The opioid antagonist naltrexone reduces the reinforcing effects of Δ9-tetrahydrocannabinol (THC) in squirrel monkeys

Rationale Experimental evidence from animal studies suggests reciprocal functional interactions between endogenous brain cannabinoid and opioid systems. There is recent evidence for a role of the opioid system in the modulation of the reinforcing effects of synthetic cannabinoid CB1 receptor agonists in rodents. Since ⁹–tetrahydrocannabinol (THC), the natural psychoactive ingredient in marijuana, is actively and persistently self-administered by squirrel monkeys, this provides an opportunity to directly study involvement of opioid systems in the reinforcing effects of THC in non-human primates.Objectives To study the effects of naltrexone, an opioid antagonist, on THC self-administration behavior in squirrel monkeys.Methods Monkeys pressed a lever for intravenous injections of THC under a ten-response, fixed-ratio (FR) schedule with a 60-s time-out after each injection. Effects of pre-session treatment with naltrexone (0.03–0.3 mg/kg intramuscularly, 15 min before session) for 5 consecutive days on self-administration of different doses of THC (2–8 µg/kg per injection) were studied.Results Self-administration responding for THC was significantly reduced by pretreatment with 0.1 mg/kg naltrexone for five consecutive daily sessions. Naltrexone pretreatment had no significant effect on cocaine self-administration responding under identical conditions.Conclusions Self-administration behavior under a fixed-ratio schedule of intravenous THC injection was markedly reduced by daily pre-session treatment with naltrexone, but remained above saline self-administration levels. These findings demonstrate for the first time the modulation of the reinforcing effects of THC by an opioid antagonist in a non-human primate model of marijuana abuse.     

Applications of Lawesson’s reagent in the synthesis of naturally occurring steroids and terpenoids

Steroids and terpenoids are among the most biologically significant classes of natural products possessing a variety of biological activities. The replacement of one or more oxygen atoms in a steroid or terpenoid molecule by a heteroatom affects the chemical properties of that particular steroid or terpenoid, and that replacement often results in alterations of its biological properties, which is sometimes valuable. One possible modification is the thionation that could have some influence on such activity. Among the various thionating reagents, Lawesson’s reagent was found to be most suitable and showed versatile properties, including chemoselectivity and functional group tolerance. In this review, we present the role of Lawesson’s reagent in the synthesis of thioanalogues of natural steroids and terpenoids.     

The role of the dynorphin–κ opioid system in the reinforcing effects of drugs of abuse

Background  

Initial hypotheses regarding the role of the κ opioid system in drug addiction suggested that κ receptor stimulation had anti-addictive effects. However, recent research suggests that κ receptor antagonists may reverse motivational aspects of dependence. In the present review, we revisit the studies that measured the effects of κ receptor ligands on the reinforcing and rewarding effects of drugs and postulate underlying neurobiological mechanisms for these effects to elaborate a more complex view of the role of κ receptor ligands in drug addiction.     

In vivo pharmacological effects of dihydro-β-erythroidine,a nicotinic antagonist,in mice

The comparative in vivo pharmacology of mecamylamine and dihydro--erythroidine (DHE) in mice was studied. Modulation of the behavioral effects (antinociception, hypomotility, motor impairment and hypothermia) of nicotine in mice by DHE and mecamylamine were carried out. After SC administration, DHE and mecamylamine were nearly equipotent in blocking nicotine's effects except for antinociception, in which mecamylamine was clearly more potent. Intrathecal injection of DHE was also effective in blocking the antinociceptive effect of nicotine. In vivo interaction of DHE with calcium and calcium channels, involved in the central actions of nicotine, showed that intrathecal administration of DHE failed to reduce the antinociception induced by diverse drugs which increase intracellular calcium such as thapsigargin, (±)-BAYK 8644 and calcium, indicating that this antagonist does not affect calcium-dependent mechanisms involved in antinociception. On the other hand, mecamylamine blocked the antinociceptive effect of the calcium modulatory drugs, suggesting that it may be acting on calcium-dependent mechanisms involved in the intracellular signaling process. We conclude that DHE, a nicotinic neuromuscular antagonist, is able to block some of the central actions of nicotine after systemic and intrathecal administration. The mechanism of blockade is different from that of mecamylamine, a classical ganglionic antagonist, and may involve a direct action of DHE on nicotine receptor.     

