Homovanillic acid (HVA) was measured in rat caudate and pre-frontal cortex after single and repeated doses of several types of neuroleptic drugs. Twice daily administration of low or high doses of haloperidol, fluphenazine, or (-) sulpiride resulted in greater tolerance to the initial HVA increase in caudate compared to prefrontal cortex.

Rats with more severe orofacial movements after 51 days of haloperidol administration showed lower levels of the dopamine metabolite homovanillic acid (HVA) in the caudate compared to animals who did not develop significant mouth movements. This effect was not observed in other brain regions sampled. This finding is consistent with the hypothesis that dopaminergic receptor supersensitivity in neostriatal structures plays some role in the development of orofacial movements in rats, in association with chronic neuroleptic administration.

Phencyclidine (PCP) and d-amphetamine (AMP) had different effects upon homovanillic acid (HVA) levels in rat prefrontal cortex as compared to caudate. Lower doses of PCP increased HVA in prefrontal cortex only while lower doses of AMP decreased HVA in caudate alone. Higher doses of both drugs produced a decreased HVA in caudate and an increase in prefrontal cortex. At some doses PCP may selectively activate mesocortical dopaminergic neurons.

Phencyclidine combined with footshock stress produced a greater increase in the homovanillic acid content of prefrontal cortex than either phencyclidine or footshock alone. Phencyclidine decreased both substance P and substance K in the ventral tegmental area. The results suggest that phencyclidine and footshock activate forebrain dopaminergic systems in part by separate mechanisms.

Stress consistently has been found to activate peripheral and central catecholamine systems. Dopamine (DA) turnover in the prefrontal cortex is especially sensitive to stress produced by relatively mild footshock, conditioned fear, or exposure to a novel cage. Because lesions of the central nucleus of the amygdala block the effects of both stress and fear in many experimental paradigms, the present study evaluated whether such lesions would block stress-induced increases in prefrontal dopamine turnover using either mild footshock or novelty as stressors. In Experiment 1 electrolytic lesions of the central nucleus of the amygdala attenuated the increase in the dopamine metabolite homovanillic acid (HVA) in the prefrontal cortex evaluated in post-mortem tissue normally produced by footshock. In Experiment 2 similar lesions attenuated the increase in dopamine turnover in the prefrontal cortex using a different stressor, novelty, and a different measure of dopamine turnover, DOPAC/DA ratios. These data provide further evidence for the critical role of the amygdala in stress.

1. THC, PCP, and MK-801 increased DOPAC in rat olfactory tubercle and prefrontal cortex without affecting DA levels, suggesting increased DA release. 2. Effects on NE and MHPG were not evident. 3. These two classes of drugs can effect dopaminergic systems independently of noradrenergic systems.

In rats, subchronic administration of desenkephalin-gamma-endorphin (DE gamma E) into the nucleus accumbens or subcutaneously for 10 days resulted in hypoactivity. Intra-accumbens administration caused a significant reduction in the nucleus accumbens tissue levels of the dopamine (DA) metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). Systemic administration of DE gamma E decreased DOPAC and 5-hydroxyindoleacetic acid (5-HIAA) levels in nucleus accumbens tissue. Subchronic subcutaneous DE gamma E treatment reduced the basal release of [3H]DA from rat nucleus accumbens slices in vitro and the basal release of endogenous DA and DOPAC in vivo as assessed with on-line dialysis in the nucleus accumbens of freely moving rats. The DA agonist N,N-dipropyl-7-hydroxy-2-aminotetralin (DP-7-ATN) was equally effective in inhibiting [3H]DA release elicited by electrical stimulation from slices of subchronically DE gamma E and placebo treated rats. Administration of a small dose of apomorphine caused similar reductions of the in vivo release of DA and DOPAC in both placebo and DE gamma E treated rats. These results indicate that subchronic DE gamma E treatment may decrease dopaminergic neurotransmission in the nucleus accumbens. This effect is probably not due to alterations in the sensitivity of presynaptically located DA autoreceptors mediating DA release in vitro and in vivo.

