Nature against depression.

Depression is a major health problem currently recognized as a leading cause of morbidity worldwide. In the United States alone, depression affects approximately 20% of the population. With current medications suffering from major shortcomings that include slow onset of action, poor efficacy, and unwanted side effects, the search for new and improved antidepressants is ever increasing. In an effort to evade side effects, people have been resorting to popular traditional herbal medicines to relieve the symptoms of depression, and there is a need for more empirical knowledge about their use and effectiveness. This review provides an overview of the current knowledge state regarding a variety of natural plant products commonly used in depression. Herbal medicines discussed that have been used in clinical trials for the treatment of mild to moderate depression states include the popular St. John's wort, saffron, Rhodiola, lavender, Echium, and the Chinese formula banxia houpu. In addition, new emerging herbal products that have been studied in different animal models are discussed including Polygala tenuifolia, the traditional Chinese herbal SYJN formula, gan mai da zao, and Cannabis sativa constituents. A comprehensive review of the chemical, pharmacological, and clinical aspects of each of the reviewed products is provided. Finally, recent preclinical studies reporting the antidepressant action of marine-derived natural products are discussed at the end of the review.

Rimcazole analogs attenuate the convulsive effects of cocaine: correlation with binding to sigma receptors rather than dopamine transporters.

Cocaine interacts with dopamine transporters and sigma receptors at concentrations that are achievable in vivo, suggesting that they may both be viable targets for the development of anti-cocaine agents. Rimcazole binds to both of these targets and also attenuates cocaine-induced locomotor activity and sensitization. To further characterize the mechanism(s) underlying the attenuation of cocaine-induced convulsions and lethality, rimcazole and three analogs (SH3/24, SH2/21, SH1/57), with a range of affinities for dopamine transporters and sigma receptors, were evaluated. The highly selective and potent sigma receptor ligand LR176 was used as a reference. Competition binding studies confirmed that the rank order of the compounds at dopamine transporters vs. sigma receptors differed, thus enabling a correlation between the relative anti-cocaine activities of the compounds in behavioral studies and their affinities for dopamine transporters vs. sigma receptors. In behavioral studies, male Swiss Webster mice were pre-treated with one of the compounds (0-60 mg/kg, i.p.), then challenged 15 min later with either a convulsive (60 mg/kg, i.p.) or lethal (125 mg/kg, i.p.) dose of cocaine. When the compounds were ranked according to their protective effect, there was a significant correlation between their anticonvulsant actions and their affinities for sigma receptors, but not dopamine transporters. Although the rimcazole analogs were ineffective against the lethal effects of cocaine, the selective sigma receptor ligand LR176 provided significant protection. These data thus suggest that sigma receptors may mediate some of the toxic effects associated with cocaine and that sigma receptor antagonists may be developed as pharmacotherapeutic agents for this application.

Conformationally restricted analogs of BD1008 and an antisense oligodeoxynucleotide targeting sigma1 receptors produce anti-cocaine effects in mice.

Cocaine's ability to interact with sigma receptors suggests that these proteins mediate some of its behavioral effects. Therefore, three novel sigma receptor ligands with antagonist activity were evaluated in Swiss Webster mice: BD1018 (3S-1-[2-(3,4-dichlorophenyl)ethyl]-1,4-diazabicyclo[4.3.0]nonane), BD1063 (1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine), and LR132 (1R,2S-(+)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-2-(1-pyrrolidinyl)cyclohexylamine). Competition binding assays demonstrated that all three compounds have high affinities for sigma1 receptors. The three compounds vary in their affinities for sigma2 receptors and exhibit negligible affinities for dopamine, opioid, GABA(A) and NMDA receptors. In behavioral studies, pre-treatment of mice with BD1018, BD1063, or LR132 significantly attenuated cocaine-induced convulsions and lethality. Moreover, post-treatment with LR132 prevented cocaine-induced lethality in a significant proportion of animals. In contrast to the protection provided by the putative antagonists, the well-characterized sigma receptor agonist di-o-tolylguanidine (DTG) and the novel sigma receptor agonist BD1031 (3R-1-[2-(3,4-dichlorophenyl)ethyl]-1,4-diazabicyclo[4.3.0]nonane) each worsened the behavioral toxicity of cocaine. At doses where alone, they produced no significant effects on locomotion, BD1018, BD1063 and LR132 significantly attenuated the locomotor stimulatory effects of cocaine. To further validate the hypothesis that the anti-cocaine effects of the novel ligands involved antagonism of sigma receptors, an antisense oligodeoxynucleotide against sigma1 receptors was also shown to significantly attenuate the convulsive and locomotor stimulatory effects of cocaine. Together, the data suggests that functional antagonism of sigma receptors is capable of attenuating a number of cocaine-induced behaviors.

