Postsynaptic Dopamine Receptor Sensitivity Research Articles

The MCH 1 receptor antagonist SNAP 94847 induces sensitivity to dopamine D 2/D 3 receptor agonists in rats and mice

Antidepressant treatment of two or more weeks in rats has been shown to enhance the locomotor-stimulating effects of dopamine D 2/D 3 receptor agonists. This action has been attributed to an increased sensitivity of postsynaptic dopamine receptors in the nucleus accumbens, thought to represent an essential mechanism by which antidepressants act therapeutically to enhance reward and motivation. We tested whether the melanin-concentrating hormone receptor 1 (MCH 1) antagonist SNAP 94847, reported to have antidepressant-like activity in several preclinical behavioral models, mimics this key feature of established antidepressants. Locomotor responses to the dopamine D 2/D 3 agonist quinpirole following acute or chronic administration of fluoxetine (18 mg/kg/day) or SNAP 94847 (20 mg/kg/day) were assessed in habituated Sprague–Dawley rats, as well as BALB/c and CD-1 mice. Rats showed a significant increase in quinpirole-induced locomotor activity following chronic (2 weeks), but not acute (1 h) fluoxetine or SNAP 94847 administration. BALB/c mice treated for 21 days with fluoxetine or SNAP 94847 showed marked increases in quinpirole-induced locomotor activity, with the onset of hyper-locomotion appearing earlier in the time course after SNAP 94847 compared to fluoxetine. Administration of either compound for 7 days was also sufficient to augment the quinpirole response in BALB/c mice. Fluoxetine and SNAP 94847 (21 days) failed to modify quinpirole responses in CD-1 mice, and the compounds were ineffective after acute administration in both mouse strains. This report demonstrates in two rodent species that chronic treatment with an MCH 1 receptor antagonist, as with clinically proven antidepressants, produces sensitization to the locomotor effects of dopamine D 2/D 3 agonists.

Cholecystokinin2 receptor-deficient mice display altered function of brain dopaminergic system.

Cholecystokinin (CCK) has been shown to coexist and interact with dopamine in the regulation of behaviour. Two different CCK receptors (CCK1 and CCK2) have an opposite influence on the activity of dopamine neurons. Stimulation of CCK2 receptors decreases the release of dopamine and that receptor could mediate the neuroleptic-like effect of CCK. To investigate the activity of the dopaminergic system in pharmacological experiments on CCK2 receptor (CCK2R)-deficient mice. We used age- and sex-matched littermates in all our experiments. To evaluate the behavioural differences, we performed the rotarod test and measured the locomotor activity of animals using computer-connected photoelectric motility boxes. Amphetamine and apomorphine, two dopaminergic drugs with different pharmacodynamic properties, were used to influence the activity of the dopaminergic system in the brain. Neurochemical differences related to the different genotype were analysed by means of high-performance liquid chromatography and radioligand binding studies. Motor co-ordination was significantly impaired in the rotarod test of CCK2R receptor-deficient mice. Moreover, the locomotor activity of heterozygous (+/-) and homozygous (-/-) CCK2R receptor-deficient mice was somewhat reduced. A low dose of apomorphine (0.1 mg/kg), an unselective agonist of dopamine receptors, suppressed locomotor activity significantly more in homozygous (-/-) and heterozygous (+/-) mutant mice than in their wild-type (+/+) littermates. Amphetamine (3-6 mg/kg), increasing release of dopamine from the presynaptic terminals, caused a dose-dependent motor stimulation in wild-type (+/+) mice. In heterozygous (+/-) and homozygous (-/-) mice, a lower dose of amphetamine (3 mg/kg) did not alter the locomotor activity, whereas the higher dose of (6 mg/kg) induced a significantly stronger increase in locomotor activity in homozygous (-/-) mice than in their heterozygous (+/-) and wild-type (+/+) littermates. Despite the changes in the action of apomorphine and amphetamine in homozygous (-/-) mice, we did not find any significant differences in the concentration of dopamine and their metabolites in the striatum or cortex. However, the density of dopamine D2 receptors was significantly increased in the striatum of homozygous (-/-) animals compared with wild-type (+/+) mice. The targeted mutation of the CCK2 receptor gene induced gene dose-dependent changes in the activity of the dopaminergic system. The sensitivity of presynaptic dopamine receptors was increased in heterozygous (+/-) and homozygous (-/-) animals, whereas the increase in sensitivity of postsynaptic dopamine receptors was apparent only in homozygous (-/-) mice.