The effects of apomorphine or sulpiride on electrically evoked dopamine release from striatal slices of rats pretreated with haloperidol were investigated. Chronic haloperidol treatment (1 mg/kg per day for 21 days) significantly reduced electrically evoked dopamine release from striatal slices until 72 h after the last injection. The apomorphine-induced reduction and the sulpiride-induced increase in evoked dopamine release were significantly enhanced by the chronic treatment with haloperidol at 72 h after the last injection. The enhancement of the sulpiride-induced increase in evoked dopamine release was inversely correlated with the dopamine release evoked by the first stimulation in striatal slices from haloperidol-treated (r = -0.85, n = 12, P < 0.01) but not from saline-treated rats. These results suggest that an increase in the sensitivity of dopamine autoreceptors due to chronic treatment with haloperidol could partially account for the reduction in dopamine release from striatal slices of rats.

Rats were pretreated for 2 weeks with similarly effective doses of the typical neuroleptic fluphenazine (FPZ) or the experimental weak partial D2 agonists S(+)N-n-propylnorapomorphine (NPA) and S(+)11-hydroxy-N-n-propylnoraporphine (11-OH-NPa). Spontaneous and dopamine (DA) agonist (apomorphine; APO) stimulated stereotyped behaviors or locomotion, and interactions with APO were evaluated over the following 2 weeks. While FPZ induced marked supersensitivity in APO stereotype, (+)NPA showed no significant change, and (+)11-OH-NPa produced only a small, transient increase in response; NPA also lacked a supersensitizing effect on locomotor arousal induced by APO. The time-course of stereotyped responses to APO following pretreatment with FLZ included a marked increase following FPZ that became maximal at day 5 and normalized by day 9; there was a parallel reduction of acute antisteotypy efficacy of FPZ. (+)11-OH-NPa had similar, but much lesser and shorter-lived effects. Spontaneous locomotion was markedly depressed following FPZ, recovered in 1 week, exceeded controls at day 9, and returned to baseline by day 11; (+)11-OH-NPa, again, had similar but smaller effects. Acute effects of FPZ to reduce spontaneous or APO-induced locomotion were greater after FPZ pretreatment and normalized within a week; (+)11-OH-NPa had a similar but smaller effect. Locomotor arousal by APO was altered inconsistently in the week after pretreatment with FPZ or (+)11-OH-NPa. Thus, FPZ appeared to induce tolerance and supersensitivity in central DA systems, most clearly seen following a several-day period to eliminate the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of chronic intermittent administration (7 months) of two neuroleptics, haloperidol (HAL) and raclopride (RAC), were compared using several different measures. Both drugs were administered weekly by subcutaneous injection at 7.0 mg/kg. Both neuroleptics consistently produced catalepsy throughout the treatment period, although HAL was generally more cataleptogenic than RAC. Assessment of dopamine (DA) release in the caudate putamen (CPu), through the use of in vivo microdialysis, showed that chronic HAL or RAC administration caused a prolonged decrease of DA release in response to a low dose of the DA D2 agonist quinpirole (0.03 mg/kg, sc). Injection of the muscarinic agonist pilocarpine (1.0 mg/kg, IP) did not have any significant within-group effects, although both neuroleptic treatment groups showed decreased DA release when compared to controls. Ultrastructural analysis of the dorsolateral CPu showed that both HAL and RAC treatment resulted in a significant increase in the number of perforated synapses, which contain a discontinuous density along the postsynaptic membrane. These results demonstrate that two different DA D2 receptor antagonists produce a similar effect on DA function and ultrastructural changes within the CPu following chronic, intermittent treatment.

