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Overexpression of the mammalian homolog of the unc-18 gene (munc18-1) has been described in the brain of subjects with schizophrenia. Munc18-1 protein is involved in membrane fusion processes, exocytosis and neurotransmitter release. A transgenic mouse strain that overexpresses the protein isoform munc18-1a in the brain was characterized. This animal displays several schizophrenia-related behaviors, supersensitivity to hallucinogenic drugs and deficits in prepulse inhibition that reverse after antipsychotic treatment. Relevant brain areas (that is, cortex and striatum) exhibit reduced expression of dopamine D(1) receptors and dopamine transporters together with enhanced amphetamine-induced in vivo dopamine release. Magnetic resonance imaging demonstrates decreased gray matter volume in the transgenic animal. In conclusion, the mouse overexpressing brain munc18-1a represents a new valid animal model that resembles functional and structural abnormalities in patients with schizophrenia. The animal could provide valuable insights into phenotypic aspects of this psychiatric disorder.

The opioid system has been implicated in mood disorders as well as in the mechanism of action of antidepressants. Since the opioid component in venlafaxine (VLX) is still a matter of discussion, we investigated the role of opioid receptors in the antidepressant-like effect of VLX in the forced swimming test in mice. The non-selective opiate antagonist naloxone at high dose (2 mg/kg, s.c.) antagonized the effect of VLX. In contrast, beta-funaltrexamine (40 mg/kg, s.c.), which preferentially blocks mu(1)/mu(2) opioid receptors, naloxonazine (35 mg/kg, s.c.), a selective mu(1) opioid antagonist, naltrindole (10 mg/kg, s.c.), a selective delta opioid antagonist, and Nor-binaltorphimine (10 mg/kg, s.c.), which selectively blocks kappa-opioid receptors, were all ineffective. Thus, although apparently mediated by the opioid system, the behavioural effect of VLX does not involve specific opioid receptors.

1. The attenuation of morphine withdrawal syndrome by acute benzodiazepine administration has been well documented. However, the pharmacological mechanisms implicated in this effect remain unclear. 2. In this study, the possible participation of noradrenergic, serotonergic and benzodiazepine receptors on flunitrazepam-modified morphine withdrawal syndrome was investigated in mice. Flunitrazepam was associated to the noradrenergic antagonists prazosin (1 mg/kg) and propranolol (0.5 mg/kg), the serotonergic agents ritanserine (1 mg/kg) and p-chloro phenylalanine (600 mg/kg), the benzodiazepine antagonist flumazenil (10 mg/kg), and the benzodiazepine partial inverse agonist Ro 15-4513 (5 mg/kg). 3. The decrease in jumping behavior-induced by flunitrazepam was potentiated by prazosin, while ritanserine, flumazenil and Ro 15-4513 blocked this effect. 4. Flunitrazepam-induced increase on wet dog shake frequency was partially reduced by flumazenil, and strongly antagonized by ritanserine and Ro 15-4513. 5. Noradrenergic and serotonergic systems seem to be primarily implicated in the changes induced on jumping and wet dog shakes respectively. These modifications are induced through the activation of the benzodiazepine receptors.

1. Various clinical and experimental reports indicate that tricyclic antidepressant drugs are specially useful in the treatment of chronic and acute pain conditions. The present work was aimed to study the mechanisms implicated in the antinociceptive response induced by these antidepressants on different experimental models of pain in mice, and particularly the role played by noradrenergic, serotonergic and opioidergic influences. 2. Electrical stimulation of the tail and formalin tests were used to evaluate pain perception in mice acutely treated with different antidepressants (imipramine, desipramine, amitriptyline, nortriptyline, clomipramine and desmethylclomipramine). Antinociceptive responses were more potent in formalin test than in tail electrical stimulation test. 3. These antinociceptive effects were inhibited by naloxone (2 mg/Kg, i.p.), alpha-methyl-p-tyrosine (200 mg/Kg) and p-chlorophenylalanine (600 mg/Kg). Naloxone elicited the same effectivity to inhibit antinociceptive responses induced by tricyclic antidepressants in both tail electrical stimulation and formalin tests. alpha-methyl-p-tyrosine and p-chlorophenylalanine were more effective on antinociceptive responses induced on formalin than in tail electrical stimulation test. 4. These results suggest that tricyclic antidepressants produce antinociception partly via the participation of the endogenous opioid system and partly by further activating noradrenergic and serotonergic pathways. Moreover, the analgesic responses and the mechanisms implicated were dependent of the analgesimeter test used.

This is a study of the effects of the endogenous opioid peptides, enkephalins, on learned helplessness, an experimental model of depression in rats. For this purpose, the responses induced by RB 38A, a mixed inhibitor of enkephalin catabolism, and RB 38B, a selective inhibitor of neutral endopeptidase EC 3.4.24.11, were compared with the antidepressive effect induced by imipramine. RB 38A and RB 38B induced an imipramine-like effect in reducing helpless behavior, as illustrated by the decrease in the number of escape failures. According to the different pharmacological potential of both inhibitors to reduce enkephalin metabolism, complete inhibition of enkephalins (RB 38A) produced a higher response than that obtained with a partial inhibitor (RB 38B). On the other hand, naloxone (NLX) was found to facilitate the induction of learned helplessness, and to antagonize the effect of both enkephalin-degrading enzyme inhibitors. These results suggest that modifications in the activity of the endogenous opioid system could take place in this model of depression. The antidepressant-like effects induced by RB 38B, and especially by RB 38A, in the learned helplessness paradigm suggest that new mixed enkephalinase inhibitors, able to cross the blood-brain barrier, could provide a new strategy in the treatment of affective disorders.

The effects of different benzodiazepine-receptor ligands on morphine withdrawal were studied: a benzodiazepine agonist, flunitrazepam; a benzodiazepine antagonist, flumazenil; a partial inverse benzodiazepine agonist, Ro 15-4513; and a partial benzodiazepine agonist, Ro 16-6028. Benzodiazepine-ligands were administered i.p. 30 min before naloxone-induced morphine withdrawal syndrome. Jumping behavior was significantly increased by Ro 15-4513 at 10 and 20 mg/kg. Flunitrazepam decreased jumps at all the doses used. Wet dog shakes were decreased by flumazenil and Ro 15-4513 and increased by Ro 16-6028 (only at the highest dose) and flunitrazepam. Our results show that the activation of the benzodiazepine receptor by agonists or high doses of partial agonists decreases jumping and increases wet dog shake behaviour, while the antagonists or the partial inverse agonists enhance jumping and decrease wet dog shakes. These modifications could be interpreted as an attenuation in the severity of the morphine withdrawal syndrome by benzodiazepine agonists.