Discriminative stimulus effects of the α2-adrenoceptor antagonist idazoxan

Rats were trained to discriminate a dose of the ₂-adrenoceptor antagonist idazoxan (10 mg/kg IP) from saline. The discriminative stimulus produced by idazoxan was dose related and generalised to yohimbine. However, generalisation did not occur with a variety of compounds from other pharmacological categories including the ₁-adrenoceptor agonist cirazoline, the ₂-adrenoceptor antagonist prazosin, and the ₂-adrenoceptor agonist clonidine. The idazoxan stimulus was not antagonised by either prazosin or clonidine, although it was clear that idazoxan antagonised the reductions in response rate produced by clonidine. Dose-related responding on the idazoxan-associated lever was produced by the anxiolytics buspirone and ipsapirone and by their metabolite MJ 13653 (1-PP), which has previously been shown to be an ₂-adrenoceptor antagonist. In general, however, high levels of generalisation occurred with these three compounds only at doses which substantially reduced response rates. These results demonstrate that idazoxan can give rise to a discriminative stimulus which is probably mediated through antagonism at ₂-adrenoceptors although the failure of clonidine to block the idazoxan stimulus is difficult to explain.     

Tetrahydronorharmane (Tetrahydro-β-carboline), a physiologically occurring compound of indole metabolism

Summary In the present paper a sensitive method is described to measure tetrahydronorharmane (THN) in the urine of man and rats as well as in the forebrain of rats. The compound is extracted into diethyl ether, separated by thin layer chromatography (TLC), acetylated with radiolabelled acetic anhydride and further isolated by two-dimensional TLC development. The existence of THN in urine of man was proven by using chromatography with different solvent systems, cocristallisation, isotope dilution technique as well as mass-spectrometry. The amount of THN in the urine varied over a wide range.With the same method it was demonstrated that THN occurs also in the forebrain of rats. The concentration increases after loading with tryptamine.The findings are discussed in view of the hypothesis that THN acts as a compound modulating neuronal mechanism.     

Serotonin involvement in the discriminative stimulus effects of κ opioids in pigeons

The purpose of the present study was to examine the role of serotonin (5HT) in the discriminative stimulus effects of opioids. Pigeons were trained to discriminate 5.6 mg/kg of the opioid, U50,488, from water. During substitution tests, both U50,488 and another opioid, spiradoline, produced >80% responding on the U50,488-appropriate key. In contrast, the nonopioid compound, phencyclidine and several serotonergic compounds failed to substitute for the U50,488 discriminative stimulus across a wide range of doses. During combination tests, the selective 5HT_1A agonist, 8-OH-DPAT (0.001–3.2 mg/kg), dose-dependently attenuated the discriminative stimulus effects of 5.6 mg/kg U50,488 and 3.2 mg/kg spiradoline. This effect was reversed by the 5HT_1A antagonist, NAN-190 (0.01–1 mg/kg), in a dose-dependent manner. Buspirone (0.01–10 mg/kg), a 5HT_1A partial agonist, also attenuated the discriminative stimulus effects of the training dose of U50,488 but ipsapirone, another 5HT_1A partial agonist, did not. Ketanserin, a 5HT₂ antagonist, and MDL72222, a 5HT₃ antagonist, attenuated the effects of U50,488, whereas the 5HT_1B,1C agonist, mCPP, and the 5HT₂ agonist, DOI, did not. Depletion of 5HT withp-CPA also attenuated U50,488's discriminative stimulus effects. Taken together, the results suggest that serotonin release is an important component in the discriminative stimulus effects produced by opioids; however, the effects of DOI and mCPP alone suggest that activation of post-synaptic 5HT receptors is not sufficient to produce the full spectrum of opioid discriminative stimulus effects.     