(+/-)-SM 21 attenuates the convulsive and locomotor stimulatory effects of cocaine in mice.

Cocaine interacts with sigma receptors at physiologically relevant concentrations. While earlier studies demonstrate that antagonism of sigma(1) receptors attenuates the behavioral actions of cocaine, the contribution of sigma(2) receptors is unclear. Therefore, in the present study, 3 alpha-tropanyl-2-(4-chlorophenoxy)butyrate ((+/-)-SM 21), a compound with high and preferential affinity for sigma(2) receptors, was tested for its ability to attenuate cocaine-induced behaviors. Pre-treatment of Swiss Webster mice with (+/-)-SM 21 significantly attenuated cocaine-induced convulsions and locomotor activity.

N-alkyl substituted analogs of the sigma receptor ligand BD1008 and traditional sigma receptor ligands affect cocaine-induced convulsions and lethality in mice.

Cocaine binds to sigma receptors with comparable affinity to its well-established interaction with dopamine transporters. Previous studies have shown BD1008 (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine) to have high affinity and selectivity for sigma receptors, and to additionally attenuate the locomotor stimulatory effects of cocaine. Therefore, in the present study, three N-alkyl substituted analogs of BD1008 were characterized in receptor binding and behavioral studies: BD1060 (N-[2-(3,4-dichlorophenyl)ethyl]-2-(1-pyrrolidinyl)ethylamine), BD1067 (N-[2-(3,4-dichlorophenyl)ethyl]-N-ethyl-2-(1-pyrrolidinyl)ethylamine), and BD1052 (N-[2-(3,4-dichlorophenyl)ethyl]-N-allyl-2-(1-pyrrolidinyl)ethylamine). Similarly to BD1008, all three analogs exhibited high affinity and selectivity for sigma receptors. In behavioral studies, BD1008, BD1060 or BD1067 attenuated cocaine-induced convulsions and lethality in Swiss Webster mice. The protective effects appear to be mediated through sigma receptor antagonism because traditional sigma receptor antagonists with high to moderate affinity for these receptors also attenuated the behavioral toxicity of cocaine. In contrast, traditional and novel sigma receptor agonists such as di-o-tolylguanidine and BD1052 worsened the behavioral toxicity of cocaine. To further characterize the actions of the N-alkyl substituted compounds, they were microinjected into the rat red nucleus, a functional assay of sigma receptor activity, where they produced agonist vs. antagonist actions that were consistent with their effects on cocaine-induced behaviors. Together, the data demonstrate that BD1008, BD1060 or BD1067 can attenuate the behavioral toxicity of cocaine, most likely through functional antagonism of sigma receptors.

Correlation between neuroleptic binding to sigma(1) and sigma(2) receptors and acute dystonic reactions.

Acute dystonic reactions are motor side effects that occur soon after the initiation of neuroleptic treatment. Although earlier studies indicate that these abnormal movements can be induced in animals and humans via activation of sigma receptors, the relative contribution of the different sigma receptor subtypes is unknown. Since sigma(1) and sigma(2) receptor are differentially represented in motor regions of the brain, the affinities of 17 neuroleptics for these sigma receptor subtypes were determined using competition binding studies. The results revealed that most neuroleptics do not exhibit selectivity for either of the sigma receptor subtypes, as reflected by a significant correlation between the affinities of the neuroleptics for sigma(1) vs. sigma(2) receptors. Moreover, when the sigma binding affinities of the neuroleptics were correlated with the tendency of the drugs to produce acute dystonic reactions in humans, there was a significant correlation for both subtypes. Together with earlier studies in animals, the data suggest that neuroleptic-induced motor side effects can be mediated through both sigma(1) and sigma(2) receptors.