Technetium-99m-ethyl cysteinate dimer brain perfusion loss in pediatric postictal psychosis

A 91/i-YEAR-OLD BOY was admitted to the hospital with status epilepticus and was treated with intravenous diazepam, phenytoin, and midazolam. After the convulsions stopped, he remained agitated and confused. Twenty-four hours later, psychotic ideation was noticed. He developed visual hallucinations, confused speech, auditory illusions, psychomotor restlessness, and disorganized behavior. His medical history was remarkable for a right hemiplegia diagnosed in the first year of life, caused by a polycythemia-related neonatal stroke. A brain computed tomography (CT) scan that was performed a year later showed an enlarged left ventricle and left hemispheric atrophy. At age 9, the patient was hospitalized for prolonged left-sided complex partial seizures, followed by Todd's paralysis on the right side. The neurological examination on the current admission revealed mild right hemiparesis, unchanged from before. Routine serum biochemistry and a complete blood count were normal. A lumbar puncture was normal. Repeated electroencephalograms (EEGs) showed left-sided slowing but no epileptic activity. A brain magnetic resonance imaging (MRI) scan showed severe atrophy of the left hemisphere with a thalamic hypodensity (Fig 1), similar to the previous imaging. The patient was diagnosed with postictal schizophrenia-like psychosis. A perfusion brain single photon emission computed tomography (SPECT) was performed 30 minutes after injecting 12 mCi (444 MBq) of Technetium (Tc)-99m-ethyl cysteinate dimer (ECD) intravenously by using a dualhead gamma camera. The images showed markedly decreased perfusion to the left hemisphere, including the basal ganglia and the thalamus (Fig 2A). The hypoperfusion was most prominent in the left medial temporal lobe. Moderately diminished perfusion was also observed in the frontal lobes. The psychosis lasted for 7 days and resolved gradually without treatment. A repeat SPECT study 3 months later (Fig 2B) showed improved perfusion to the left temporal lobe and to the fight frontal lobe. The patient remained asymptomatic after a 6-month follow-up. Brief psychotic episodes may follow a bout of seizure clusters or a recent exacerbation in seizure frequency. 17 Postictal psychosis may develop in nearly 10% of adult patients, 6 but it is rare in children. The psychosis may be caused by repeated electrical discharges that change local neurotransmitter activity. It is also conceivable that structural brain abnormalities, eg, cortical dysgenesis or diffuse brain lesions, may lead to both the epilepsy and the psychosis. Postictal psychosis usually resolves within a few days. 5 Recurrent seizures may exacerbate the psychosis, and careful monitoring of anticonvulsant therapy is mandatory. EEG abnormalities persist in the majority of patients during the psychosis. 1 Some suggested risk factors are early onset and severe epilepsy, secondary generalization of seizures, certain anticonvulsive drugs, and temporal lobectomy. Most investigators suggest that psychosis in epilepsy is preferentially associated with temporal lobe seizures. 8-a2 MRI studies show that postictal psychosis is most likely to occur in patients with resistant temporal lobe epilepsy stemming from mesial temporal sclerosis, especially on the left side. 6 Changes in postsynaptic dopamine receptor sensitivity have been suggested as the mediating mechanism. SPECT studies have shown low levels of striatal dopamine D2 receptors in patients with peri-ictal psychosis. 13 Possible differential diagnoses for our patient are listed below.

Influence of dopaminergic transmission on severity of withdrawal syndrome in alcoholism.

Dysfunction of dopaminergic transmission has been suggested as influencing withdrawal syndrome in alcohol-dependent patients. Therefore, dopamine levels and sensitivity of dopamine receptors were correlated with the severity of withdrawal syndrome in 40 alcoholics. Dopamine blood plasma levels and apomorphine-induced Growth Hormone (GH) release were measured on the first day of detoxification (Day 1) and after 8 days of abstinence (Day 8). Severity of withdrawal syndrome was assessed daily by the Clinical Institute Withdrawal Assessment (CIWA) score. In the 22 patients (out of the 40) treated by chlormethiazole, severity of withdrawal was measured by the required chlormethiazole dose. A positive correlation was found between dopamine levels on Day 1 and the total CIWA score and necessary chlormethiazole dose, respectively. Correlation with the CIWA score was even stronger when the sensitivity of post-synaptic dopamine receptors was taken into account. No significant correlation between dopamine levels on Day 8 and withdrawal syndrome was found. Our findings indicate an influence of dopaminergic transmission on withdrawal syndrome during early withdrawal.