Discovery of a novel glucagon receptor antagonist N-[(4-{(1S)-1-[3-(3, 5-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbonyl]-β-alanine (MK-0893) for the treatment of type II diabetes

A potent, selective glucagon receptor antagonist 9m, N-[(4-{(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbonyl]-β-alanine, was discovered by optimization of a previously identified lead. Compound 9m is a reversible and competitive antagonist with high binding affinity (IC(50) of 6.6 nM) and functional cAMP activity (IC(50) of 15.7 nM). It is selective for glucagon receptor relative to other family B GPCRs, showing IC(50) values of 1020 nM for GIPR, 9200 nM for PAC1, and >10000 nM for GLP-1R, VPAC1, and VPAC2. Compound 9m blunted glucagon-induced glucose elevation in hGCGR mice and rhesus monkeys. It also lowered ambient glucose levels in both acute and chronic mouse models: in hGCGR ob/ob mice it reduced glucose (AUC 0-6 h) by 32% and 39% at 3 and 10 mpk single doses, respectively. In hGCGR mice on a high fat diet, compound 9m at 3, and 10 mpk po in feed lowered blood glucose levels by 89% and 94% at day 10, respectively, relative to the difference between the vehicle control and lean hGCGR mice. On the basis of its favorable biological and DMPK properties, compound 9m (MK-0893) was selected for further preclinical and clinical evaluations.     

2-Aminoethyl methylphosphonate, a potent and rapidly acting antagonist of GABA(A)-ρ1 receptors

2-Aminoethyl methylphosphonate (2-AEMP), an analog of GABA, has been found to exhibit antagonist activity at GABA(A)-ρ1 (also known as ρ1 GABA(C)) receptors. The present study was undertaken to elucidate 2-AEMP's action and to test the activities of 2-AEMP analogs. Whole-cell patch-clamp techniques were used to record membrane currents in neuroblastoma cells stably transfected with human GABA(A)-ρ1 receptors. The action of 2-AEMP was compared with that of 1,2,5,6-tetrahydropyridin-4-yl methylphosphinic acid (TPMPA), a commonly used GABA(A)-ρ1 antagonist. With 10 μM GABA, 2-AEMP's IC(50) (18 μM) differed by less than 2.5-fold from that of TPMPA (7 μM), and results obtained were consistent with a primarily competitive mode of inhibition by 2-AEMP. Terminating the presentation of 2-AEMP or TPMPA in the presence of GABA produced a release from inhibition. However, the rate of inhibition release upon the termination of 2-AEMP considerably exceeded that determined with termination of TPMPA. Moreover, when presented at concentrations near their respective IC(50) values, the preincubation period associated with 2-AEMP's onset of inhibition was much shorter than that for TPMPA. Analogs of 2-AEMP possessing a benzyl or n-butyl rather than a methyl substituent at the phosphorus atom, as well as analogs bearing a C-methyl substituent on the aminoethyl side chain, exhibited reduced potency relative to 2-AEMP. Of these analogs, only (R)-2-aminopropyl methylphosphonate significantly diminished the response to 10 μM GABA. Structure-activity relationships are discussed in the context of molecular modeling of ligand binding to the antagonist binding site of the GABA(A)-ρ1 receptor.     

Hexachlorobenzene induces TGF-β1 expression,which is a regulator of p27 and cyclin D1 modifications

Hexachlorobenzene (HCB) is an organochlorine pesticide widely distributed in the environment. In this study we have demonstrated that HCB induced loss of cell viability and alterations in cell cycle regulation in FRTL-5 rat thyroid cells. Analysis of cell cycle distribution by flow cytometric analysis demonstrated that HCB induced cell cycle arrest at G2/M and at G0/G1 phase, inhibiting cell cycle progression at the G1/S phase, after 24 h and 72 h of treatment.     

Naloxone benzylhydrazone is a µ-selective opioid antagonist without kappa agonist effects in rhesus monkeys

Naloxone benzoylhydrazone (NalBzoH) has been suggested to be a selective opioid agonist, exerting its effects through the kappa(3) subtype of opioid receptor. In the present experiments NalBzoH was studied for its discriminative stimulus, analgesic, and respiratory effects in rhesus monkeys. Up to the largest doses administered (1.0-3.2mg/kg), NalBzoH failed to substitute for the discriminative stimulus effects of the kappa agonist ethylketocyclazocine or those of the μ agonist alfentanil. However, in morphine-treated (3.2mg/kg/day) monkeys NalBzoH substituted completely for the discriminative stimulus effects of the opioid antagonist naltrexone. NalBzoH antagonized the discriminative stimulus effects of alfentanil in morphine-treated subjects and, at larger doses, antagonized the discriminative stimulus effects of ethylketocyclazocine. NalBzoH did not produce analgesic effects and had only modest effects on respiration. However, NalBzoH antagonized the analgesic effects as well as the respiratory-depressant effects of alfentanil; at doses 10-15 times larger than those that antagonized alfentanil, NalBzoH also antagonized analgesic effects of the kappa agonist U-50,488. For both μ and kappa agonists, NalBzoH was slightly more potent in antagonizing discriminative stimulus effects as compared to analgesic effects. Thus, NalBzoH is a μ-selective opioid antagonist in rhesus monkeys and is equipotent to naloxone in antagonizing alfentanil. While demonstrating μ-selective antagonism, the current study fails to provide support for the proposed kappa agonist actions of NalBzoH.     