Involvement of GABA(A) receptors in myoclonus.

Alterations in multiple neurochemical systems have been reported in animal and human studies of posthypoxic myoclonus. It is impossible, however, to establish causative relationships between the observed changes and the myoclonic movements from these studies. Therefore, to establish causative links between neurochemical changes and myoclonus, ligands that target neurotransmitter systems that are altered in posthypoxic myoclonus were microinjected into the lateral ventricles of normal rats to identify the changes that can produce myoclonus. Of the ligands that were tested, only the GABA(A) antagonists produced myoclonus after intracerebroventricular administration, suggesting the importance of disinhibition of GABAergic systems in myoclonus. To further examine the role of GABA in myoclonus, GABAergic antagonists were microinjected into the nucleus reticularis of the thalamus (NRT), an area of the brain in which extensive pathologic changes are seen in posthypoxic animals. GABA(A), but not GABA(B), antagonists produced myoclonus after microinjection into the NRT. Earlier investigators have further reported the ability of GABA(A) antagonists to produce myoclonus after microinjection into the caudate. The data therefore suggest that disruption of activity at GABA(A) receptors at any one of a number of levels in the neural axis can produce myoclonus.

Prevention of cocaine-induced convulsions and lethality in mice: effectiveness of targeting different sites on the NMDA receptor complex.

N-methyl-D-aspartate (NMDA) receptors appear to be involved in the behavioral toxic effects of cocaine. Therefore, different classes of NMDA receptor antagonists were compared for their ability to attenuate cocaine-induced convulsions and lethality in male, Swiss Webster mice. The mice were pre-treated (i.p.) with vehicle or an antagonist from one of the following classes: NMDA/glycine site antagonist (7-chlorokynurenic acid, ACEA-1021, ACEA-1031, ACEA-1328, DCQX, R(+)-HA-966), competitive antagonist (CPP, D-AP7), channel blocker (MK-801, memantine), or allosteric modulator (ifenprodil, CP-101,606, Co 101022, haloperidol). After a 15 min pre-treatment period, the mice were administered a convulsive (60 mg/kg, i.p.) or lethal (125 mg/kg, i.p.) dose of cocaine, equivalent to the calculated ED/LD97 values. Pre-treatment with competitive or NMDA/glycine site antagonists dose-dependently attenuated cocaine-induced convulsions and lethality (P<0.05). Pre-treatment with channel blockers or allosteric modulators of the NMDA receptor protected against cocaine-induced convulsions (P<0.05), but were ineffective or less effective than the competitive and glycine site antagonists in preventing death. The glutamate release inhibitor riluzole failed to prevent both the convulsions and lethality induced by cocaine. Significantly, post-treatment with NMDA/glycine site antagonists (ACEA-1021, ACEA-1031, ACEA-1328) after a cocaine overdose prevented death in a significant number of animals. The data suggest that NMDA receptors are involved in the pathophysiology of a cocaine overdose.

Relationship between modulation of the cerebellorubrospinal system in the in vitro turtle brain and changes in motor behavior in rats: effects of novel sigma ligands.

