Recurrent long-lasting tethering reduces BDNF protein levels in the dorsal hippocampus and frontal cortex in pigs.

Brain-derived neurotrophic factor (BDNF) signaling has been implicated in the onset of depression and in antidepressant efficacy, although the exact role of this neurotrophin in the pathophysiology of depression remains to be elucidated. Also, the interaction between chronic stress, which may precede depression, corticosteroids and BDNF is not fully understood. The present study aimed at investigating whether long-lasting, recurrent tethering of sows during a period of 1.5 or 4.5 years leads to enduring effects on measures that may be indicative of chronic stress, compared with animals kept in a group housing system ('loose' sows). Immediately after slaughter, the frontal cortex, dorsal and ventral hippocampus were dissected and protein levels of BDNF and its receptors were analyzed and compared with plasma cortisol levels and adrenal weights. Results indicate that tethering stress reduced BDNF protein levels in the dorsal hippocampus and the frontal cortex, but not in the ventral hippocampus. In addition, levels of TrkB, the high affinity receptor for BDNF, were increased in the dorsal hippocampus. Plasma cortisol levels and adrenal weight were increased after tethering. These stress effects on BDNF levels were more pronounced after 4.5 years of recurrent tethering and negatively correlated in particular in the frontal cortex with cortisol levels and adrenal weight. This suggests that the stress effect of tethered housing on neurotrophin levels may be mediated via cortisol. Taken together, these data indicate that recurrent tethering stress in sows over 4.5 years results in a loss of neurotrophic support by BDNF, mediated by an overactive neuroendocrine system.

Synergistic interaction between the two mechanisms of action of tapentadol in analgesia.

The novel centrally acting analgesic tapentadol [(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride] combines two mechanisms of action, µ-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition (NRI), in a single molecule. Pharmacological antagonism studies have demonstrated that both mechanisms of action contribute to the analgesic effects of tapentadol. This study was designed to investigate the nature of the interaction of the two mechanisms. Dose-response curves were generated in rats for tapentadol alone or in combination with the opioid antagonist naloxone or the α(2)-adrenoceptor antagonist yohimbine. Two different pain models were used: 1) low-intensity tail-flick and 2) spinal nerve ligation. In each model, we obtained dose-effect relations to reveal the effect of tapentadol based on MOR agonism, NRI, and unblocked tapentadol. Receptor fractional occupation was determined from tapentadol's brain concentration and its dissociation constant for each binding site. Tapentadol produced dose-dependent analgesic effects in both pain models, and its dose-effect curves were shifted to the right by both antagonists, thereby providing data to distinguish between MOR agonism and NRI. Both isobolographic analysis of occupation-effect data and a theoretically equivalent methodology determining interactions from the effect scale demonstrated very pronounced synergistic interaction between the two mechanisms of action of tapentadol. This may explain why tapentadol is only 2- to 3-fold less potent than morphine across a variety of preclinical pain models despite its 50-fold lower affinity for the MOR. This is probably the first demonstration of a synergistic interaction between the occupied receptors for a single compound with two mechanisms of action.

[Tapentadol: with two mechanisms of action in one molecule effective against nociceptive and neuropathic pain. Preclinical overview]. / Tapentadol: mit zwei Mechanismen in einem Molekül wirksam gegen nozizeptive und neuropathische Schmerzen. Präklinischer Überblick.

Tapentadol (3-[(1R, 2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl] phenol) is a centrally acting analgesic of a new substance class for the treatment of severe nociceptive and neuropathic pain. Tapentadol combines µ-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition (NRI) in one molecule. Because of the combined mechanisms of action tapentadol offers a broad therapeutic spectrum for nociceptive as well as neuropathic pain. In different animal models its high efficacy was shown in acute nociceptive, acute and chronic inflammatory as well as in chronic neuropathic pain. Using several preclinical approaches it was shown that the noradrenergic component of tapentadol interacts with the opioid component and that both synergistically contribute to the analgesic effect of the substance. In comparison to known drugs with only one of the two modes of action, tapentadol, despite its high potency, has an improved tolerability profile in the relevant animal models, particularly with regard to gastrointestinal and central side effects. Tapentadol acts directly without metabolic activation and without formation of analgesically relevant metabolites. In different interaction studies a low potential for interactions was shown, thus clinically relevant drug-drug interactions are unlikely. Overall, tapentadol provides a safe pharmacodynamic-pharmacokinetic profile.

