European Neuropsychopharmacology (v.10, #6)

There is growing evidence that a dysfunction of central noradrenergic neurotransmission is involved in age-related impairments of cognitive performance and the pathophysiology of Alzheimer’s disease (AD). A reduction of density of central α1-adrenergic receptors (α1-AR) has been shown in aging and AD brains. Three α1-AR subtypes (α1a, α1b and α1d) have been identified by molecular cloning. However, very little is known about the functional role of distinct α1-AR subtypes in the brain. This problem was specifically addressed using a model of knockout mouse deficient in α1b-AR (α1B−/−) because these animals show a 40% reduction of α1-AR density in the brain as already reported. In comparison to the wild-type mice (α1B+/+), α1B−/− mice showed significantly reduced square entries and a reduced rearing behaviour was observed over all sessions in the open field. In passive avoidance procedures, α1B−/− mice showed a tendency towards decreased short-term-latency and a significant decline in long-term-latency. The present results indicate that mutation of a single member of the α1-AR gene family creates a distinct phenotype and provide evidence that α1B-AR is possibly involved in modulation of memory consolidation and fear-motivated exploratory activity. Furthermore, this model of knockout mice may be useful in elucidating the role of α1B-AR in dementias involving deficits of the noradrenergic system.

Acute psychological stress is the presumed immediate cause of post-traumatic stress disorder (PTSD), and may also contribute to other anxiety disorders. Abnormal activity of the hypothalamic-pituitary-adrenal (HPA) axis has been tentatively implicated in some of the features of these disorders. Ketoconazole (KTCZ), an imidazole derivative, is a potent inhibitor of gonadal and adrenal steroidogenesis. The aim of this study was to explore the effects of KTCZ blockade of adrenal steroidogenesis, and consequent elevation of adreno-corticotropic hormone (ACTH), on a model of chronic post-traumatic anxiety in rats. Amelioration of anxious behaviors after reduction of corticosterone would suggest that corticosterone (and by implication cortisol in humans) is an important mediator of anxious symptoms: exacerbation of such behaviors would suggest that corticosterone elevations are only secondary, and possibly implicate corticotropin releasing hormone (CRH) and/or ACTH in the pathogenesis of anxious symptoms. We exposed rats for 10 min to cat scent, a prima facie valid model for acute psychological stress, with and without high dose KTCZ for 14 days. Treatment with KTCZ abolished the chronic behavioral effects of acute exposure to a cat scent. Lower levels of anxious behavior in KTCZ-treated and exposed rats were accompanied by lower plasma corticosterone, ACTH and prolactin (PRL) levels compared to untreated exposed rats. Results in this model implicate corticosterone, but not ACTH, in the pathogenesis of chronic anxiety following acute psychological stress.
Keywords: ACTH; Animal model; Anxiety; Anxiety-related behavior; Corticosterone; Hypothalamic-pituitary-adrenal; Ketoconazole; Posttraumatic stress disorders; Prolactin; Steroid; Stress.;

The effects of substituted benzamides, sulpiride and raclopride on experimental models of depression were studied in male rats after acute or chronic administration in comparison to those of the classical antidepressant, clomipramine. In contrast to clomipramine (50 mg/kg), acute doses of sulpiride or raclopride (1 or 5 mg/kg) failed to change the behavioral response of animals tested in the despair (constrained swim) test or in the model of reserpine-induced changes in the open field behavior. These doses also did not modify the grooming response of rats exposed to a novel environment. Sulpiride or raclopride 10 mg/kg increased the immobility time in the despair test and reduced novelty-induced grooming. The repeated injection for 21 days of sulpiride or raclopride (1 or 5 mg/kg, but not 10 mg/kg) induced a reduction of the immobility period during the constrained swim test similar to that following the chronic treatment with clomipramine 50 mg/kg. This appeared to be a clear-cut reversed dose–response relationship for both substituted benzamides, being the dose potency 1 mg/kg>5 mg/kg>10 mg/kg. Raclopride was more potent than sulpiride in this respect. Furthermore, like clomipramine, sulpiride (1 or 5 mg/kg) and raclopride (1 mg/kg) antagonized reserpine-induced changes in the open field behavior and enhanced novelty-induced grooming. These results indicate that, in contrast to acute injection, repeated administration of small doses of the substituted benzamides, sulpiride or raclopride induce an effect similar to that of the classical antidepressant, clomipramine. The reverse dose–response relationship suggests that these drugs in small doses act on presynaptic dopamine D 2 receptors. This may be consistent with a postsynaptic action of greater doses that exert sedative effects and increase immobility time in the despair test.
Keywords: Substituted benzamides; Sulpiride; Raclopride; Grooming; Despair test; Reserpine-induced behavioral changes; Depression;

