Drosophila modifier screens to identify novel neuropsychiatric drugs including aminergic agents for the possible treatment of Parkinson's disease and depression.

Small molecules that increase the presynaptic function of aminergic cells may provide neuroprotection in Parkinson's disease (PD) as well as treatments for attention deficit hyperactivity disorder (ADHD) and depression. Model genetic organisms such as Drosophila melanogaster may enhance the detection of new drugs via modifier or 'enhancer/suppressor' screens, but this technique has not been applied to processes relevant to psychiatry. To identify new aminergic drugs in vivo, we used a mutation in the Drosophila vesicular monoamine transporter (dVMAT) as a sensitized genetic background and performed a suppressor screen. We fed dVMAT mutant larvae ∼ 1000 known drugs and quantitated rescue (suppression) of an amine-dependent locomotor deficit in the larva. To determine which drugs might specifically potentiate neurotransmitter release, we performed an additional secondary screen for drugs that require presynaptic amine storage to rescue larval locomotion. Using additional larval locomotion and adult fertility assays, we validated that at least one compound previously used clinically as an antineoplastic agent potentiates the presynaptic function of aminergic circuits. We suggest that structurally similar agents might be used to development treatments for PD, depression and ADHD, and that modifier screens in Drosophila provide a new strategy to screen for neuropsychiatric drugs. More generally, our findings demonstrate the power of physiologically based screens for identifying bioactive agents for select neurotransmitter systems.

Acute dopamine D(1) and D(2) receptor stimulation does not modulate mismatch negativity (MMN) in healthy human subjects.

RATIONALE: Schizophrenia is commonly associated with an impairment in pre-attentive change detection, as represented by reduced mismatch negativity (MMN), an auditory event related potential. While the neurochemical basis of MMN has been linked to the integrity of the glutamatergic system involving N-methyl-D-aspartate (NMDA) receptors, the role of the dopaminergic system and in particular, the role of D(1) and D(2) receptors on MMN is yet to be determined. OBJECTIVES: The aim of the present project was to investigate the acute effects of dopamine D(2) (bromocriptine) and D(1)/D(2) (pergolide) receptor stimulation on the human MMN in healthy subjects. METHODS: Fifteen healthy male subjects participated in a double-blind, placebo-controlled, cross-over design in which each subject was tested under three acute treatment conditions separated by a 1-week wash out period; placebo, bromocriptine (2.5 mg) and pergolide (0.1 mg). The subjects were exposed to a duration-MMN paradigm with 50 ms standard tones (91%) and 100 ms deviant tones (9%). RESULTS: The results showed that neither D(2) receptor stimulation with bromocriptine, nor simultaneous D(1) and D(2) receptor stimulation with pergolide, modulated MMN. CONCLUSIONS: These findings suggest that acute D(1) and D(2) receptor stimulation does not modulate MMN. While the role of dopamine cannot be completely ruled out, the findings support the view that the aberrant MMN reported in schizophrenia may be linked primarily to glutamate dysfunction involving NMDA receptors.

Dopamine receptor stimulation does not modulate the loudness dependence of the auditory evoked potential in humans.

RATIONALE: The Loudness Dependence of the Auditory Evoked Potential (LDAEP) has been suggested as a reliable measure of central serotonin function in humans; however, its specificity for the serotonin system remains a topic of debate, with possible modulation of this purported serotonin marker by other neurotransmitters, including dopamine. OBJECTIVES: We examined the effect of dopaminergic modulation on the LDAEP using the D1/D2/D3 dopamine receptor agonist pergolide and the D2/D3 agonist bromocriptine. METHODS: The study was a double-blind, placebo-controlled repeated-measures design in which healthy participants were tested under three acute treatment conditions: placebo, bromocriptine (2.5 mg), and pergolide (0.1 mg). Changes in the amplitude of the N1/P2 at intensities (60, 70, 80, 90, and 100 dB) were examined at C Z. RESULTS: Acute stimulation of D1/D2/D3 receptors with pergolide and D2/D3 receptors with bromocriptine in comparison with placebo had no effect on the LDAEP. CONCLUSION: These findings indicate that acute stimulation of dopamine D1, D2, and D3 receptors does not modulate the LDAEP in humans. Although the findings suggest that the LDAEP may not be modulated by acute changes in dopamine neurotransmission, further studies are needed to fully characterize its dopaminergic sensitivity.