Motor fluctuations in levodopa treatment: clinical pharmacology.

Fluctuations in motor performance and dyskinesias are a common problem in the long-term management of Parkinson's disease. The pharmacokinetics and the pharmacodynamics of levodopa, loss of presynaptic dopamine terminals, alterations in postsynaptic dopamine receptor sensitivity, or changes in the modulatory influences of nondopaminergic transmitter system could play a pathogenic role. The short half-life of levodopa and its absorption and transport are important factors. The pharmacodynamic response to levodopa changes during long-term therapy. An absolute threshold in plasma levodopa level, below which the patients are off, appears. The patients show a therapeutic window for levodopa which becomes narrower with time. This therapeutic window can be widened by giving continuous infusion of dopaminergic drugs. Motor fluctuations can be ameliorated by a more physiological continuous stimulation of the receptor site and by avoiding repeated shifting in levodopa levels. Long-term complications are attenuated by an early combination of levodopa with dopamine agonist.

Remoxipride in Parkinsonʼs Disease

Remoxipride is a novel substituted benzamide that more effectively blocks mesolimbic than striatal D2 dopamine receptors. We used remoxipride in the management of nine patients with Parkinson's disease (PD) who were experiencing visual hallucinations due to dopaminergic therapy. Remoxipride was begun in a dose of 25 mg three times daily and gradually increased to 75-225 mg/d (mean 161 mg). The psychiatric status improved in eight patients. Little or no change in the severity of parkinsonism was noted in five, a mild increase in two, and a moderate increase in two. Because one patient with moderately severe levodopa-induced dyskinesias experienced a reduction in the abnormal movements without a substantial increase in parkinsonism, we began a trial of remoxipride for disabling peak-dose dyskinesias. The trial was abandoned after every one of the first four patients entered experienced an immediate, severe, and prolonged increase in off periods with single 10- to 25-mg doses. This striking differential response to an atypical neuroleptic with weak striatal D2 antagonist properties indicates that different states of postsynaptic dopamine receptor sensitivity or synaptic dopamine levels may be associated with various disease- and treatment-related problems found in late-stage PD.

The relationship between diabetes mellitus and Parkinson's disease.

It has been reported that 50% to 80% of patients with Parkinson's disease have abnormal glucose tolerance which may be further exacerbated by levodopa therapy. Little is known about the impact of chronic hyperglycemia on the severity of the motor manifestations and the course of the disease as well as its impact on the efficacy of levodopa or other dopaminergic drugs. This issue, which has been largely ignored, is of clinical relevance since animal studies indicate that chronic hyperglycemia decreases striatal dopaminergic transmission and increases the sensitivity of postsynaptic dopamine receptors. In addition, evidence from experimental animal studies indicates that diabetic rats are resistant to the locomotor and behavioral effects of the dopamine agonist amphetamine. The resistance to the central effects of amphetamine is largely restored with chronic insulin therapy. In the present communication, I propose that in Parkinson's disease diabetes may exacerbate the severity of the motor disability and attenuate the therapeutic efficacy of levodopa or other dopaminergic agents as well as increase the risk of levodopa-induced motor dyskinesias. Thus, it is advocated that Parkinsonian patients should be routinely screened for evidence of glucose intolerance and that if found aggressive treatment of the hyperglycemia may improve the response to levodopa and potentially diminish the risk of levodopa-induced motor dyskinesias.

Behavioural and Biochemical Effects of Subchronic Treatment with Raclopride in the Rat: Tolerance and Brain Monoamine Receptor Sensitivity

Male Sprague-Dawley rats were treated with the dopamine (DA) D2 receptor blocking agent raclopride 0.5 or 8.0 mg kg-1 subcutaneously (1.0 and 16.0 mumol kg-1, respectively), twice daily for 21 days. The animals treated with raclopride gained weight at the same rate as saline controls, and gross observation did not indicate any behavioural abnormalities due to the subchronic raclopride treatment. Possible changes in brain DA receptor sensitivity due to prolonged blockade of DA receptors were evaluated in behavioural and biochemical models. There were no effects on locomotor activity, as observed by means of photobeam-equipped activity cages, 24 hr or 72 hr after withdrawal of 0.5 or 8.0 mg kg-1 subchronic raclopride treatment. Twenty-four hr after withdrawal of the raclopride treatment there was an increased post-synaptic DA receptor sensitivity as evidenced by increased behavioural and biochemical responses to apomorphine, and by an attenuated response to acute raclopride treatment, 0.1 mg kg-1. Thus, there was an increase in locomotor activity by the apomorphine treatment in animals pretreated with the 8 mg kg-1 dose, as compared to the response obtained in saline controls. Furthermore, the suppression of locomotor activity in saline controls produced by acute raclopride treatment was dose-dependently antagonized by the raclopride pretreatment and this also applied to the increase in striatal DOPAC levels produced by acute raclopride treatment. Finally, there was an increased DA receptor sensitivity presynaptically as evidenced by an enhanced effect on striatal DOPA levels by apomorphine in rats treated with NSD 1015 and reserpine.(ABSTRACT TRUNCATED AT 250 WORDS)