Biochemical and behavioural effects of isamoltane,a β-adrenoceptor antagonist with affinity for the 5-HT1B receptor of rat brain

Summary The biochemical and behavioural effects of isamoltane, a \-adrenoceptor and 5-HT_1B receptor antagonist that has higher affinity for 5-HT_1B receptors than for 5-HTIA receptors, on 5-HT neurotransmission in the rat brain were examined. In binding experiments isamoltane was found to be about five times more potent as a ligand for the 5-HT_1B receptor than for the 5-HT_1A receptor (K_i values 21 and 112 nmol/l, respectively). Isamoltane increased the K⁺-evoked overflow of ³H from ³H-5-HT loaded slices of rat occipital cortex at 0.1 mol/l, consistent with inhibition of the terminal 5HT autoreceptor. In vivo, isamoltane significantly increased the concentration of 5-hydroxyindoleacetic acid in hypothalamus and hippocampus indicating an increased 5-HT turnover with a maximal effect at 3 mg/kg s.c. A higher dose produced a less pronounced effect. This effect did not seem to be due to the -adrenoceptor blocking action of isamoltane since the -adrenoceptor antagonists, (–)-alprenolol, betaxolol or ICI 118,551 had no significant effects on 5-HT turnover at 5 mg/kg s.c. Isamoltane at 3 mg/kg s.c. induced the wet-dog shake response which was blocked by the tryptophan hydroxylase inhibitor p-chlorophenylalanine. In contrast, the same response induced by the 5-HT₂ receptor agonist quipazine was not blocked by pretreatment with p-chlorophenylalanine. The wet-dog shakes evoked by isamoltane and quipazine were blocked by ritanserin, which indicates that 5-HT₂ receptors are involved in their expression. These observations indicate that isamoltane, by inhibiting the terminal 5-HT autoreceptors, increased the synaptic concentration of 5-HT to a level that induced a behavioural response. Send of offprint requests to S. B. Ross at the above addressThe present results have been presented in part at the Second IUPHAR Satellite Meeting on Serotonin, Basel, Switzerland, July 11–13, 1990     

Selective attenuation of the antinociceptive effects of μ opioids by the putative dopamine D3 agonist 7-OH-DPAT

Rationale: The purpose of the present investigation was to evaluate the effects of the D₃ agonist (±)-7-hydroxy-dipropylaminotetralin (7-OH-DPAT), various dopamine (DA) agonists and DA antagonists on the antinociceptive effects of μ opioids. Methods: Antinociception was assessed using a warm-water tail-withdrawal procedure in rats. Results: The μ opioids morphine (0.3–10 mg/kg) and dezocine (0.03–3.0 mg/kg) produced dose-dependent increases in antinociception with maximal effects obtained at the higher doses tested. Pretreatment with the putative D₃ agonist 7-OH-DPAT (1.0–10 mg/kg) produced a dose-dependent attenuation of the antinociceptive effects of morphine and dezocine. At the highest dose of 7-OH-DPAT tested, the morphine dose-effect curve was shifted rightward by approximately 1.5 log units and the dezocine curve by greater than 2.3 log units. The (+)-isomer of 7-OH-DPAT (1.0 and 3.0 mg/kg) also shifted the morphine dose-effect curve to the right in a dose-dependent manner. The DA D₃/D₂ agonist (−)-quinpirole (0.1–10 mg/kg) attenuated the effects of morphine, but these effects were small in magnitude, not dose-dependent and observed only under a limited set of conditions. The DA D₂/D₃ antagonist spiperone failed to alter the morphine dose-effect curve, but reversed the effects of 7-OH-DPAT on morphine antinociception. Pretreatment with the DA D₁ agonist (±)-SKF38393 (1.0 and 10 mg/kg) and the D₁ antagonist (+)-SCH23390 (0.1 and 1.0 mg/kg) failed to alter the morphine dose-effect curve. Conclusion: The finding that 7-OH-DPAT markedly attenuated the effects of morphine and that these effects were reversed with spiperone suggests that activity at the D₃, and possibly the D₂, receptor can modulate μ agonist-induced antinociception. Received: 30 June 1998/Final version: 12 January 1999     