Acute antipsychotic drug administration lowers body temperature in drug-free male schizophrenic patients by Roni Shiloh; Haggai Hermesh; Nehama Weizer; Pnina Dorfman-Etrog; Abraham Weizman; Hanan Munitz (443-445).
We examined, in a controlled design, potential alterations in body temperature of male schizophrenic patients following acute antipsychotic drug (APD) administration. Fourteen drug-free (study group) and seven schizophrenic patients maintained on APDs (comparison group) initiated or received higher dose of their APD, respectively, for 27 days. Initial body temperature was 0.36°C higher in the study group (P=0.01) and decreased within 24 h to values comparable to that of the comparison group (all within normal range).
Keywords: Schizophrenia; Antipsychotic drugs; Body temperature;

Influence of buprenorphine, butorphanol and nalbuphine on the initiation of intravenous cocaine self-administration in drug naive mice by Alexander V. Kuzmin; Mirjam A.F.M. Gerrits; Edwin E. Zvartau; Jan M. van Ree (447-454).
The influence of different mixed μ–κ-opioid receptor agonists–antagonists on cocaine reinforcement was studied using the method of initiation of intravenous cocaine self-administration in naive mice. Self-administration of cocaine was readily initiated according to an inverted U-shaped unit dose–response curve. Buprenorphine, butorphanol and nalbuphine tested against the optimal unit dose of cocaine (0.8 μg per infusion), inhibited initiation of cocaine self-administration in a dose-dependent manner. When tested against a scale of cocaine unit doses (0.2 –1.6 μg per infusion) buprenorphine (0.1 mg/kg, s.c.) and nalbuphine (2 mg/kg, s.c.) produced a shift of the optimal cocaine dose from 0.8 to 0.4 μg/inf, while butorphanol (1 mg/kg, s.c.) shifted the optimal unit dose of cocaine to the right along the cocaine unit doses axis. Co-administration of naloxone (0.1 mg/kg, s.c.) significantly reduced the effect of buprenorphine but failed to influence the effect of nalbuphine and butorphanol on cocaine intake. Taken together, these results suggest that nalbuphine is capable of affecting cocaine’s reinforcing properties in the same manner as buprenorphine during the initiation phase of cocaine self-administration behavior, while butorphanol causes the opposite effect. Although the exact opioid profile of action of the mixed opioid receptor agonists–antagonists is as yet not precisely known, the present findings suggest that multiple opioid receptor systems (i.e. μ and κ) play a role in reinforcing properties of cocaine and that a co-operative interaction between μ- and κ-opioid systems may be of importance during initiation of cocaine self-administration.
Keywords: Cocaine; Self-administration; Buprenorphine; Nalbuphine; Butorphanol; Naloxone;

Local modulation of the 5-HT release in the dorsal striatum of the rat: an in vivo microdialysis study by Marı́a T. Abellán; Raúl Martı́n-Ruiz; Francesc Artigas (455-462).
Using in vivo microdialysis in freely moving rats, we examined the involvement of major striatal transmitters on the local modulation of the 5-HT release. Tetrodotoxin reduced the striatal 5-HT output to 15–20% of baseline. The selective 5-HT1B receptor agonist CP 93129 (50 μM) reduced (50%) and the 5-HT2A/2C receptor agonist DOI (1–100 μM) increased (220%) the 5-HT output. Neither GABA nor baclofen (100 nM–100 μM) altered the 5-HT output. The glutamate reuptake inhibitor l-trans-PDC (1–4 mM) raised 5-HT to 280% of baseline. This effect was not antagonized by the NMDA receptor antagonist MK-801 (0.5 mg/kg i.p.). Local MK-801 (10–100 μM) did not significantly alter the 5-HT output. Finally, neither carbachol (10–100 μM) nor quipirole (10 μM–1 mM) affected 5-HT. These data suggest that the striatal 5-HT release is influenced by local serotonergic and glutamatergic (but not GABAergic) inputs.
Keywords: 5-Hydroxytryptamine; 5-HT receptors; Acetylcholine; Dopamine; GABA; Glutamate;