5-HT1A receptors are differentially involved in the anxiolytic- and antidepressant-like effects of 8-OH-DPAT and fluoxetine in the rat.

Fluoxetine, a selective serotonin reuptake inhibitor, shows moderate efficacy and potency in the rat forced swimming depression test and the shock-induced ultrasonic vocalization anxiety test, whereas the 5-HT(1A) receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) is highly efficient and potent in both models. Whereas the 5-HT(1A) receptor antagonist WAY 100,635 abolishes the effect of 8-OH-DPAT in both models, it only attenuates the antidepressant-like effect of fluoxetine. Pretreatment with the 5-HT-depleting agent parachlorophenylalanine attenuates the antidepressant-like effect of fluoxetine, but not that of 8-OH-DPAT. This suggests that the antidepressant-like effect of fluoxetine and 8-OH-DPAT results from indirect (via increased synaptic availability of 5-HT) and direct stimulation of postsynaptic 5-HT(1A) receptors, respectively; whereas the anxiolytic-like effect of fluoxetine is not mediated by 5-HT(1A) receptors. The data support the hypothesis that the antidepressant- and anxiolytic-like effect of 8-OH-DPAT is predominantly mediated by post- and presynaptic 5-HT(1A) receptors, respectively, and that 5-HT(1A) receptors are only partially involved in the antidepressant-like effect of fluoxetine.

Behavioral effects of cannabinoids show differential sensitivity to cannabinoid receptor blockade and tolerance development.

This study compared the potency and efficacy of the cannabinoids delta-tetrahydrocannabinol (delta-THC), HU-210, WIN 55,212-2 and CP 55,940 in suppressing food-reinforced operant behavior, increasing reaction latency in a hot-plate test and inducing hypothermia, and tested whether these behavioral effects induced by CP 55,940 showed differential sensitivity to the cannabinoid CB1 receptor antagonist SR141716A, and to tolerance development. After acute i.p. administration to rats, operant behavior was more potently affected than reaction latency and body temperature, but the order of potency of the different drugs was similar across the tests: HU-210

Partial agonist-like profile of the cannabinoid receptor antagonist SR141716A in a food-reinforced operant paradigm.

Both cannabinoid CB1 receptor agonists, such as delta-tetrahydrocannabinol (delta-THC), CP 55,940 and WIN 55,212-2, and the antagonist/inverse agonist SR141716A, dose-dependently suppress operant behavior. The present study investigated to what extent combined i.p. application of SR141716A with these cannabinoids resulted in mutually antagonistic effects, in additive effects, or in no interactive effects on operant responding in rats trained in a fixed-ratio 10, food-reinforced 10-min procedure. Pretreatment with SR141716A either had no effect on (at 0.3-1mg/kg), or partially blocked (at 3 mg/kg), the inhibitory effects on responding induced by delta-THC (3-5 mg/kg) and CP 55,940 (0.03-0.2 mg/kg). Interestingly, while 3 mg/kg SR141716A induced moderate inhibitory effects on operant responding, its combination with either agonist resulted in the same level of inhibitory activity on responding as that obtained by SR141716A when tested alone. Pretreatment with a low dose of CP 55,940 (0.01 mg/kg) or WIN 55,212-2 (0.3 mg/kg) did not affect response inhibition induced by SR141716A. Combination of SR141716A (0.5 and 1mg/kg) with delta-THC (3 mg/kg) resulted in the same level of response inhibition, independently of whether SR141716A was given 5 min before or 15 min after delta-THC. Although alternative explanations are conceivable, the data may indicate that SR141716A is a partial agonist at those cannabinoid receptors mediating the response-rate suppressive effects of cannabinoids.

Discovery and optimization of 2-aryl oxazolo-pyrimidines as adenosine kinase inhibitors using liquid phase parallel synthesis.

Adenosine kinase inhibition is an attractive therapeutic approach for several conditions for example, neurodegeneration, seizures, ischemia, inflammation and pain. Several nucleosidic and non-nucleosidic inhibitors are available. Using a virtual screening approach, we have discovered that 2-aryl oxazolo-pyrimidines are adenosine kinase inhibitors. Subsequent high throughput derivatization enabled the optimization of this new inhibitor chemotype resulting in highly potent derivatives. A variety of analogues were produced by applying liquid phase parallel synthesis to vary the 7-amino residues as well as the 2-aryl moiety.