This study provides in vitro evidence that rats pretreated with fluphenazine for 10 days, but not acutely, developed moderate but significant striatal autoreceptor supersensitivity as measured by the ability of S(+)-NPA, a selective DA autoreceptor agonist and very weak postsynaptic agonist, to inhibit tyrosine hydroxylase activity. In contrast, autoreceptor supersensitivity was not found with the nonselective auto- and postsynaptic receptor agonist R(-)-NPA. Presumably, this effect represents some modification of a presynaptic regulatory mechanism controlling DA synthesis which can occur despite a reportedly high striatal DA autoreceptor reserve in rat striatum [2, 7]. Such a mechanism, by tending to reduce synaptic availability of DA, may contribute to tolerance to the transient, early DA-synthesis stimulating actions of acutely administered neuroleptics [4], and help to counterbalance increases in postsynaptic DA receptor abundance and sensitivity associated with long-term neuroleptic treatment.

1. The authors review the literature describing acute symptomatology produced by the gradual or abrupt withdrawal of heterocyclic antidepressants, monoamine oxidase inhibitors (MAOI) and neuroleptics. 2. Withdrawal of heterocyclic antidepressants and antipsychotic agents causes similar symptomatology. Symptoms produced by the discontinuation of these drugs include nausea, emesis, anorexia, diarrhea, rhinorrhea, diaphoresis, myalgias, paresthesias, anxiety, agitation, restlessness, and insomnia. 3. Psychotic relapse is often presaged by anxiety, agitation, restlessness, and insomnia. Prodromal symptoms are distinguished from the effects of neuroleptic withdrawal by a temporal relationship of the latter to reductions in the dosage or discontinuation of antipsychotic agents. 4. Withdrawal of MAOIs can result in severe anxiety, agitation, pressured speech, sleeplessness or drowsiness, hallucinations, delirium, and paranoid psychosis. 5. MAOI withdrawal phenomena resemble the symptoms produced by the discontinuation of chronically administered psychostimulants. 6. The capacity of MAOIs to exert amphetamine-like effects presynaptically and the propensity of somatic treatments for depression to subsensitize presynaptic receptors regulating the release of catecholamines provide a basis for the development of psychotic symptoms upon the withdrawal of MAOI. Evidence for this hypothesis is reviewed.

The effects of the dopamine D2 selective receptor antagonist, remoxipride, on dopamine turnover in the rat brain were studied after acute and repeated administration and compared with the effects of haloperidol. Acute administration of remoxipride produced a dose-dependent increase of the concentrations of DOPAC and HVA in both striatum and olfactory tubercle + nucleus accumbens. The maximal effect of both acute remoxipride and haloperidol on dopamine turnover was attained approximately 2 hours after a single intraperitoneal administration, whereas a biphasic response was seen after oral remoxipride. Tolerance to the effects of repeated haloperidol (20 mumol/kg orally) treatment on dopamine turnover was observed as soon as after 3 days, whereas no such tolerance could be found during the first 15 days of repeated treatment with remoxipride (20 mumol/kg orally). A dose-related tolerance to the effects of remoxipride was, however, seen at higher dosages (40, 150 and 600 mumol/kg orally) and after a longer period (6 months) of treatment.

Changes in extracellular DOPAC levels were monitored simultaneously in the nucleus accumbens and striatum of halothane/N2O anaesthetised rats using in vivo differential pulse voltammetry with carbon fibre electrodes following repeated administration of the atypical neuroleptics thioridazine and clozapine. Thioridazine (20 mg/kg s.c.) increased the DOPAC peak in the nucleus accumbens and striatum of rats treated with saline for the previous 21 days by 66% +/- 5 S.E.M. and 91% +/- 16 respectively. No such increase was recorded in the nucleus accumbens of rats previously treated with thioridazine (20 mg/kg s.c.) for 21 days. Similarly the increase in the striatum produced by a challenge dose on day 22 was markedly attenuated compared to controls although analysis of absolute DOPAC peak heights revealed extracellular DOPAC to be elevated above basal levels in this region (but not the nucleus accumbens) indicating a possible selective action of this drug to induce absolute tolerance to its acute effects in the nucleus accumbens after repeated administration. Administration of increasing doses of apomorphine (0.05, 0.1, 0.25 mg/kg s.c.) 1 h after a challenge dose of thioridazine (20 mg/kg s.c.) on day 22 to rats treated with the neuroleptic for the previous 21 days produced a progressive decrease in extracellular DOPAC levels both in the nucleus accumbens and striatum. Repeated administration of clozapine (50 mg/kg s.c.) for 21 days failed to induce tolerance to the acute effects of this drug, extracellular DOPAC levels increasing by 60% +/- 8 and 90% +/- 18 in the nucleus accumbens and striatum respectively following challenge with the drug on day 22.(ABSTRACT TRUNCATED AT 250 WORDS)