Enhancing effect of taurine in the rat caudate spindle. II: Effect of bilateral 6-hydroxydopamine lesions of the nigro-striatal dopamine system

Bilateral injections of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle of rats resulted in destruction of dopamine (DA) nerve terminals in the striatum. DA contents decreased to 16.8, 15.0 and 13.7% of control values on 3, 5 and 7 days after the lesions, respectively. The time course of the effect of 6-OHDA lesions on apomorphine (0.5 mg/kg, IV)-induced stereotypy was investigated as the index of the development of supersensitivity. Stereotypy was unchanged on 3 days, but was enhanced 5 and 7 days after 6-OHDA lesions. Therefore, the sensitivity of postsynaptic DA receptors for apomorphine did not change 3 days after 6-OHDA lesions, although the striatal DA was depleted. The effects of bilateral injections of taurine into the striatum on the rat caudate spindle were determined 3 days after 6-OHDA lesions. Taurine, at a dose of 30 μg, enhanced the spindle in sham-operated rats, but this enhancement was not seen after 6-OHDA lesions. Intravenous administration of apomorphine (0.5 mg/kg) to lesioned rats suppressed the spindle, and this effect was prevented by a lower dose (3 μg) of taurine. These results provide further evidence that taurine enhances the spindle, possibly by decreasing the activity of the nigro-striatal DA system at the pre- and postsynaptic sites.

Experimental studies on genetically determined predisposition to catatonia in rats as a model of schizophrenia

To check experimentally the hypothesis of schizophrenia being a manifestation of extremely low threshold of hypnotic (catatonic) type of reaction, changes of some neurophysiologic and neurochemical systems in rats with a genetic predisposition to catalepsy were compared to analogous changes found so far in schizophrenia or chronic amphetamine intoxication considered nowadays as the most adequate pharmacological model of schizophrenia. It is found that in rats predisposed to catalepsy the threshold of audiogenic seizures is elevated; the activity of tryptophan hydroxylase in striatum is higher in rats predisposed to catalepsy genetically and due to a chronic methylphenidate intoxication as compared to control animals; noradrenaline content and noradrenaline/dopamine ratio is lower in the diencephalon of rats predisposed to catalepsy than in controls; cataleptic rats have a higher content of homovanillic acid in N.accumbens , and a higher frequency of inversion of hemispheric asymmetry as estimated by levels of dopamine and dioxyphenylacetic acid in N.accumbens and caudate nucleus, than normal rats; MAO-B/MAO-A ratio is higher in the brain stem of cataleptic than normal rats. The effects of haloperidol and apomorphine on motor activity of cataleptic and normal animals point to a higher sensitivity of postsynaptic dopamine receptors in the former. Conditioned avoidance reaction is formed slower, but preserved longer in rats predisposed to catalepsy. Blood serum of wild rats predisposed to akinetic catatonic reactions, unlike the serum of normal wild rats, inhibits the electric activity of snail neurons. The above indicated changes are analogous to those known to be present in schizophrenia and/or chronic intoxication with amphetamine or its pharmacological analogues, which witnesses in favour of the proposed hypothesis.

Apomorphine-induced inhibition of neostriatal activity is enhanced by lesions induced by 6-hydroxydopamine but not by long-term administration of amphetamine

Single-unit activity was recorded in the neostriatum of locally-anesthetized, immobilized rats which had received either a unilateral injection of 6-hydroxydopamine (6-OHDA) into the nigroneostriatal dopamine pathway, or repeated injections (twice daily for 6 days) of saline, 1.0, 5.0 or 10.0 mg kg (+)-amphetamine. A staircase regimen of apomorphine was administered intravenously to each rat to determine if the long-term administration of amphetamine changed the sensitivity of postsynaptic dopamine receptors in a way comparable to that produced by 6-hydroxydopamine. In all groups, the most frequent response to apomorphine was inhibition of neostriatal activity. In saline-treated rats, most units were moderately excited by small doses of apomorphine (0.0025–0.02 mg kg ) and then inhibited by doses exceeding 0.04 mg kg . In rats with lesions induced by 6-hydroxydopamine, apomorphine caused significantly more inhibition than in saline-treated animals. By contrast, neuronal responses in amphetamine-treated rats were not significantly different from those of saline controls. These results indicate that the long-term administration of amphetamine produces an augmentation of behavior by some mechanism other than an increase in the sensitivity of postsynaptic dopamine receptors.