Saturation and competition binding studies showed that the turtle brain contains sigma sites labeled by both [3H]di-o-tolylguanidine (DTG) and [3H](+)-pentazocine. There was a significant correlation between the IC50 values of sigma ligands for [3H]DTG sites in the turtle vs. rat brain, suggesting that the sites are comparable in the two species. In contrast, [3H](+)-pentazocine, which primarily labels sigma1 sites in the rodent brain, labels a heterogeneity of sites in the turtle brain. In extracellular recordings from the in vitro turtle brainstem, some sigma ligands enhanced the burst responses of red nucleus (RN) neurons (DTG, haloperidol, BD1031, BD1052, BD1069) while other sigma ligands decreased the burst responses (BD1047, BD1063). Control compounds (turtle Ringer vehicle control, opiate antagonist naloxone, atypical neuroleptic sulpiride) had no significant effects on the RN burst responses recorded from the in vitro turtle brain. The ED50s of the ligands for altering the burst responses in RN neurons from the turtle brain were correlated with their IC50s for turtle brain sites labeled with [3H]DTG, but not [3H](+)-pentazocine; this pattern is identical to that previously reported in rats, where there is a correlation between the potencies of sigma ligands for producing dystonic postures after microinjection into the rat RN and their binding to rat brain sites labeled with [3H]DTG, but not [3H](+)-pentazocine. When the novel sigma ligands were microinjected into the rat RN, dystonic postures were produced by ligands that increased the burst duration of RN neurons in the turtle brain. Novel sigma ligands that reduced the burst responses in the in vitro turtle brain have previously been reported to have no effects on their own when microinjected into the rat RN, but to block the dystonic postures produced by other sigma ligands. Taken together, the data suggest that the opposite effects of the novel ligands in the turtle electrophysiological studies represent the actions of agonists vs. antagonists, and that the directionality of the effects has predictive value for the expected motor effects of the drugs.

Two novel sigma receptor ligands, BD1047 and LR172, attenuate cocaine-induced toxicity and locomotor activity.

The ability of cocaine to interact with sigma receptors indicates that these sites may mediate the negative properties associated with cocaine use, such as toxicity and addiction. Previous studies have shown that the novel sigma receptor ligand, BD1008 (N-[2-(3,4-dicholophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylam ine), effectively protects against cocaine-induced convulsions and locomotor activity in mice. Therefore, BD1047 ([2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(diamino)ethylamine) and LR172 (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-homopiperidinyl)eth ylamine), two analogs of BD1008, were tested to determine if they also have anti-cocaine properties. Receptor binding assays showed that BD1047 and LR172 both have high affinities for a receptors, but low to negligible affinities for dopamine, opioid, phencyclidine, and 5-HT2 sites. In behavioral studies, pretreatment of mice with BD1047 or LR172 reduced the convulsions, lethality, and locomotor activity produced by cocaine. The data indicates a possible role for sigma receptor ligands in the treatment of cocaine overdose and addiction.

Novel sigma receptor ligands attenuate the locomotor stimulatory effects of cocaine.

Cocaine interacts with sigma receptors, suggesting that these sites are important for many of its behavioral effects. Therefore, two novel sigma receptor ligands, BD1008 (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine) and BD1063 (1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine), were evaluated for their ability to attenuate cocaine-induced locomotor activity. Receptor binding studies showed that BD1008 and BD1063 have nanomolar affinities for sigma1 and sigma2 sites, but a 250-fold or lower affinity for nine other receptors, making them among the most selective sigma receptor ligands identified. In behavioral studies, pretreatment of mice with BD1008 or BD1063 produced a two-fold increase in the ED50 for the locomotor stimulatory effects of cocaine. These results suggest that sigma receptors are involved in the behavioral effects of cocaine.

Effects of AMPA/kainate glutamate receptor antagonists on cocaine-induced convulsions and lethality in mice.