Metoclopramide and sulpiride, two benzamide compounds, are equally potent in terms of their ability to block postsynaptic D2 dopamine receptors. However these compounds show a marked divergence in their ability to block dopamine autoreceptors, as metoclopramide is 20-25-fold more potent than sulpiride in blocking these receptors. When injected twice daily for 16 days, metoclopramide at a dose of 10 mg/kg/day will result in the development a postsynaptic dopamine receptor hypersensitivity (i.e., increased behavioral response to apomorphine upon cessation of the chronic treatment). An equivalent dose and treatment schedule with sulpiride has no apparent effect on dopamine receptor sensitivity. Because of the divergent pre- and postsynaptic potency of these two drugs it was possible to construct an autoreceptor "dose response curve" by varying the amount of these two drugs injected. Combinations of these two drugs were chosen so that the level or amount of postsynaptic dopamine receptor blockade was held constant while the amount of dopamine autoreceptor blockade was gradually increased. The results of this autoreceptor blockade "dose response curve" indicated that chronic autoreceptor blockade was involved in the increased dopamine receptor sensitivity that develops upon withdrawal from the neuroleptic drugs. These results suggest that the blockade of dopamine autoreceptors, and perhaps the resulting increase in autoreceptor sensitivity, is an integral component of the neuroleptic-induced dopamine receptor hypersensitivity.

delta 9-Tetrahydrocannabinol (10 mg/kg) increased homovanillic acid in rat prefrontal cortex and olfactory tubercle. This dose did not affect homovanillic acid in the caudate. Higher doses increased homovanillic acid in all 3 regions. Cocaine (20, 30, or 50 mg/kg) did not affect homovanillic acid in any of these brain regions.

Developing and adult Sprague-Dawley rats were tested after acute or repeated haloperidol administration. Although 8-day-old rat pups showed a form of immobility in response to a single injection of haloperidol (1 mg/kg), 14-day-old rats did not show any behavioral response to the neuroleptic. By 21 days of age, an acute dose of haloperidol induced a cataleptic response similar to that described for adult animals. Following 7 days of repeated haloperidol administration, the cataleptogenic effects of haloperidol were attenuated in animals aged 21 days and older, but not in 8- and 14-day-old rats. Subjects were sacrificed 70 min after the injection of the test dose of haloperidol or saline and the corpus striatum and olfactory tubercles were dissected for HPLC determination of dopamine (DA) and its metabolites, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC). In the corpus striatum, an area believed to be important for DA-related catalepsy, acute and repeated haloperidol induced a slight increase in concentrations of HVA in 8-day-old rats, and an increase in both DOPAC and HVA concentrations in animals aged 14 days and older. Tolerance after repeated haloperidol administration, in the form of an attenuation of the haloperidol-induced increase in DA metabolites, was not apparent until 35 days of age. These data contrast with the behavioral data, which indicate that the ability to develop a tolerance to the cataleptogenic effects of haloperidol matures by 21 days of age. The pattern of responses in the olfactory tubercles differed from those observed in the striatum. Following acute haloperidol, subjects did not show any increase in HVA until 14 days of age, and in both HVA and DOPAC until 21 days of age. At no age, including adults, was one week of repeated administration of haloperidol sufficient to induce tolerance to the effects of haloperidol on DA metabolites in the olfactory tubercles. In addition to providing information about the development of certain aspects of DA systems in rats, these studies suggest that an attenuation of the haloperidol-induced increase in DA metabolites is not necessary for the development of tolerance to haloperidol-induced catalepsy.