Chronic L-dopa treatment of rats and mice does not change the sensitivity of post-synaptic dopamine receptors.

The effects of L-Dopa + benserazide (L-Dopa + B) treatment on pre- and postsynaptic dopamine (DA) receptors were studied. Mice treated once daily P.O. with L-Dopa (200 mg/kg) + B (50 mg/kg) or vehicle for 10 days were used on the 11th day. After premedication with reserpine and alpha-methyltyrosine (alpha-MT), apomorphine (0.5-2.0 mg/kg) produced locomotor stimulation which was of equal intensity in the 3 treatment groups, even when the treatment dose of L-Dopa was increased to 400 mg/kg per day. In contrast, low doses of apomorphine (0.1-0.5 mg/kg) produced locomotor depression in B- and vehicle-treated mice but not in L-Dopa + B-treated mice. In rats treated I.P. twice daily with L-Dopa (200 mg/kg) + B (50 mg/kg), B (50 mg/kg) or vehicle for 12 days, apomorphine produced an equivalent degree of stereotypy on the 13th day in each of the 3 treatment groups. There were no treatment group differences in the binding of [3H]-spiperone or [3H]-leu-enkephalin to rat striatal membranes. The data suggest that long-term L-Dopa + B treatment of mice and rats does not change the sensitivity of postsynaptic DA receptors but may affect the sensitivity of DA autoreceptors.

Tolerance to amphetamine-induced inhibition of neuronal activity in the central amygdaloid nucleus

Rats were pretreated twice daily for 5 consecutive days with saline or 2.5 mg/kg d-amphetamine. Approximately 12 hr after the last injection, neuronal activity was recorded bilaterally from the central amygdaloid nucleus (CAN) and the animals were challenged every 2 min with 0.2 mg/kg d-amphetamine or with increasing incremental doses of apomorphine. In saline controls, all CAN neurons were inhibited by the 5th amphetamine injection and two-thirds were suppressed by 0.64 mg/kg apomorphine. In amphetamine-pretreated animals, on the other hand, the majority of CAN neurons failed to respond even by the 10th amphetamine injection and less than one-third were inhibited by apomorphine even at a dose of 2.56 mg/kg. These results indicate that tolerance develops to the inhibitory effects of d-amphetamine in the CAN and that this effect is mediated, at least in part, by a decrease in the sensitivity of postsynaptic dopamine receptors.

Long-term d-amphetamine in rats: Lack of change in post-synaptic dopamine receptor sensitivity

Long-term d-amphetamine in rats: Lack of change in post-synaptic dopamine receptor sensitivity

Effects of ovariectomy, castration, and chronic lithium chloride treatment on stereotyped behavior in rats.

The effects of ovariectomy, castration, and chronic lithium chloride treatment on stereotyped behavior (SB) induced by apomorphine (APO) (0.3--0.6 mg/kg) were investigated in rats. Duration of stereotyped behavior (interval between APO injection and termination of SB) increased in ovariectomized rats compared to female control rats. Castration had no effect on the duration of stereotyped behavior. On the other hand, ovariectomized rats that were treated chronically with LiCl (2mEq/kg daily) showed no difference in duration of stereotyped behavior compared to female controls chronically treated with LiCl. Neither treatment group showed a significantly altered intensity of stereotyped behavior compared with the appropriate control. These findings are consistent with the hypothesis that estrogen deficit contributes to a greater incidence of neuroleptic-induced tardive dyskinesia in postmenopausal women than in men of comparable age. Furthermore, LiCl may attenuate the symptoms associated with increased postsynaptic dopamine receptor sensitivity following ovariectomy.