Short review on dopamine agonists: insight into clinical and research studies relevant to Parkinson's disease.

Parkinson's disease (PD) is a chronic and progressive neurological disorder characterized by selective degeneration of dopaminergic neurons (DAergic) in the substantia nigra pars compacta (SNpc) and subsequent decrease in dopamine (DA) levels in the striatum. Although levodopa replacement therapy is initially effective in symptomatic treatment of parkinsonian patients, its effectiveness often declines and various levodopa-related side effects appear after long-term treatment. The disabling side effects of levodopa therapy include motor fluctuations such as the wearing-off or on-off phenomena, dyskinesias and psychiatric symptoms. Nowadays, DA receptor agonists are often regarded as first choice in de novo and young parkinsonian patients to delay the onset of levodopa therapy. In advanced stages of the disease, they are also used as adjunct therapy together with levodopa to retard the development of motor complications. DA receptor agonists mimic the endogenous neurotransmitter, dopamine, and act by direct stimulation of presynaptic (autoreceptors) and postsynaptic DA receptors. Next to their clinical role in treating parkinsonian patients, laboratory studies reported antioxidative and neuron-rescuing effects of DA receptor agonists either in vivo or in vitro. This may involve reduced DA turnover following autoreceptor stimulation and direct free radical scavenging activity. In this review, we focus on and summarize the recently reported effects of the most commonly used DA agonists either in clinical or in research studies relevant to PD treatment.

The effects of dopamine agonists on prepulse inhibition in healthy men depend on baseline PPI values.

RATIONALE AND OBJECTIVES: Dopamine (DA) agonists reliably disrupt prepulse inhibition (PPI) of the startle reflex in animals but less so in humans despite cross-species similarities in the neural regulation of PPI. This study examines whether individual variation in baseline PPI may account for the inconsistencies in DA agonist-induced PPI disruption in humans. METHODS: Baseline PPI measures were obtained from 32 healthy adult men. Subjects were subsequently tested in three sessions after ingestion of placebo or active drug in a balanced double-blind design. Seventeen subjects were given 0.05 and 0.1 mg of pergolide (a direct DA agonist) and 15 subjects were given 100 and 200 mg of amantadine (an indirect DA agonist). In each treatment group, subjects were assigned to "high" and "low" PPI subgroups based on the median split of their baseline PPI. RESULTS: Amantadine and pergolide disrupted PPI in high- but not in low-PPI subjects. In contrast, low-PPI subjects showed a trend towards PPI facilitation especially with pergolide. CONCLUSIONS: Our results suggest that baseline PPI is an important determinant of the effect of DA agonists on PPI.

Towards a cross-species pharmacology of sensorimotor gating: effects of amantadine, bromocriptine, pergolide and ropinirole on prepulse inhibition of acoustic startle in rats.

Animal models in behavioral pharmacology can be evaluated based on their face, predictive and construct validity. A further level of validity may be achieved if a model is reproduced precisely across species--from laboratory animal to human--using identical conditions and manipulations to elicit identical behavioral changes. Under circumstances in which a model achieves 'homologous' validity, it should be possible to demonstrate that the same pharmacological agents produce parallel changes in the same behavior (as distinct from the clinical condition that the animal behaviors are hypothesized to model), when studied in laboratory animals and in humans. Studies have demonstrated that the disruption of sensorimotor gating of the startle reflex, measured by prepulse inhibition (PPI), in rats by dopamine agonists exhibits face, predictive and construct validity for the relative loss of PPI in schizophrenia patients. To assess the homologous validity of this model, and to expand its utility in understanding the pathophysiology of sensorimotor gating deficits and in developing novel antipsychotic agents to reverse these deficits, it will be important to study PPI across species, comparing response profiles to identical pharmacological manipulations. In the present studies, we report that PPI in rats is reduced in a dose-dependent manner by four dopamine agonists that can be administered with relative ease to humans. We also report that the PPI-disruptive effects of the clinically useful dopamine agonist pergolide are reversed by both typical and atypical antipsychotics. These studies establish a foundation for pursuing human pharmacological studies of PPI, and for extrapolating the substantial neurochemical and neurophysiological information from animal studies of PPI, towards understanding the neural basis for deficient sensorimotor gating in specific neuropsychiatric disorders.