Haloperidol, a butyrophenone neuroleptic, is metabolically reduced in man, but not in rat and not in many other experimental animals. Here we present data that describes reductive haloperidol metabolism in guinea pigs in vivo. When haloperidol was injected intraperitoneally to guinea pigs, it was converted to reduced haloperidol so quickly that 1 hr after the injection the concentration of haloperidol was only about one fifth of that of reduced haloperidol. Dopamine metabolism was enhanced in the striatum after the administration of reduced haloperidol, but this enhancement could mostly be explained by oxidation of a small amount of reduced haloperidol back to haloperidol. The molecular mechanisms of haloperidol reduction should be further studied using guinea pigs as a model for human haloperidol metabolism.

Homovanillic acid (HVA) was measured in rat caudate and pre-frontal cortex 3 h following a single dose of a variety of neuroleptics. Thioridazine, haloperidol, fluphenazine, and metoclopramide increased HVA levels in caudate more than in pre-frontal cortex; whereas sulpiride and clozapine produced greater increases in HVA in pre-frontal cortex. These results are consistent with the proposal that rat pre-frontal cortex is relatively deficient in dopamine autoreceptors.

Electrocortical and behavioral arousal are separate phenomena subserved by different neural substrata operating in parallel. A comprehensive theory of 'activation' must take into account the relationships between the electrical and behavioral activating systems. In pathological or experimentally induced states paradoxes, resolvable by a theory positing functional interaction between these systems, arise. EEG arousal is directly mediated, in both the waking and sleeping state, by cholinergic mechanisms. Antidepressant withdrawal precipitates cholinergic overdrive; this would account for the apparent disturbances of REM sleep occurring when antidepressants are stopped. Generally, cholinergic overdrive would produce behavioral inhibition but in particular instances it triggers marked psychomotor arousal by mobilizing a 'limbic activating system'. The existence of a monoaminergic 'limbic activating system', system 'A', with the properties attributed to it in this paper, is supported by both clinical and laboratory observations. System 'A' theory provides a parsimonious means of adequately explaining many phenomena. This theory also has in its favor explanatory power and scope. The Cholinergic-Monoaminergic Interaction Theory of antidepressant withdrawal induced activation and of rapidly-cycling manic-depressive illness maintains that system 'A' and a cholinergic inhibitory system interact dynamically, and that excessive monoaminergic function can precipitate excessive cholinergic function and a dearth of monoaminergic function (due to autoregulation) and hence depression. Likewise, excessive cholinergic function is posited to activate monoaminergic systems and hence to secondarily cause behavioral activation. Rapidly-cycling manic-depressive patients, according to the model, develop alternating cholinergic and monoaminergic overdrive states because the homeostatic mechanisms which should serve to maintain, within normal limits, the composite of cholinergic inhibitory and monoaminergic activating influences are defective. Consequently, rather than reaching a reasonable balance compatible with adaptive function there is oscillation between extremes. Each oscillatory movement is actually a move towards the 'golden mean' and is induced by deviation from this ideal but the defective homeostatic mechanisms promote ' perpetual ' overshooting. Lithium and ECT may be useful in the treatment of rapidly-cycling patients as both treatments may down-regulate muscarinic receptors, and otherwise modify cholinergic and monoaminergic systems in ways promoting homeostasis.(ABSTRACT TRUNCATED AT 400 WORDS)

Prophylactic treatment with lithium has been reported to prevent haloperidol-induced dopamine (DA) receptor supersensitivity. If such an effect exists, then lithium may be useful in the prevention of tardive dyskinesia, which is related to the neuroleptic-induced DA hyperfunction. In the experiments reported here chronic lithium administration had no effect on DA synthesis or utilization in the nigrostriatal, mesolimbic, or mesocortical DA pathways in the rat brain. Similarly, lithium had no effect on the increase in DA metabolism induced by the acute administration of haloperidol. Also, chronic lithium treatment failed to modify the biochemical tolerance which developed after prolonged administration of the neuroleptic drug. Supersensitivity of the presynaptic DA receptors, which was induced by prolonged exposure to haloperidol, likewise was unaffected by prophylactic lithium treatment. We conclude that lithium does not affect changes in DA metabolism or receptor supersensitivity induced by haloperidol. These results do not support the use of lithium in neurological disorders that may be related to neuroleptic-induced DA receptor supersensitivity.