Prior studies demonstrate that NMDA receptor antagonists attenuate cocaine-induced convulsions and lethality. Since glutamate is the primary neurotransmitter for NMDA receptors, pharmacological interventions to lower glutamatergic activity through non-NMDA ionotropic receptor-mediated mechanisms were evaluated for their ability to prevent the convulsive and lethal effects of cocaine. Pre-treatment of male, Swiss Webster mice with the alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA)/kainate receptor antagonists 1,2,3,4-tetrahydro-6-nitro-2, 3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX; 10-80 mg/kg, i.p.) or 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2, 3-benzodiazepine hydrochloride (GYKI 52466; 10-20 mg/kg, i.p.) failed to significantly attenuate cocaine-induced convulsions or lethality. Although ineffective when administered alone, NBQX enhanced the protective effects of 5-nitro-6,7-dichloro-1, 4-dihydro-2,3-quinoxalinedione (ACEA-1021), an NMDA/glycine site antagonist, when administered in combination. The mixed NMDA/non-NMDA receptor competitive antagonist 5-chloro-7-trifluoromethyl-1,2,3,4-tetrahydroquinoxaline-2,3-dione (ACEA-1011) also protected against the convulsive effects of cocaine. The data suggest that AMPA/kainate receptors indirectly influence the pathophysiological changes that occur after a cocaine overdose through modulation of NMDA receptors.

Microinjection of sigma ligands into cranial nerve nuclei produces vacuous chewing in rats.

Many typical neuroleptics carry a high risk for producing motor side effects in humans, and have significant affinities for sigma (sigma) receptors. Sigma receptors are densely concentrated in cranial nerve nuclei that comprise the final common pathways for lingual, facial and masticatory movements; thus, they may serve as important substrates for some of the unwanted movements that can accompany neuroleptic treatment. Therefore, the purpose of this study was to evaluate whether microinjection of sigma ligands into the facial nucleus or spinal trigeminal nucleus, oralis would cause orofacial dyskinesias, and whether these effects could be attenuated with sigma receptor antagonists. Microinjection of the high affinity sigma ligands, di-o-tolylguanidine or haloperidol (0-10 nmol/0.5 microl), produced a marked increase in vacuous chewing and facial tremors in rats, while coadministration of the functional sigma antagonists, BD1047 or BD1063 (5 nmol), greatly attenuated these drug-induced movements. Sulpiride and clozapine (10 nmol/0.5 microl), sigma inactive/dopamine active atypical antipsychotic drugs with a much reduced risk for producing motor side effects in humans, were unable to elicit orofacial dyskinesias when microinjected into the facial or spinal trigeminal nucleus, oralis. These studies indicate that sigma receptors may contribute to some forms of motor side effects resulting from antipsychotic drug treatment.

Neuroprotective effects of the strychnine-insensitive glycine site NMDA antagonist (R)-HA-966 in an experimental model of Parkinson's disease.

The neuroprotective effects of (R)-HA-966 and (S)-HA-966 (3-amino-1-hydroxy-2-pyrrolidinone) were examined in an MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced animal model of Parkinson's disease. Systemic pretreatment of C57 black mice with the strychnine-insensitive glycine site antagonist, (R)-HA-966 (3-30 mg/kg, i.p.), dose-dependently attenuated MPTP-induced depletion of striatal dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC). Pretreatment with (R)-HA-966 also significantly protected the degeneration of tyrosine hydroxylase-positive neurons in the substantia nigra of mice treated with MPTP and alleviated the acute behavioral changes caused by the neurotoxin. In contrast, the other racemic form, (S)-HA-966, neither prevented the neurochemical depletions nor the neuronal injury caused by MPTP. These results indicate that excitatory mechanisms of neurodegeneration are involved in the pathophysiology of Parkinson's disease, and that strychnine-insensitive glycine site NMDA antagonists may serve as dopaminoprotective agents which intervene in the progressive neurodegeneration in Parkinson's disease.

Subchronic administration of N-[2-(3,4-dichlorophenyl) ethyl]-N-methyl-2-(dimethylamino) ethylamine (BD1047) alters sigma 1 receptor binding.