Long-term d-amphetamine in rats: Lack of change in post-synaptic dopamine receptor sensitivity

Treatment of rats with d-amphetamine (5 mg/kg) once daily for 25 days did not change locomotor responses, on day 7 of withdrawal, to dopamine (DA) or d-amphetamine into the nucleus accumbens. Nor was there a change in 3H-spiperone binding of caudate nucleus membranes. There was no effect of treatment on the locomotor response of rats to 1.0, 1.5 or 2.0 mg/kg d-amphetamine IP. However, d-amphetamine-treated rats were significantly less sensitive to 0.5 mg d-amphetamine. Although 1, 2 or 3 mg/kg apomorphine produced in same degree of stereotypy in both treatment groups, there was a significant difference in the response of the two groups to 0.5 mg apomorphine, d-amphetamine-treated animals being less sensitive than vehicle-treated animals. No change was found in brain DA levels with or without synthesis inhibition. The present data do not support the hypothesis that chronic treatment of rats with d-amphetamine can produce supersensitive post-synaptic DA receptors.

Dopamine receptor changes after long-term haloperidol treatment in rats.

Abstract Tardive dyskinesia is a neurological syndrome associated with prolonged neuroleptic treatment of schizophrenic patients (Crane 1968; Faurbye 1970; Faurbye et al 1964). It has been suggested that tardive dyskinesia results from chemical denervation of central dopamine neurons and subsequent development of supersensitivity of the postsynaptic receptor (Rubovits & Klawans 1972). Experiments based on animal models of tardive dyskinesia support this hypothesis. Chronic neuroleptic treatment increases postsynaptic dopamine receptor sensitivity when measured either behaviourally or biochemically (Christensen et al 1976; Klawans & Rubovits 1972; Moore & Thornburg 1975; Sayers et al 1975; Tarsy & Baldessarini 1974; Von Voigtlander et al 1975). The molecular basis for this behavioural change has been reported to be an increase in the number of receptor sites with no change in their affinity as measured by 3H-neuroleptic binding to striatal membrane homogenates (Burt et al 1977; Klawans et al 1977; Muller & Seeman 1977). Previous biochemical reports of the development of model tardive dyskinesia after neuroleptic treatment of animals have generally used treatment periods of 3 weeks or less (Burt et al 1977; Klawans et al 1977; Muller & Seeman 1977). Only one report treated animals for longer periods (Clow et al 1978). In the present experiments we studied the kinetics of [3H]spiroperidol binding to rat caudate nucleus homogenates after 3 and 10 weeks of haloperidol treatment.

The contrasting actions of TRH and cycloheximide in altering the effects of centrally acting drugs: Evidence for the non-involvement of dopamine sensitive adenylate cyclase

Cycloheximide inhibited the locomotor activity produced in rats by injection of a monoamine oxidase inhibitor and l-dihydroxyphenylalanine and increased the time before onset of pentylenetetrazol-induced convulsions. Previously it has been shown that thyrotropin releasing hormone (TRH) prctreatment enhances this type of locomotor activity and shortens the time before onset of pentylenctetrazol-induced convulsions. Pentobarbital-induced sleeping time was shortened by TRH pretreatment and lengthened by Cycloheximide pretreatment. although neither drug significantly altered pentobarbital metabolism. Cycloheximide inhibited locomotor activity produced by low doses of methamphetamine (0.5 mg/kg) but not when the methamphetamine dose was raised to 2.5 mg/kg. Thyrotropin releasing hormone only enhanced this activity when the animals had also been given a monoamine oxidase inhibitor. Circling behaviour produced in rats with a unilateral nigro-striatal lesion by the dopamine agonist apomorphine was not altered by Cycloheximide or TRH and neither drug affected the locomotor activity produced in normal rats by apomorphine. This suggests that neither drug acts by altering postsynaptic dopamine receptor sensitivity. This view was strengthened by the observation that adenylate cyclase activity and the response of this enzyme to dopamine were unaltered in the caudate nucleus of animals pretreated with TRH or Cycloheximide. Furthermore neither drug added in vitro altered the activity of this enzyme or its stimulation by dopamine. Thyrotropin releasing hormone pretreatment did not alter brain dopamine or noradrenaline concentrations. Cycloheximide did not alter the brain noradrenaline concentration but did increase the concentration of dopamine in the brain. Turnover studies indicated that TRH decreased and Cycloheximide increased dopamine synthesis, suggesting that Cycloheximide inhibits dopamine release while TRH may enhance it. This may be the mechanism by which TRH and Cycloheximide produce some of their behavioural effects and explain why it has been reported that TRH appears to have an amphetamine-like action in both experimental animals and clinical studies. While our results suggest that the peptide TRH and the protein synthesis inhibitor Cycloheximide act in contrasting ways, it has not been demonstrated definitively that they act at the same site in the brain.