To evaluate the effect of lithium treatment on haloperidol-induced changes of brain dopamine systems, cerebrospinal fluid homovanillic acid (HVA) was assessed in nine patients during a sequential treatment protocol with placebo, lithium, lithium plus acute haloperidol, and lithium plus chronic haloperidol. None of the patients developed tolerance to the rise in HVA during treatment with haloperidol and lithium. Concurrent treatment with lithium appears to prevent the development of tolerance in dopamine metabolism during chronic haloperidol treatment. These data provide the first evidence in man that lithium may prevent neuroleptic-induced functional supersensitivity of brain dopamine systems.

A gas chromatographic-mass spectrometric assay, which allowed simultaneous measurement of 3-methoxy-4-hydroxyphenylglycol (MHPG) and 3,4-dihydroxyphenylglycol (DHPG), was used to show that the concentration of MHPG in primate CNS far exceeded that of DHPG and that both metabolites were mainly in the unconjugated form. In rat brain, DHPG concentration was generally higher than that of MHPG, and both existed predominantly as conjugates. Rat and primate plasma contained more MHPG than DHPG. In plasma of primates but not of rats, higher proportions of the metabolites were conjugated, compared to those in brain. Significant correlations existed between MHPG and DHPG in rat brain, monkey brain, human plasma, and both monkey CSF and plasma. In monkeys, a significant CSF-plasma correlation was found for MHPG, but not for DHPG. Acute administration of piperoxane raised rat brain MHPG and DHPG concentration; desipramine prevented this rise in DHPG, but not in MHPG. Desipramine alone decreased DHPG, but not MHPG, concentration. Piperoxane increased monkey brain MHPG, but not DHPG, concentration. These data suggest that DHPG is a valuable metabolite to measure when assessing norepinephrine metabolism in the rat. Under certain conditions, measurement of rat brain MHPG and DHPG may provide information concerning the site of norepinephrine metabolism. However, in primates the importance of monitoring DHPG, in addition to MHPG, is uncertain.

Acute administration of neuroleptic drugs causes blockade of cerebral dopamine receptors. It has been discovered that chronic administration of neuroleptic drugs may have different effects on cerebral dopamine systems. Initial antagonism of dopamine mediated behaviour, such as stereotypy, disappears and may be replaced by supersensitivity to dopamine agonists. Changes also occur in biochemical indices of dopamine receptors, such as in the number and affinity of specific binding sites identified by 3H-ligands labelling D-2 receptors, and in dopamine-stimulated adenylate cyclase activity. All these changes occur obviously in the striatum in response to chronic administration of a range of neuroleptic drugs. Lesser changes take place in the mesolimbic dopamine system. What happens in the mesocortical dopamine pathways is unknown. The consequence of such adaptive responses to chronic neuroleptic therapy may be of importance to understanding of tardive dyskinesia and schizophrenia.

A single injection of fluphenazine decanoate (FD) antagonized effects of acute d-amphetamine (2.5 mg/kg) for a variable period of time (4 to 28 days), depending upon the dosage of the neuroleptic used (2.5 or 5.0 mg/kg) and the behavioural parameter(s) monitored. Locomotion and rearing were antagonized for a longer duration than was sniffing. Normal locomotor response to amphetamine was attained 12 and 28 days following the administration of 2.5 and 5.0 mg/kg FD, respectively. However, the 2.5 mg/kg FD group displayed significantly more locomotor activity on days 20 and 24 post-treatment. A similar supersensitive response was not demonstrable with the higher dose of FD (5.0 mg/kg), or with the other behavioural measures. The prompt and pronounced elevation of serum prolactin returned to within the normal range by days 4 and 14, following administration of 2.5 and 5.0 mg/kg FD, respectively. These results indicate that the behavioural paradigm is more sensitive in monitoring the effects of FD and could serve as a useful model in investigating the dose- and time-related effects of other long-acting neuroleptics.