BD1047 (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine) is known to bind with high affinity and selectivity to sigma sites in vitro. In prior in vivo studies, it has been shown to attenuate the dystonic postures and orofacial dyskinesias that are produced by sigma receptor ligands, including the neuroleptic haloperidol. Since abnormal movements, such as dystonic postures and orofacial dyskinesias, are side effects that are associated with many sigma-active neuroleptics, compounds such as BD1047 may have therapeutic potential for preventing and treating these unwanted movements. A possible limitation to the therapeutic potential of BD1047, however, is that at least in cell culture and albeit weak, it can be cytotoxic. Therefore, the present study analyzed the possible neurotoxic effects of in vivo subchronic intracerebroventricular infusion of BD1047 (10 nmol/h) or artificial cerebrospinal fluid (CSF) into rat brains using osmotic minipumps for 7 or 14 days. Following a 24 h wash-out period, the animals were killed, the brains removed, and P2 membranes prepared. Membranes from rats treated for 7 or 14 days with BD1047 showed a marked decrease in [3H](+)-pentazocine binding as compared to membranes from CSF-treated animals, suggesting a loss of sigma 1 receptor binding. Histological examination of brain sections processed for Nissl stains and glial fibrillary acidic protein (GFAP) immunohistochemistry excluded the possibility of a cytotoxically induced down-regulation, suggesting possible receptor internalization or desensitization mediated via sigma 1 sites. Under the conditions used in our study, BD1047 does not appear to be neurotoxic, and the data, when taken together with other studies, suggest that BD1047 acts as a partial agonist at sigma sites.

Novel NMDA/glycine site antagonists attenuate cocaine-induced behavioral toxicity.

N-Methyl-D-aspartate (NMDA)/glycine site antagonists were tested for their ability to prevent cocaine-induced convulsions and lethality in Swiss Webster mice. Pre-treatment of mice with the novel NMDA/glycine site antagonists ACEA-1021 (5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione) or ACEA-1328 (5-nitro-6,7-dimethyl-1,4-dihydro-2,3-quinoxalinedione) attenuated cocaine-induced convulsions; these effects were pharmacologically antagonized with D-cycloserine. The structurally-related NMDA/glycine site antagonist DCQX (6,7-dichloroquinoxaline-2,3-dione) and the structurally-unrelated NMDA/glycine site partial agonist HA-966 (3-amino-1-hydroxy-2-pyrrolidinone) also attenuated cocaine-induced convulsions, with the R(+)-isomer of HA-966 being more effective than the S(-)-isomer. In contrast, the selective alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA) receptor antagonist, NBQX (1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide) , failed to provide statistically significant protection although it shares the 2,3-quinoxalinedione structure of DCQX and the ACEA compounds. Pre-treatment with ACEA-1021, ACEA-1328, DCQX, or R(+)-HA-966 also attenuated cocaine-induced lethality in mice. Significantly, post-treatment with ACEA-1021, immediately prior to or after the onset of seizures, prevented death in up to 86% of mice receiving a lethal dose of cocaine; post-treatment with vehicle resulted in death of all mice. The results suggest the utility of targeting excitatory mechanisms for the treatment of cocaine overdose and offer a novel base structure from which effective pharmacotherapies can be developed.

Dissociation of the motor effects of (+)-pentazocine from binding to sigma 1 sites.

Radioligand binding and behavioral studies were conducted to determine whether a relationship existed between the motor effects produced by (+)-pentazocine and its binding to sigma sites. Scatchard analyses revealed decreased [3H](+)-pentazocine binding in middle aged rats (5-6 months old) compared to young adult rats (2-3 months old). However, there was no difference between the extent of circling behavior or dystonia produced by microinjection of (+)-pentazocine into the substantia nigra or red nucleus in the older animals compared to the young adult rats. There was also a significant decrease in [3H](+)-pentazocine binding in rats chronically treated with haloperidol. Again, however, despite the reduction in [3H](+)-pentazocine binding, there was no difference between the extent of dystonia produced by unilateral intrarubral microinjection of (+)-pentazocine into animals chronically treated with haloperidol vs. saline. The postural changes produced by (+)-pentazocine could not be attenuated with coadministration of the putative sigma receptor antagonist BD1047 (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino) ethylamine), or the opiate receptor antagonist naloxone. However, the (+)-opiate, (+)-nordihydrocodeinone, partially attenuated the postural effects of (+)-pentazocine, despite its very low affinity for sigma 1, sigma 2, or opiate receptors. Taken together with previous studies, the results suggest that [3H](+)-pentazocine is a potent and selective probe for sigma 1 binding sites, but the in vivo effects of (+)-pentazocine cannot be fully attributed to actions through these sites. Some of the in vivo effects of (+)-pentazocine appear to involve other binding sites that are not detected under the conditions normally used in in vitro assays.