Nicotine modulates nitric oxide in rat brain by Sakire Pogun; Serdar Demirgoren; Dilek Taskiran; Lutfiye Kanit; Ozlem Yilmaz; Ersin O. Koylu; Burcu Balkan; Edythe D. London (463-472).
Nicotine exerts its central actions by regulating cationic fluxes through nicotinic acetylcholine receptors (nAChRs). By this effect, the drug likely also modifies events occurring beyond the nAChR, including the regulation of nitric oxide (NO) synthesis. The present study was undertaken to assess the effects of acute and chronic nicotine administration (0.4 mg/kg, s.c.) on levels of NO 2+NO 3, stable metabolites of NO, in brain regions of male and female rats. Nicotine increased levels of the metabolites, and therefore presumably of NO, with sex differences in the degree of stimulation, the brain regions affected, and the variance between the effects of acute and chronic administration. Prior inhibition of NO synthase eliminated the effect of nicotine in all regions studied. While nicotine appeared to increase NO indirectly via glutamate receptors in the cortex and hippocampus, this was not true of the corpus striatum, where blocking NMDA-type glutamate receptors with MK-801 had no effect. The findings support the view that NO is likely involved in some of the central effects of nicotine.
Keywords: Nicotine; Nitric oxide; Glutamate; Hippocampus; Striatum; Sex differences;

The possible antidepressant effect of physiological and pharmacological doses of melatonin was investigated in the Porsolt forced swimming-induced behavioral despair test. The duration of immobility period of BALB/c and C57BL/6J mice during a 6-min swim test was measured at noon (11:00–12:00 h), early dark (20:00–21:00 h) and at midnight (1:00–2:00 h), respectively. The circadian time cycle did not alter the duration of immobility in either strains of mice. Similarly, exogenously administered melatonin (10–1000 μg/kg≅50 nM to 5 μM/mouse), a dose that could act on high affinity melatonin receptors, did not modify the duration of immobility period at any of the time intervals studied in either strains of the mice. This suggested that neither circadian variation influenced the duration of immobility period of BALB/c and C57BL/6J mice nor at physiological doses melatonin showed any anti-depressant action. Acute administration of higher doses of melatonin (2.5–10 mg/kg) failed to induce any anti-depressant activity in mice which were subjected to forced swimming test for the first time. However, daily administration of melatonin (2.5–10 mg/kg) prior to swimming test significantly reversed the increase in immobility period that was observed on chronic exposure to swimming test. This effect was comparable with the effect of GABA-benzodiazepine (BZ) receptor agonists. Similarly, like GABAergic drugs, acute administration of melatonin also showed anti-depressant activity in a mice which were exposed to chronic forced swimming test. The anti-depressant action of melatonin was sensitive to reversal by peripheral BZ receptor antagonist, PK11195. Whereas, flumazenil failed to reverse the anti-depressant action of melatonin, thereby suggesting that central BZ receptor were not involved in its action. In conclusion the study showed that at pharmacological doses melatonin has anti-depressant action in chronic forced swimming-induced despair behavior by an action involving peripheral BZ receptors.
Keywords: Melatonin; Porsolt forced swimming; Central/peripheral BZ receptors; Depression;

Chemical kindling and seizure susceptibility in morphine dependent rats by N. Atapour; T.P. Kalantaripour; M. Nourpanah; M. Niazi (483-487).
In the present study, we investigated whether and how chronic morphine administration changes seizure susceptibility in rats. The role of morphine-dependence on the seizure susceptibility has been evaluated with models of pentylenetetrazol (PTZ)-kindling and acute convulsions induced by PTZ, N-methyl-d-aspartic acid (NMDA), picrotoxin and caffeine in adult male rats. The results showed that morphine-dependence increased seizure severity only at 1–4th PTZ injections in the kindling model. In acute convulsion tests, dependent rats demonstrated a significantly lower seizure threshold only for PTZ, while they demonstrated a significantly lower tendency to show tonic–clonic convulsions only for NMDA. It is concluded that morphine-dependence may modulate PTZ-kindling and seizure susceptibility in rats with emphasis on the role of GABA and NMDA neurotransmitter systems.
Keywords: Morphine-dependence; PTZ-kindling; NMDA; Picrotoxin; Caffeine;