Intrinsic activity estimation of cannabinoid CB1 receptor ligands in a drug discrimination paradigm.

The present study estimated the apparent intrinsic activity of the cannabinoid CB1 receptor ligands CP 55,940, Delta9-tetrahydrocannabinol (Delta9-THC) and SR 141716A in a highly sensitive in vivo assay. Rats were trained to discriminate the cannabinoid CB1 receptor agonist CP 55,940 (either 0.03 or 0.014 mg/kg, i.p., t=30 min) from vehicle, in a two-lever food-reinforced procedure, and were subsequently tested with the three compounds. Although reduction of the training dose did not affect the maximum level of generalization or antagonism (>80% generalization for CP 55,940 and Delta9-THC; 0% generalization and >80% antagonism for SR 141716A), the potency of the compounds was differentially affected. Thus, the generalization curves obtained with CP 55,940 and Delta9-THC were shifted three- and sixfold to the left; whereas no potency difference was obtained for the antagonism of CP 55,940 by SR 141716A. The data are consistent with the hypothesis that the level of intrinsic activity of CP 55,940 is higher than that of Delta9-THC, and that SR 141716A may have a very low level of intrinsic activity. It is concluded that variation of the training dose increases the sensitivity of the in vivo intrinsic activity estimation of cannabinoid CB1 receptor ligands.

Effects of serotonin 5-HT(1/2) receptor agonists in a limited-access operant food intake paradigm in the rat.

Hypophagic effects of serotonergic drugs have mostly been investigated in free-feeding paradigms and are generally ascribed to drug-induced acceleration of satiety, or to behavioral disruption. The present study investigated the hypophagic effects of various 5-HT(1/2) receptor agonists in an operant paradigm. Because of its limited duration (10-min session) the procedure was considered to be relatively insensitive to satiety processes. The behavioral specificity of the hypophagic effect was assessed by additional testing of the compounds in a locomotor activity assay. Male Wistar rats, maintained at about 80% of their free-feeding weights, were trained to acquire stable operant responding in daily fixed ratio:10 food-reinforced sessions; after which they were tested once a week with a 5-HT receptor agonist. Each compound dose-dependently suppressed the number of earned pellets after i.p. administration: DOI (5-HT(2A/2C) receptor agonist; ED(50): 0.36 mg/kg), TFMPP (5-HT(1B/2C/2A); 0.37 mg/kg), m-CPP (5-HT(2C/1B/2A); 0.54 mg/kg), ORG 37684 (5-HT(2C/2A); 0.85 mg/kg), CP-94,253 (5-HT(1B); 2.09 mg/kg), BW 723C86 (5-HT(2B); 6.26 mg/kg) and ipsapirone (5-HT(1A); 10.17 mg/kg). When tested at the dose equivalent to the ED(50) value in the operant paradigm, only ORG 37684 and DOI weakly suppressed activity counts in a locomotor activity assay; suggesting that the inhibition of operant food intake obtained with the other compounds at these doses is not a direct consequence of unconditioned motor effects. It is suggested that the hypophagic effect induced by relatively low doses of CP-94,253, TFMPP and m-CPP, and by moderate doses of ipsapirone and BW 723C86, is partly due to a drug-induced suppression of appetite. Although the exact contribution of the diverse 5-HT(1/2) receptor subtypes to appetite control remains to be studied in more detail, it is hypothesized that activation of 5-HT(1B) and/or 5-HT(2C) receptors attenuates appetite.

Role of the NMDA receptor NR2B subunit in the discriminative stimulus effects of ketamine.

The noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine, is a dissociative anesthetic with antihyperalgesic properties. However, its clinical use is compromised by psychotomimetic side-effects. As ketamine and other noncompetitive NMDA antagonists, such as phencyclidine and dizocilpine, are not selective for the NR2A-2D subunits of the NMDA receptor, it is unclear which of these subunits is responsible for the psychotomimetic side-effects. This study investigated the role of the NR2B subunit in the ketamine drug discrimination model, a possible correlate for such side-effects. In a first experiment aimed at assessing general potency and time dependency, ketamine, dizocilpine, phencyclidine and the NR2B-selective antagonists ifenprodil and Ro 25-6981, dose-dependently suppressed fixed ratio 10 food-reinforced responding in rats, with peak efficacy obtained around 15-40 min. In rats trained to discriminate ketamine from vehicle in a two-lever fixed ratio 10 food-reinforced procedure, ketamine, dizocilpine, phencyclidine and Ro 25-6981 induced complete generalization (>80%); whereas ifenprodil induced partial generalization (33%). These findings suggest that the NR2B subunit is involved in the discriminative stimulus effects of noncompetitive NMDA antagonists, and that selective NR2B antagonists may also induce psychotomimetic side-effects.