The response of the plasma dopamine (DA) metabolite, homovanillic acid (HVA), to two DA agonists was investigated in the rat. Apomorphine administered i.p. (2 mg/kg) produced, within one hour, a significant decrease in plasma HVA. The response of plasma HVA to apomorphine was also investigated after pretreatment with debrisoquin, a drug which selectively blocks peripheral HVA production by inhibition of MAO. Pretreatment with debrisoquin did not significantly alter the decrement in plasma HVA produced by apomorphine indicating that a substantial portion of the plasma HVA response to apomorphine is due to the drug's action on brain. Bromocriptine (2 mg/kg) was also found to produce a significant decrease in plasma HVA. Since the response of brain HVA to DA agonists reflects the sensitivity of the DA receptor, the plasma HVA response to DA agonists might be a practical method of assessing brain DA receptor sensitivity in humans.

This study was carried out to evaluate the postulated dopaminergic auto-receptor regulatory effect in man of low-dose apomorphine. Behavior and serum homovanillic acid concentrations following low-dose apomorphine were investigated. Five medicated chronic schizophrenic patients had serum homovanillic acid concentrations measured by mass fragmentography before and after 0.005 mg/kg of apomorphine or saline placebo. Results demonstrate significant reductions in serum homovanillic acid concentrations in all five subjects following apomorphine as compared with placebo. These findings present direct evidence of a specific dopamine autoreceptor effect of low-dose apomorphine in schizophrenic patients.

Using liquid chromatography and electrochemical detection (LCEC), we have measured the accumulation of 3,4-dihydroxyphenylalanine (DOPA) (after L-aromatic amino acid decarboxylase inhibition), dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in the frontal cortex and in the corpus striatum of the rat. Mild-footshock stress increased frontal cortex DOPA accumulation, as well as DA and DOPAC, without changing the concentration of these substances in the corpus striatum. The increases in cortical DA synthesis and metabolism were antagonized by diazepam which, given alone, tended to decrease DOPA accumulation to a small degree. In addition, we have measured the indoles serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA), and the noradrenergic metabolite MHPG, none of which were altered by stress. The accumulation of 5-hydroxytryptophan (5-HTP) was also unaffected by stress but, like DOPA accumulation, was reduced to a small degree by diazepam. This study directly demonstrates a selective activation of frontal cortex catechol synthesis (in vivo tyrosine hydroxylation) by a mild stress, which did not significantly alter cortical noradrenergic or serotonergic metabolism.

Lithium administered in chow produced a small increase in DA metabolites (DOPAC and HVA) in rat caudate but not cortex and augmented the increase in DA metabolites in both regions produced by haloperidol administration for 2 days. Given for 10 days with haloperidol, lithium attenuated the tolerance to an increase in DA metabolites in caudate. When administered with haloperidol for 22 days, lithium prevented the tolerance to catalepsy produced by daily administration of haloperidol alone. Lithium can augment and prolong the increase in regional DA metabolites and extend the duration of catalepsy produced by chronic haloperidol.

