apparent at longer intervals. Evidently, systemic TNF-alpha proactively influences the response to subsequent treatment; however, the nature of the effects (i.e., the behavioral, neuroendocrine, and central transmitter alterations) vary over time after initial cytokine treatment. It is suggested that the sensitization may have important repercussions with respect to cognitive effects of TNF-alpha and may also be relevant to analyses of the neuroprotective or neurodestructive actions of cytokines.     

The effects of chronic neuroleptic treatment on neurotensin-like immunoreactivity in the rat central nervous system

The dopamine receptor antagonist fluphenazine decanoate, when administered for a total period of 10 months, produced a large increase in neurotensin-like immunoreactivity in dopamine-rich brain areas, such as the nucleus accumbens, the striatum and the frontal cortex. A smaller, non-significant increase was observed in the substantia nigra with no change in either the hypothalamus or the spinal cord. The present results provide further evidence in favour of a functional interaction between neurotensin and dopamine in the central nervous system.     

Gradual reduction of neuroleptic drugs among chronic schizophrenics

Neuroleptic drugs were gradually reduced from 25 hospitalized chronic schizophrenics while 23 such patients were maintained on matched dosages of neuroleptics. At the end of 15 weeks, 74% of the drug-reduced subjects and 80% of the drug-maintained subjects were rated to have decompensated. Drug-reduced patients decompensated while receiving a mean of 75 mg equivalent of chlorpromazine. Clinical stability was obtained at 150 mg equivalent of chlorpromazine. Twenty-six percent of the drug-reduced patients showed no signs of clinical relapse at the end of the 15-week trial and were receiving a mean of 8 mg equivalent of chlorpromazine. The results suggest that gradual and successive reductions in maintenance antipsychotic drugs can be implemented with minimal risk to the clinical status of the chronic mental patient.     

Calcium channel blockade interacts with a neuroleptic to attenuate the conditioning of amphetamine's behavioral effects in the rat.

Conditioned responses to drug-related cues appear to be related to the maintenance of stimulant addiction. These conditioned responses are not blocked by treatments that block the direct effects of stimulants and may contribute to the high rate of relapse of addicts. Rats administered (+)-amphetamine in a specific environment exhibit conditioned locomotion when subsequently placed in that environment without drugs. The neuroleptic haloperidol significantly attenuated amphetamine-induced locomotor activity but failed to reduce conditioned locomotion. Nimodipine, an L-type calcium channel antagonist, had no effect on amphetamine-induced unconditioned or conditioned locomotion. However, combined nimodipine and haloperidol treatment blocked the unconditioned and attenuated the conditioned locomotor response to amphetamine. Conjunctive therapy with nimodipine and haloperidol may provide an efficacious treatment for stimulant addiction. In addition, nimodipine may provide an important adjunctive therapy for schizophrenia, allowing the use of lower doses of neuroleptic to avoid extrapyramidal side effects.     

Rationalizing neuroleptic polypharmacy in chronic schizophrenics: effects of changing to a single depot preparation.

This study investigated the effects of transferring patients on combined depot and oral neuroleptics to a single depot preparation; a secondary objective was to assess the effects of transferring patients from one depot neuroleptic to another. It was found that, whereas transferring from one depot preparation (flupenthixol) to another (fluphenazine) had no clear disadvantage for the patients, changing over from a combined oral and depot (fluphenazine) regimen to equivalent doses of depot alone resulted in an unacceptably high rate of relapse. The reasons for this may relate to either the unique pharmacokinetics of these drugs or subtle qualitative differences between them. It is suggested that caution is necessary whenever attempts are made to rationalize polypharmacy in schizophrenic patients.     

Acute and chronic effects of neuroleptic drugs on plasma and brain homovanillic acid in the rat