Metabotropic glutamate mGlu1 receptor mRNA expression in dorsal root ganglia of rats after peripheral nerve injury.

Although cerebral and spinal metabotropic glutamate mGlu(1) receptors are thought to be involved in nociception and in the development/maintenance of chronic pain, it is still unclear to what extent mGlu(1) receptors are present in the dorsal root ganglia of peripheral sensory afferents, and whether their expression is affected during development of chronic pain. It was found in the present study that mGlu(1) receptor messenger RNA (mRNA) is present in rat L5 dorsal root ganglia and that it is strongly downregulated after unilateral axotomy of the tibial branch of the sciatic nerve, a model of chronic neuropathic pain. However, as sham-operated animals showed a similar downregulation, it is suggested that peripheral tissue damage is sufficient to result in a reduction of peripheral mGlu(1) receptor expression.

Neuroprotective and behavioral effects of the selective metabotropic glutamate mGlu(1) receptor antagonist BAY 36-7620.

This study characterized the neuroprotective and behavioral effects of (3aS,6aS)-6a-naphtalen-2-ylmethyl-5-methyliden-hexahydro-cyclopenta[c]furan-1-on (BAY 36-7620), a novel, selective and systemically active metabotropic glutamate (mGlu)(1) receptor antagonist. In the rat, neuroprotective effects were obtained in the acute subdural hematoma model (efficacy of 40-50% at 0.01 and 0.03 mg/kg/h, i.v. infusion during the 4 h following surgery); whereas in the middle cerebral artery occlusion model, a trend for a neuroprotective effect was obtained after triple i.v. bolus application of 0.03-3 mg/kg, given immediately, 2 and 4 h after occlusion. Hypothermic effects were mild and only obtained at doses which were considerably higher than those at which maximal neuroprotective efficacy was obtained, indicating that the neuroprotective effects are not a consequence of hypothermia. BAY 36-7620 protected against pentylenetetrazole-induced convulsions in the mouse (MED: 10 mg/kg, i.v.). As assessed in rats, BAY 36-7620 was devoid of the typical side-effects of the ionotropic glutamate (iGlu) receptor antagonists phencyclidine and (+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclohepten-5,10-imine (MK-801). Thus, BAY 36-7620 did not disrupt sensorimotor gating, induce phencyclidine-like discriminative effects or stereotypical behavior, or facilitate intracranial self-stimulation behavior. Although behavioral stereotypies and disruption of sensorimotor gating induced by amphetamine or apomorphine were not affected by BAY 36-7620, the compound attenuated some behavioral effects of iGlu receptor antagonists, such as excessive grooming or licking, and their facilitation of intracranial self-stimulation behavior. It is concluded that mGlu(1) receptor antagonism results in neuroprotective and anticonvulsive effects in the absence of the typical side-effects resulting from antagonism of iGlu receptors.

Cannabinoid CB(1) receptor upregulation in a rat model of chronic neuropathic pain.

Although cannabinoids are known to be more effective analgesics against chronic rather than acute pain, the mechanism underlying this phenomenon is still unclear. We report now that contralateral thalamic cannabinoid CB(1) receptors are upregulated after unilateral axotomy of the tibial branch of the sciatic nerve, a rat model of chronic neuropathic pain, and hypothesize that cannabinoid CB(1) receptor upregulation contributes to the increased analgesic efficacy of cannabinoids in chronic pain conditions.

Effects of serotonin(1/2) receptor agonists on dark-phase food and water intake in rats.