Excitoprotective effect of felbamate in cultured cortical neurons.

The effect of felbamate on excitatory amino acid-induced biochemical changes was investigated in cultured cortical neurons. Felbamate inhibited NMDA- and glutamate-induced neuronal injury in a dose-dependent manner, but it did not rescue cells from kainate-induced neurotoxicity. The neuroprotective effect was accompanied by a decrease in NMDA- and glutamate-induced neuronal calcium (Ca2+) influx. Exogenous addition of glycine failed to modulate the effect of felbamate on NMDA-induced neurotoxicity or Ca2+ influx, although corresponding changes induced by the strychnine-insensitive glycine antagonist, 5,7-dichlorokynurenic acid could be modulated with glycine. Taken together, these results suggest that felbamate acts through a site on the NMDA receptor that is distinct from the strychinine-insensitive site, and that the effect of the drug on neuronal Ca2+ may be pivotal to its neuroprotective mechanism.

Effects of selective serotonergic ligands on posthypoxic audiogenic myoclonus.

Male Sprague-Dawley rats underwent cardiac arrest and resuscitation, subsequently exhibiting posthypoxic myoclonus. The audiogenic posthypoxic myoclonus in these animals could be attenuated with the following drugs: 5-hydroxytryptophan (5-HTP, serotonin [5-HT] precursor), N-(3-trifluoro-methylphenyl)piperazine hydrochloride (TFMPP, 5-HT1B/1C/2 agonist), (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrobromide (DOI, 5-HT2 agonist), and 1-(m-chlorophenyl)-biguanide hydrochloride (m-CPBG, 5-HT3 agonist). In contrast, the following drugs were ineffective: (+/-)-8-hydroxy-dipropylaminotetralin hydrobromide (8-OH-DPAT, 5-HT1A agonist), buspirone hydrochloride (5-HT1A agonist), 7-trifluoromethyl-4(4-methyl-l-piperazinyl)-pyrrolo[1,2- a]quinoxaline maleate (CGS 12066B, 5-HT1B agonist), ketanserin tartrate (5-HT2 antagonist), methysergide maleate (5-HT2 antagonist), fluoxetine (5-HT uptake blocker), and saline (vehicle). The data suggest that enhancement of serotonergic activity, particularly through 5-HT2 and 5-HT3 receptors, have therapeutic potential for the treatment of posthypoxic myoclonus.

Evidence for the involvement of histamine in the antidystonic effects of diphenhydramine.

Although diphenhydramine hydrochloride is known to eliminate or reduce the symptoms of dystonia in human patients with acute dystonic reactions and idiopathic torsion dystonia, its mechanism of action is still unclear. In the present study, we show that the antihistamine properties of diphenhydramine may contribute to its beneficial effects. Acute dystonic reactions were produced in rats with unilateral microinjection of haloperidol into the red nucleus as previously described. Similar to the pattern in humans, this effect could be attenuated by coadministration of diphenhydramine. Unilateral microinjection of histamine itself into the rat red nucleus produced dystonic postures (torticollis) in a dose-dependent manner, demonstrating that a histamine dysfunction could contribute to the pathophysiology of dystonia. The torticollis produced by histamine could be significantly attenuated with coadministration of the H1 antagonists diphenhydramine or pyrilamine or the H2 antagonist cimetidine. These effects are thought to be mediated through the red nucleus because significantly more torticollis was observed when histamine was injected into the red nucleus rather than surrounding mid-brain areas, the substantia nigra, or the lateral ventricle. The present data, taken together with studies in humans, suggest the involvement of histamine in some types of dystonia. Furthermore, the red nucleus and related motor pathways may have a more important role in dystonia than previously thought.