Central and peripheral involvement of μ receptors in gastric secretory effects of opioids in the dog

The effects of dermorphin and morphine on gastric acid secretion were studied in conscious dogs with both gastric fistulas (GF) and Heidenhain pouches (HP). Under basal conditions demorphin and morphine, infused systematically at graded doses, produces a significant increase in acid secretion from both GF and HP. This increase was significantly inhibited by naloxone, naltrexone methylbromide and N-methyl-levallorphan methanesulphonate. Dermorphin did not modify the acid output stimulated by 2-deoxy-D-glucose from GF, while morphine significantly inhibited it; on the contrary acid secretion from HP was increased in this test by both dermorphin and morphine. Acid secretion from GF stimulated by pentagastrin was unaffected by morphine and significantly enhanced by dermorphine. Under this conditions a significant increase in acid secretion from HP was recorded with dermorphin and morphine. Naloxone and N-methyl-levallorphan methanesulphonate, given during pentagastrin-stimulated secretion, significantly inhibited acid output ‘per se’ from GF and HP and prevented the stimulatory effect of dermorphin and morphine. Bethanechol-induced secretion from GF and HP was significantly increased by both dermorphin and morphine. The present results demonstrate that opioids have simultaneous yet opposite effects on acid secretion in the dog and that μ receptors are involved in both the excitatory and inhibitory effects. Excitatory effects do not seem to be mediated via a vagal pathway (peripheral ?), in contrast to the inhibitory effects (central ?). The inhibitory effects of opiate antagonists on pentagastrin-stimulated secretion suggest a physiological role of peripheral opioid receptors in gastric acid secretion.     

Behavioural effects of β,β′-iminodipropionitrile (IDPN) in the domestic fowl (Gallus domesticus)

• 1.1. The behavioural effects of ββ′-iminodipropionitrile (IDPN) were studied in chicks and adult fowls.
• 2.2. Repeated administration of IDPN (75 mg/kg) for 5 days induced behavioural changes in chicks and adult fowls characterized by excitation, choreiform head and neck movements and circling (ECC-syndrome).
• 3.3. Both acute and chronic administration of IDPN induced EEG desynchronization, EMG activation and enhancement of photic-evoked response (PER) in the hyperstriatum and pontine reticular formation while a decrease in PER was observed in the optic tectum.
• 4.4. d-Amphetamine (2.5–5 mg/kg), apomorphine (0.1–0.25 mg/kg), piribedil (2.5–5 mg/kg), atropine (2.5–5 mg/kg), hyoscine (2.5–5 mg/kg) and cyproheptadine (0.5 mg/kg) potentiated the circling and choreiform head and neck movements. These activities were antagonized by pimozide (1 mg/kg), physostigmine (0.5 mg/kg) and quipazine (2.5–5 mg/kg).
• 5.5. The results suggest that dopaminergic, serotoninergic and cholinergic mechanisms may be involved in IDPN-induced behavioural effects in chicks.

     

Pharmacological interaction with the sigma1 (σ1)-receptor in the acute behavioral effects of antidepressants