Various neuroleptic-induced motor disorders that appear in primates previously treated with neuroleptics are collectively designated the acute dyskinetic syndrome. The relative incidence of these motor disorders was examined as the syndrome was repeatedly elicited by haloperidol and other dopamine antagonists in individual monkeys. After several weekly or biweekly treatments with haloperidol (1.25 mg/kg orally), catalepsy began to appear, which was then accompanied by athetoid movements (writhing and limb extensions) as intermittent neuroleptic treatment continued. Other dyskinetic movements ('duck walk', oral dyskinesias, pushing of the head into a cage corner, and perseverative circling) that were suggestive of hyperkinesia subsequently began to be elicited by haloperidol and other neuroleptics after additional treatments with these drugs had intervened. As intermittent treatments continued, tolerance to the athetoid movements gradually developed and, eventually, only circling and pushing could be consistently elicited by haloperidol. In monkeys that had reached this phase, the athetoid movements were not again induced by higher doses of haloperidol (up to 5 mg/kg), chlorpromazine (3 mg/kg), or metoclopramide (3 mg/kg). In these tolerant monkeys, haloperidol impaired Sidman avoidance performance less and benztropine more than in drug-naive monkeys. Neither pharmacokinetic changes nor behavioral tolerance could readily account for these results. It is hypothesized that they reflect progressive functional alterations in dopaminergic or cholinergic neurotransmission.

Unilateral intranigral administration of baclofen (50-200 ng), muscimol (2.5--20 ng), or THIP (50--400 ng) in the rat led to contralateral circling behavior of a qualitatively similar nature. The potency of all three GABA-mimetics was enhanced in animals which had received the depot neuroleptic fluphenazine decanoate (10 mg/kg SC) 7 days prior to their intranigral administration. Significant differences between the nigral actions of the drugs could be demonstrated by their altered activity in the presence of a benzodiazepine. Flurazepam (500 ng) enhanced the intranigral potency of THIP, but reduced that of intranigral baclofen. Muscimol-induced circling behavior was unaffected by concomitant flurazepam. The data provide evidence for a functional supersensitivity of GABA-sensitive nondopaminergic projections from the substantia nigra in response to chronic neuroleptic treatment and reveal differences between the precise sites or modes of action of baclofen, muscimol, and THIP within this structure.

Chronic lithium administration prevents both haloperidol-induced dopaminergic behavioral supersensitivity and increased tritiated neuroleptic binding to dopamine (DA) receptors in rat corpus striatum. Since chronic haloperidol treatment also induces tolerance to the activating effects to the drug on striatal DA synthesis, the ability of lithium to block neurochemical tolerance development was investigated. Whereas lithium treatment significantly (P less than 0.01) attenuated haloperidol-induced behavioral supersensitivity to apomorphine (0.33 and 0.66 mg/kg s.c.), it did not prevent tolerance to the elevation of striatal 3, 4-dihydroxyphenylacetic acid (DOPAC) levels 1 h after last treatment or in response to challenge with a low dose (0.1 mg/kg) of haloperidol during withdrawal. These results demonstrate a dissociation between the development of behavioral supersensitivity and the reduction in DOPAC increase. An assessment of lithium's demonstrated effects on supersensitivity development at various DA receptor sites suggests that tolerance may be mediated by presynaptic DA receptors on terminals of nigrostriatal neurons.

This study was designed to assess the temporal relationship between the appearance and retention of cell nuclear progestin receptors in hypothalamus and the facilitation and decline of feminine sexual behavior following an i.v. injection of progesterone (P). Nuclear translocation of progestin receptors preceded the earliest appearance of behavior. The behavioral effects of P outlasted the nuclear progestin receptor elevation by several hours. Our results are consistent with the idea that P-induced effects on feminine sexual behavior involve genomic activation.

The effects of kainic acid lesions and chronic haloperidol treatment on rat striatal dopaminergic presynaptic receptors were studied. Following the gamma-butyrolactone-induced inhibition of dopaminergic impulse flow, and after dopa decarboxylase inhibition, dopa accumulation and its reversal by dopamine agonists was measured in vivo. 3H-apomorphine (a dopamine receptor ligand with purported presynaptic specificity) was used for in vitro binding experiments. Presynaptic dopamine receptors, as assessed by both methods, were unaffected by intrastriatal kainic acid injection 5-6 days before sacrifice. Seven days after termination of chronic haloperidol treatment (28 days, 0.5 mg/kg/day s.c.) both an increased apomorphine response using the dopa accumulation method and an increase in 3H-apomorphine binding were observed, indicating the development of presynaptic dopamine receptor supersensitivity.