The effects of serotonin (5-hydroxytryptamine, 5-HT)(1/2) receptor agonists for 5-HT(1) and 5-HT(2) receptors on dark-phase ingestive behavior were evaluated in 12-h food-deprived, female Wistar rats. The amount of food and water consumed after 1, 2, 6 and 12 h was measured. The following agonists were tested: ipsapirone [preferred 5-HT receptor(s) and dose range in mg/kg, IP: 5-HT(1A) and 3-30, respectively], CP-94,253 (5-HT(1B); 0.3-3), TFMPP (5-HT(1B/2C); 0. 3-10), m-CPP (5-HT(2C/1B); 0.3-10), ORG 37684 (5-HT(2C); 0.3-10), BW 723C86 (5-HT(2B); 3-30) and DOI (5-HT(2A/2C); 0.3-3). Ipsapirone induced hyperphagia during the first hour of food access and hypophagia during the last interval. All other compounds induced dose- and time-dependent hypophagia. m-CPP and TFMPP induced the most marked reduction of food intake and were the only drugs inducing rebound hyperphagia. Except for m-CPP and TFMPP, effects on food intake could generally be dissociated from effects on water intake. The receptor profile of the compounds tested suggests that stimulation of 5-HT(1B), 5-HT(2C), 5-HT(2A) or 5-HT(2B) receptors results in hypophagia. As the less selective agonists were the more potent anorexics, it is suggested that simultaneous activation of these receptors results in synergistic effects on ingestive behavior. Additional antagonism studies are required to ascertain the proposed role of particular 5-HT receptor subtypes in the hypophagic effects of the tested compounds.

Flupenthixol as a potential pharmacotreatment of alcohol and cocaine abuse/dependence.

Preclinical and clinical studies suggest that the mesolimbic dopamine system plays a major role in mediating the reinforcing effects of drugs of abuse, including alcohol and psychostimulants, and that pharmacological blockade of dopamine D1 and/or D2 receptors may reduce intake of these drugs, as well as relapse rates. The neuroleptic flupenthixol, which has dopamine D1 and D2 receptor antagonist properties and which may be given intramuscularly in order to improve compliance, has been studied as a possible anti-craving drug in substance abuse disorders. Flupenthixol has been shown to attenuate the discriminative stimulus effects of psychostimulants, as well as their intake in animal models of drug abuse. In addition, the compound was found to reduce alcohol intake in a rat model of alcoholism, but the 'anti-alcohol' effect appeared to be only weakly selective and nonspecific. Clinically, the drug has been studied in alcoholics, cocaine addicts and in patients with comorbid psychiatric disorders. Although the data base is still limited and a number of recent trials have not been completely analyzed, these studies suggest that flupenthixol may be useful in decreasing cocaine consumption. Recent studies in alcoholism, however, have shown disappointing results. A number of pilot studies suggest that probably the most promising area may be the treatment of substance abuse/dependence in patients with comorbid psychiatric disorders. Future studies should focus on dosing issues, the differentiation between short- and long-term effects and the identification of subgroups of patients with particular psychopathology.

Palatable fluids do not affect alcohol intake and its reduction by serotonergic compounds in alcohol-preferring cAA rats.

1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI) decreases alcohol intake by alcohol-preferring cAA rats more selectively than fluoxetine in a two-bottle alcohol vs. water paradigm. We report now that availability of sucrose or saccharin in a 3rd bottle does not affect (1) alcohol intake, supporting further the validity of this model of alcoholism, nor (2) the selectivity profile of the alcohol intake-reducing effects of these compounds. It is hypothesized that reduction of alcohol intake by DOI is not simply due to decreased intake of palatable fluids.

Effects of serotonin 5-HT(1) and 5-HT(2) receptor agonists in a conditioned taste aversion paradigm in the rat.

Although 5-HT(1/2) receptor agonists can inhibit ingestive behavior, it remains unclear whether this effect is confounded by drug-induced "malaise." The present study assessed the potential of such compounds to induce conditioned taste aversion (CTA), a possible correlate of aversive stimulus properties. Male Wistar rats were tested in a two-bottle saccharin versus water choice paradigm. DOI [5-HT(2A/2C) receptor agonist; ED(50) (95% confidence limits) in mg/kg, IP: 0.29 (0.14-0.63)], m-CPP [5-HT(2C/1B); 1.69 (0.96-2.99)], TFMPP [5-HT(1B/2C); 2.45 (1.46-4.11)], ORG 37684 [5-HT(2C); 2.96 (1. 17-7.52)], BW 723C86 [5-HT(2B); 3.49 (1.29-9.47)], CP-94,253 [5-HT(1B); 3.74 (1.54-9.08)], and ipsapirone [5-HT(1A); 20.15 (11. 25-36.09)] dose dependently suppressed saccharin preference, with potencies that correlated with their previously reported potencies to inhibit ingestive behavior in operant- and free feeding paradigms. Although these results did not necessarily imply that such hypophagic effects result from a drug-induced "malaise," it can be hypothesized that they involve, at least partly, the same physiological mechanism/substrate underlying CTA. As the hypophagic effects of serotonergic compounds have been ascribed to their effects on satiety processes and generally occur at doses that are lower than those inducing CTA, it is speculated that weak activation of this substrate results in satiety, whereas strong activation will result in aversive effects, or drug-induced "malaise."