In the rat, the acute administration of the neuroleptic drug, haloperidol, produces a parallel increase in brain and plasma concentrations of the dopamine metabolite, homovanillic acid (HVA). The effect of other neuroleptic drugs, which may differ from haloperidol in their central and peripheral actions, on brain and plasma HVA has not been systematically investigated. Therefore, in this report we examine the acute effects of six different neuroleptic drugs, representing most major chemical classes of these drugs, on plasma and brain concentrations of HVA. Metoclopramide, fluphenazine, loxapine, and molindone produce parallel increases in brain and plasma HVA which closely resemble those produced by haloperidol. Compared to these neuroleptics, chlorpromazine produces a much greater increase in plasma HVA but a similar effect on brain HVA. The large chlorpromazine-induced increase in plasma HVA suggests that this drug alters peripheral production or clearance of HVA, perhaps via blockade of peripheral alpha-receptors. Of the available neuroleptics, sulpiride is one of the most specific and potent at blocking the dopamine vascular receptor. Administration of high doses of sulpiride produces only modest increases in both plasma and brain HVA, suggesting that blockade of peripheral dopamine receptors does not substantially alter peripheral clearance of HVA. After chronic administration of haloperidol for up to 21 days, plasma HVA continued to reflect the brain HVA response to drug administration.     

Withdrawal from chronic amphetamine induces depressive-like behavioral effects in rodents.

BACKGROUND: Amphetamine withdrawal and major depression share many behavioral commonalities in humans. Therefore, the examination of the behavioral effects of amphetamine withdrawal in rodents may provide insights into the neurobiological mechanisms underlying both disorders and aid in the development of animal models of depression that are sensitive to antidepressant agents. METHODS: We examined the behavioral effects of withdrawal from chronic continuous infusion of amphetamine (via minipump) in three behavioral paradigms: the intracranial self-stimulation (ICSS) procedure in rats, the modified forced swim test in rats, and the tail suspension test in mice. RESULTS: Amphetamine withdrawal resulted in a prolonged (5 day) deficit in brain reward function as assessed by elevations in ICSS thresholds. Using a similar regimen of amphetamine administration, we examined the behavioral effects of withdrawal in a modified rat forced swim test. Animals that were treated with the highest dose of amphetamine (10 mg/kg/day) exhibited increased climbing behavior and decreased immobility 24 hours after withdrawal; by the 48-hour testing time point, this effect had dissipated. In contrast, animals that had been pretreated with 5 mg/kg/day amphetamine exhibited a pronounced increase in immobility indicative of an increase in "depressive-like" behavior, coupled with decreases in swimming and climbing. In the mouse tail suspension test, both regimens of amphetamine pretreatment induced increases in immobility scores, also indicative of "depressive-like" behavior, 24 hours following withdrawal. CONCLUSIONS: Withdrawal from chronic amphetamine administration results in behavioral changes that may be analogous to some aspects of depression in humans, such as reward deficits (i.e., elevations in brain reward thresholds) and behaviors opposite to those seen after treatment with antidepressant drugs, such as decreased immobility in the forced swim test and the tail suspension test.     

Residual behavioral and neuroanatomical effects of short-term chronic ethanol consumption in rats

The residual effects of short-term chronic ethanol consumption were investigated in rats maintained on an ethanol liquid diet for 26 consecutive days (mean intake = 16.1 g/kg/day). Animals were assessed for spontaneous motor activity (12 days post-ethanol), spatial working memory (17 days post-ethanol), spatial reference memory (184 days post-ethanol), and retention of passive avoidance (201 days post-ethanol). Measurements of brain weights and cortical thickness vertices within the dorsomedial and ventrolateral cortex of eight coronal planes were determined 260 days post-ethanol. Two-dimensional cell profile densities within six coronal planes and within CA1 region of the hippocampus were also obtained, along with the total volumetric measurement of the hippocampus proper. Results indicated between group differences when subjects were assessed on working memory with ethanol-treated animals exhibiting longer escape latencies in a Morris water maze, an effect partially attributed to the perseverance of ethanol-treated animals in exhibiting thigmotaxicity. No other ethanol-related behavioral impairment was noted. Neuroanatomically, ethanol-treated rats had thinner cortical mantles (6.3% and 6.6% reductions) within the frontoparietal cortex and had lower two-dimensional cell profile densities within the most caudal cortical region studied. Interestingly, control animals with thicker cortical mantles tended to perform better on the working memory task, whereas the opposite was true for ethanol-treated subjects. These data led to the conclusion that chronic ethanol consumption of a relatively short duration produces working memory impairments, albeit mild, that are partially related to an inability to abandon ineffectual behavioral strategies, and also produces neuroanatomical alterations within the cortex.     