Differential regulation of adenosine A1 and A2A receptors in serotonin transporter and monoamine oxidase A-deficient mice by Rainald Mössner; Dietmar Albert; Antonio M. Persico; Thomas Hennig; Dietmar Bengel; Bettina Holtmann; Angelika Schmitt; Flavio Keller; Rabi Simantov; Dennis Murphy; Isabelle Seif; Jürgen Deckert; K.Peter Lesch (489-493).
The serotonin (5HT) transporter (5HTT) removes 5HT from the synaptic cleft and is thus critical to the control of serotonergic neurotransmission. Mice with a targeted inactivation of the 5HTT represent a novel and unique tool to study serotonergic system functioning. Because the release of 5HT is regulated by adenosine, we investigated 5HTT-deficient mice for possible adaptive changes of adenosine A1 and A2A receptors. A1 and A2A receptors were studied by means of quantitative autoradiography using the radioligands [3H]8-cyclopentyl-1,3-dipropylxanthine and [3H]CGS 21680, respectively. A comparison of 5HTT knockout versus control mice revealed upregulation of A1 receptors in the dorsal raphe nucleus (DRN, +21%), but not in any of the serotonergic projection areas, and downregulation of A2A receptors in basal ganglia. The adaptive changes of A1 and A2A receptors in 5HTT-deficient mice are likely to represent a compensatory neuroprotective effect mediated by the adenosinergic modulatory system. For comparison, these receptors were also studied in monoamine oxidase A (MAOA) knockout mice and in 5HTT/MAOA double knockout mice. 5HTT/MAOA double knockout mice showed adaptive changes of adenosine A1 and A2A receptors similar to 5HTT knockout mice, while investigation of MAOA-deficient mice revealed an upregulation of A2A receptors, which may relate to a role of both MAOA and adenosine A2A receptors in anxiety.
Keywords: Serotonin transporter; Adenosine A1 receptor; Adenosine A2A receptor; Dorsal raphe nucleus; Accumbens nucleus; Monoamine oxidase A; Knockout mouse; Autoradiography;

Effects of acute and chronic electroconvulsive stimuli on cAMP and cGMP efflux in the rat striatum and hippocampus by George G. Nomikos; Susanne Gruber; Torgny H. Svensson; Aleksander A. Mathé (495-500).
The effects of acute and chronic electroconvulsive stimuli (ECS) on extracellular concentrations of the cyclic nucleotides, cAMP and cGMP, from the striatum and hippocampus of awake rats were studied with in vivo microdialysis in conjunction with radioimmunoassay. Acute ECS, but not acute sham-ECS, significantly increased cAMP and cGMP efflux from the striatum by about 75 and 50%, respectively. Chronic ECS did not influence significantly basal efflux of cAMP or cGMP from the striatum or the hippocampus in comparison to control animals receiving chronically sham-ECS. Administration of a challenge ECS in animals treated chronically with sham-ECS resulted in an increase in cAMP and cGMP concentrations in the striatum by 20%, but it failed to affect significantly efflux of these nucleotides in animals treated chronically with ECS. Similarly, in the hippocampus, administration of a challenge ECS in animals treated chronically with sham-ECS resulted in an increase in cAMP and cGMP concentrations by about 40 and 65%, respectively, whereas it failed to affect significantly efflux of these nucleotides in animals treated chronically with ECS. Thus, acutely administered ECS increases cAMP and cGMP efflux in the striatum and hippocampus of rats, an effect that is greatly diminished in animals chronically receiving ECS. These findings suggest changes in the cAMP and cGMP signal transduction mechanisms in response to acute and chronic ECS that may be related to the therapeutic effects of this antidepressant and antipsychotic treatment.
Keywords: Electroconvulsive treatment; Microdialysis; Cyclic AMP; Cyclic GMP;

We and others have earlier shown that severe serotonin depletion leads to a compensatory down-regulation in the expression of the serotonin transporter (5HTT) gene. We have now investigated the expression of both the 5HTT and the norepinephrine transporter (NET) gene to assess the possible interaction between the noradrenergic and the serotonergic neurotransmitter systems. Acute severe serotonin depletion induced by p-chlorophenylalanine (PCPA) treatment leads to enhanced NETLong mRNA levels and reduced 5HTT mRNA level. This change in transporter mRNA expression was paralleled by a non-significant change in protein expression. Chronic severe serotonin depletion combined with treatment with the antidepressant imipramine leads to enhanced NETLong mRNA levels. Acute treatment with the monoamine oxidase A inhibitor clorgyline, acute moderate NE reduction (α-methyl-p-tyrosine treatment) or less severe depletion for 3 weeks have no effect on the gene expression of the transporters. Taken together, the present data demonstrate that the NET gene expression is enhanced in case of severe serotonin depletion.
Keywords: Serotonin transporter; Norepinephrine transporter; mRNA; Northern blot; Serotonin depletion; Rat;

Index (527-530).

Index (531-541).