Acute stress induced modifications of calcium signaling in learned helpless rats.

Previous reports have demonstrated reduced elevations of free intracellular calcium concentration in blood cells of depressed patients after various stimuli. Therefore, a disturbance of intracellular calcium (Ca2+) homeostasis has been postulated to be involved in the pathophysiology of mood disorders. It was the aim of the present study to investigate whether Ca2+ signaling was affected in spleen T-lymphocytes of rats submitted to a learned helplessness paradigm, an animal model of depression with a high level of construct, face and predictive validity. In addition, we tested for effects of acute stress on the Ca2+ signaling in helpless rats, as compared to non-stressed rats. It was found that mitogen-induced Ca2+ signaling only tended to be reduced in helpless rats. However, when helpless rats were submitted to acute immobilization stress, Ca2+ signaling appeared to be significantly blunted, whereas the same stressor did not affect Ca2+ signaling in the non-helpless control rats. These acute stress-induced differences in Ca2+ signaling were not paralleled by a differential increase in plasma corticosterone. It is hypothesized that blunted Ca2+ signaling, as assessed in spleen T-lymphocytes of helpless rats, may be a correlate of the increased vulnerability of helpless rats to acute stressors.

Effects of selected serotonin 5-HT(1) and 5-HT(2) receptor agonists on feeding behavior: possible mechanisms of action.

Serotonin (5-HT) receptor agonists with high affinity for the different subtypes (i.e. 5-HT(1A-1F), 5-HT(2A-2C)) of the 5-HT(1)- and 5-HT(2) receptor families have been shown to affect ingestive behavior. It has been assumed that: (1) stimulation of hypothalamic 5-HT(2C) or 5-HT(1B) receptors leads to a behaviorally specific hypophagic effect by accelerating satiety processes; (2) stimulation of 5-HT(2A) receptors leads to a disruption of the feeding cascade; and (3) stimulation of 5-HT(1A) and 5-HT(2B) receptors leads to a hyperphagic effect. The present paper reviews studies performed with the relatively selective receptor agonists ipsapirone (5-HT(1A)), CP-94,253 (5-HT(1B)), BW 723C86 (5-HT(2B)) and ORG 37684 (5-HT(2C)), as well as the nonselective receptor agonists TFMPP (5-HT(1B/2C)), m-CPP (5-HT(2C/1B)) and DOI (5-HT(2A/2C)) in a variety of feeding paradigms in rats, both after systemic and local injection. These studies support a role for other neuroanatomical regions (i.e. brain stem) and behavioral mechanisms (i.e. appetitive processes) in the hypophagic effects of these compounds, possibly as a function of the administered dose. Studies with 5-HT receptor antagonists indicate that the proposed role of particular 5-HT(1/2) receptor subtypes in the hypophagic effects of these 5-HT receptor agonists may be more complicated than originally thought. Further characterization of the role of 5-HT(1/2) receptor subtypes in the control of ingestive behavior will require extensive pharmacological and behavioral studies, using more selective receptor agonists and antagonists and different behavioral procedures, as well as verification in transgenic animals.

LY354740 affects startle responding but not sensorimotor gating or discriminative effects of phencyclidine.

LY354740 ¿(1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2, 6-dicarboxylate monohydrate¿, a selective group II metabotropic glutamate (mGlu) receptor agonist, was recently reported to attenuate the behavioral effects of phencyclidine (PCP) in rats. In the present study, LY354740 failed to attenuate the discriminative stimulus properties of PCP and its disruption of prepulse inhibition of the acoustic startle response, at a dose range which decreased startle responding. The suggestion that mGlu group II receptor activation induces antipsychotic effects may be premature.