Selective agonists of the sigma-1 (σ(1)) ligand-operated chaperone protein, like igmesine or PRE-084, are antidepressants in preclinical depression models. σ(1)-Protein activation may contribute to the antidepressant efficacy of drugs known to act as selective serotonin-reuptake inhibitors (SSRI) or noradrenaline reuptake inhibitors through direct or indirect involvement of the σ(1)-receptor in the drug effect. We here compared antidepressant effects in two behavioral procedures, the forced swimming test (FST) and conditioned fear stress (CFS). The involvement of the σ(1)-receptor was examined using a co-treatment with the σ(1)-antagonist BD1047 or using σ(1)-knockout (KO) mice. Igmesine but not PRE-084 decreased FST immobility. The SSRI fluoxetine and sertraline, but not fluvoxamine, and the tricyclic antidepressants imipramine, desipramine, and amitriptyline were also effective. Only the effect of igmesine was blocked by BD1047 or in σ(1)-KO mice. Igmesine, PRE-084, fluvoxamine, and sertraline decreased the CFS immobility in a BD1047- and σ(1)-KO-sensitive manner. Among tricyclics, only amitriptyline was effective and its effect was unaffected by BD1047 or in σ(1)-KO mice. The behavioral effects induced by mixed σ(1)-receptor/SSRI antidepressants, like fluvoxamine or sertraline, may therefore involve a non-selective action at both targets. Moreover, the CFS appears to more reliably uncover a σ(1) pharmacological component in antidepressant screening.     

Comparison of dynamics of extracellular accesses to the β(1) and β(2) adrenoceptors binding sites uncovers the potential of kinetic basis of antagonist selectivity

From the molecular mechanism of antagonist unbinding in the β(1) and β(2) adrenoceptors investigated by steered molecular dynamics, we attempt to provide further possibilities of ligand subtype and subspecies selectivity. We have simulated unbinding of β(1)-selective Esmolol and β(2)-selective ICI-118551 from both receptors to the extracellular environment and found distinct molecular features of unbinding. By calculating work profiles, we show different preference in antagonist unbinding pathways between the receptors, in particular, perpendicular to the membrane pathway is favourable in the β(1) adrenoceptor, whereas the lateral pathway involving helices 5, 6 and 7 is preferable in the β(2) adrenoceptor. The estimated free energy change of unbinding based on the preferable pathway correlates with the experimental ligand selectivity. We then show that the non-conserved K347 (6.58) appears to facilitate in guiding Esmolol to the extracellular surface via hydrogen bonds in the β(1) adrenoceptor. In contrast, hydrophobic and aromatic interactions dominate in driving ICI-118551 through the easiest pathway in the β(2) adrenoceptor. We show how our study can stimulate design of selective antagonists and discuss other possible molecular reasons of ligand selectivity, involving sequential binding of agonists and glycosylation of the receptor extracellular surface.     

The antipsychotic potential of l-stepholidine—a naturally occurring dopamine receptor D<Subscript>1</Subscript> agonist and D<Subscript>2</Subscript> antagonist

RATIONALE: l-Stepholidine, a dopamine D(2) antagonist with D(1) agonist activity, should in theory control psychosis and treat cognitive symptoms by enhancing cortical dopamine transmission. Though several articles describe its impact on the dopamine system, it has not been systematically evaluated and compared to available antipsychotics. MATERIALS AND METHODS: We examined its in vitro interaction with dopamine D(2) and D(1) receptors and compared its in vivo pharmacokinetic profile to haloperidol (typical) and clozapine (atypical) in animal models predictive of antipsychotic activity. RESULTS: In vitro, l-stepholidine showed significant activity on dopamine receptors, and in vivo, l-stepholidine demonstrated a dose-dependent striatal receptor occupancy (RO) at D(1) and D(2) receptors (D(1) 9-77%, 0.3-30 mg/kg; D(2) 44-94%, 1-30 mg/kg), though it showed a rather rapid decline of D(2) occupancy related to its quick elimination. In tests of antipsychotic efficacy, it was effective in reducing amphetamine- and phencyclidine-induced locomotion as well as conditioned avoidance response, whereas catalepsy and prolactin elevation, the main side effects, appeared only at high D(2)RO (>80%). This preferential therapeutic profile was supported by a preferential immediate early gene (Fos) induction in the nucleus accumbens over dorsolateral striatum. We confirmed its D(1) agonism in vitro, and then using D(2) receptor, knockout mice showed that l-stepholidine shows D(1) agonism in the therapeutic dose range. CONCLUSIONS: Thus, l-stepholidine shows efficacy like an "atypical" antipsychotic in traditional animal models predictive of antipsychotic activity and shows in vitro and in vivo D(1) agonism, and, if its rapid elimination does not limit its actions, it could provide a unique therapeutic approach to schizophrenia.