Barakol, a natural anxiolytic, inhibits striatal dopamine release but off uptake in vitro.

The present study investigated the effects of barakol on the in vitro release of endogenous and radiolabelled dopamine from rat striatal slices in comparison with the dopamine receptor agonists, quinelorane dihydrochloride (1 microM) and pergolide methanesulfonate (100 microM), and the dopamine receptor antagonist, S(-)-eticlopride hydrochloride (10 microM) using a semi-superfusion method and high-performance liquid chromatography with electrochemical detector measurement of endogenous dopamine. Barakol (1, 10 and 100 microM) reduced K(+)-stimulated endogenous dopamine release as did the dopamine D2 receptor agonists but had no effect on [3H]dopamine release. The inhibition of barakol (10 microM) on K(+)-stimulated endogenous dopamine release was antagonised by a dopamine D2 receptor antagonist, eticlopride. Barakol (0.1 nM-10 microM) had no effect on [3H]dopamine uptake except at the highest concentration (100 microM) when inhibition was observed. The results indicate that barakol might act as a dopamine agonist to inhibit endogenous dopamine release without a change in dopamine uptake.

Aromatization is not required for androgen induced changes in proopiomelanocortin gene expression in the hypothalamus.

Testosterone regulation of POMC mRNA and peptide levels has been previously demonstrated in the medial basal hypothalamus (MBH) of the rat. Although both dihydrotestosterone (DHT) and estradiol are known to affect POMC peptide levels in the MBH, it is unclear if the effects of testosterone on POMC gene expression are due to conversion by aromatization to estradiol or due to independent androgen actions. We have therefore compared the effects of the nonaromatizable androgen DHT and estradiol on POMC gene expression and beta-endorphin (beta-EP) levels in the MBH of castrated male rats. We have also examined the effect of the dopamine agonist, pergolide, on POMC in the DHT and estradiol treated animals in light of previous studies in female rats. In the first study POMC mRNA in the MBH, as measured by a solution hybridization assay, was 0.85 +/- 0.07 pg/microgram RNA 3 weeks after castration and decreased to 0.64 +/- 0.07 pg and 0.65 +/- 0.07 pg in the DHT treated rats with and without pergolide (P < 0.05). In the second study the mean POMC mRNA concentration in the MBH was 0.95 +/- 0.10 pg/microgram RNA and decreased to 0.68 +/- 0.06 pg and 0.70 +/- 0.08 pg in the estradiol treated rats with and without pergolide (P < 0.05). In both studies significant changes in beta-EP peptide levels paralleled the changes in POMC mRNA levels. We conclude that both androgens and estrogens can affect POMC mRNA levels in the male rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Neuroendocrine evidence for antagonism of serotonin and dopamine receptors by olanzapine (LY170053), an antipsychotic drug candidate.

Olanzapine, 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-B] [1,5]benzodiazepine (LY170053), antagonized the quipazine-induced elevation of serum corticosterone concentration in rats with an ED50 value of 0.57 mg/kg i.p. LY170053 was less potent in antagonizing the pergolide-induced elevation of serum corticosterone concentration in rats, and increases in corticosterone elicited by olanzapine alone at higher doses complicated the precise estimate of an ED50 value, which was approximately 3 mg/kg. These relative potencies in blocking quipazine and pergolide effects are taken as indices of antagonism of serotonin 5HT2 and of dopamine D2 receptors, respectively. Olanzapine is more potent than clozapine in blocking 5HT2 and D2 receptors, and its ability to block these receptors supports its possible usefulness as an antipsychotic drug.