Acute and chronic cocaine behavioral effects in novel versus familiar environments: open-field familiarity differentiates cocaine locomotor stimulant effects from cocaine emotional behavioral effects

Cocaine is a potent stimulant drug, but its stimulant effects can be substantially modulated by environmental novelty versus familiarity. In this report, we varied exposures to a novel environment as a way to assess the impact of environmental familiarity versus novelty upon the locomotor activation induced by acute and chronic cocaine treatments. In experiment 1, the effects of 1 (PE1) versus 0 (PE0) pre-exposures to the test environment were compared for their impact upon the locomotor stimulant, central zone entry and grooming effects induced by an acute cocaine (10 mg/kg) treatment. In experiment 2, the effects of 10 (PE10) versus 0 (PE0) pre-exposures upon the cocaine effects were compared. Experiment 3 assessed the effects of nine cocaine treatments (10.0 mg/kg) initiated in a novel environment (PE0) versus familiar environment (PE10). In all experiments, cocaine had a potent locomotor stimulant effect in a novel environment, which was attenuated by environmental familiarity such that in PE10 groups, cocaine did not reliably induce an acute locomotor stimulant effect. Environmental novelty/familiarity, however, did not reliably alter cocaine effects upon central zone penetration, grooming behavior, or the neurochemical effects induced by cocaine. In the chronic treatment regimen, the PE0 group exhibited a tolerance-like decrease in locomotor activation, but the PE10 group exhibited a sensitization-like increase in locomotor activation. Despite the marked directional changes in the locomotor stimulant effects of cocaine treatments, initiated in a novel (PE0) versus familiar (PE10) environment, the same asymptotic levels of locomotor activation were achieved. In contrast, the behavioral measures of central zone activity progressively increased with repeated treatments regardless of whether the environment was initially novel (PE0) or familiar (PE10). Thus, habituation factors can profoundly alter the locomotor stimulant effects of cocaine and can induce pseudo-tolerance phenomena. In contrast, central zone activity undergoes sensitization-like effects independent of habituation state and therefore appears to represent a more fundamental behavioral effect of cocaine. In that, central zone penetration in an open-field is linked to emotional processes; this finding is of substantial importance in understanding the effects of repeated cocaine usage.     

The effects of chronic cocaine pretreatment on kindled seizures and behavioral stereotypies

Male Sprague-Dawley rats were implanted with electrodes in the left basolateral amygdala and caudates. After recovery, rats received daily injections of 40 mg/kg cocaine or saline i.p. for 14 days. Daily electrostimulation (400 μA) of the left amygdala, i.e., kindling, was carried out until rats exhibited poststimulation clonic seizures on two consecutive days. Rats treated with cocaine prior to kindling reached criterion significantly faster than the controls. This difference, however, was wholly attributable to the faster kindling observed in subjects (Ss) in which cocaine-induced convulsions had been noted during the daily treatment. Augmentation of behavioral stereotypies was greater and propagation of afterdischarges to the caudate occurred significantly earlier in rats that had received cocaine prior to the initiation of kindling regardless of whether or not convulsions had occurred. These data in conjunction with those of other investigators suggest that chronic cocaine administration may deplete dopamine and thus diminish inhibitory neural function allowing earlier propagation of afterdischarges and augmenting drug-induced stereotypies.     

The effect of chronic neuroleptic treatment on gonadotrophin release

Although neuroleptic-induced hyperprolactinaemia is a common cause of amenorrhoea in women, the mechanism by which ovarian function is disturbed is unknown. Previous studies on both hyperprolactinaemic women and rats have indicated that an impairment of the pituitary response to LH-RH may be involved. We have investigated this possibility in female psychiatric patients undergoing chronic treatment with depot neuroleptics. The patients and a group of healthy controls were subjected to a standard LH-RH provocation test. Basal and post-stimulation serum levels of gonadotrophins, prolactin and oestradiol were determined. We have found that the LH responses of the patients fell into three groups: exaggerated, normal and impaired. Differences in the basal levels of gonadotrophins were also observed. The abnormal basal hormone levels and LH-RH responses appear to be related to neuroleptic dose and/or serum prolactin concentration, but no well-defined relationship was found. The results suggest that an action of the neuroleptics which is independent of high serum prolactin levels may be involved in the disruption of pituitary function. Thus the amenorrhoea caused by neuroleptic drug treatment may be etiologically different from that of other forms of hyperprolactinaemic amenorrhoea.