European Neuropsychopharmacology (v.19, #4)

Contents (OBC).

Superiority of escitalopram to paroxetine in the treatment of depression by Siegfried Kasper; David S. Baldwin; Sara Larsson Lönn; Jean-Philippe Boulenger (229-237).
Post-hoc pooled analysis of data from two 6-month randomised controlled trials in patients with major depressive disorder (MDD) revealed superior efficacy and tolerability of escitalopram when compared with paroxetine. Escitalopram (n  = 394) produced a significantly (p  < 0.01) greater mean treatment difference of 2.0 points in primary endpoints, judged using the Montgomery–Åsberg Depression Rating Scale (MADRS) total score, compared with paroxetine (n  = 383). Significant differences were also observed in Clinical Global Impression (CGI) — severity (escitalopram, 2.1; paroxetine, 2.4; p  < 0.01) and CGI — improvement (escitalopram, 1.8; paroxetine, 2.0: p  < 0.01). In the sub-group of severely depressed patients (baseline MADRS ≥ 30), escitalopram showed further improved efficacy compared with paroxetine in all scores. This analysis supports previous observations of superior efficacy and tolerability of long-term escitalopram treatment (10 to 20 mg/day) compared with paroxetine (20 to 40 mg/day). Escitalopram is a good therapeutic option for the long-term treatment of MDD, particularly in severely depressed patients.
Keywords: Escitalopram;; Major depressive disorder (MDD);; Selective serotonin reuptake inhibitors (SSRIs);; Severe depression;; Paroxetine;

Steady-state methadone blocks cocaine seeking and cocaine-induced gene expression alterations in the rat brain by Francesco Leri; Yan Zhou; Benjamin Goddard; AnneMarie Levy; Derek Jacklin; Mary Jeanne Kreek (238-249).
To elucidate the effects of steady-state methadone exposure on responding to cocaine conditioned stimuli and on cocaine-induced alterations in central opioid, hypocretin/orexin, and D2 receptor systems, male Sprague–Dawley rats received intravenous infusions of 1 mg/kg/inf cocaine paired with an audiovisual stimulus over three days of conditioning. Then, mini pumps releasing vehicle or 30 mg/kg/day methadone were implanted (SC), and lever pressing for the stimulus was assessed in the absence of cocaine and after a cocaine prime (20 mg/kg, IP). It was found that rats treated with vehicle, but not methadone, responded for the cocaine conditioned stimulus and displayed elevated mu-opioid receptor mRNA expression in the nucleus accumbens core and basolateral amygdala, reduced hypocretin/orexin mRNA in the lateral hypothalamus, and reduced D2 receptor mRNA in the caudate-putamen. This is the first demonstration that steady-state methadone administered after cocaine exposure blocks cocaine-induced behavioral and neural adaptations.
Keywords: Methadone;; Cocaine;; Mu-opioid receptor;; Hypocretin/orexin;; Dopamine receptor;

Vagus nerve stimulation (VNS) is a recently approved adjunctive intervention for treatment-resistant depression. This therapy enhances the firing rate of rat norepinephrine neurons after 1 h and that of serotonin (5-HT) neurons only after 14 days. Various stimulation parameters were thus tested on their capacity to enhance 5-HT neuronal firing because of the delayed action of VNS on the 5-HT system and its important role in the antidepressant response. Rats were implanted with a stimulator and treated for 14 days, each group of rats having only one stimulation parameter modified from the standard ones (0.25 mA, 20 Hz, 500 µs, 30 s ON/5 min OFF). Electrophysiological recordings showed that the usual parameters utilized in depressed patients, with the exception of current intensity, produced an optimal activation of 5-HT neurons. Excessive enhancement of the charge delivered to the nerve can lead to a loss of VNS effect on 5-HT neuronal firing.
Keywords: Vagus nerve stimulation (VNS); Stimulation parameters; Serotonin; Electrophysiology; Depression;

Excitatory and inhibitory neurotransmission is chronically altered following perinatal NMDA receptor blockade by Teresa Marie du Bois; Chao Deng; Mei Han; Kelly Anne Newell; Xu-Feng Huang (256-265).
N-methyl-d-aspartate (NMDA) receptor blockade in rodents induces behavioural and neurochemical changes reminiscent of schizophrenia symptoms and pathology. To examine how NMDA receptor blockade affects glutamatergic and GABAergic pathways when administered during early brain development, [3H]MK-801 and [3H]muscimol binding to NMDA and GABAA receptors was examined at four time-points following injections of phencyclidine (PCP) or saline on postnatal days (PN)7, 9 and 11. [3H]MK-801 binding was significantly increased in PCP-treated rats in the thalamus from PN18 to PN96, in the prefrontal and anterior cingulate cortices at PN32, and in the hippocampus at PN96. In a similar manner, [3H]muscimol binding was increased in PCP-treated rats in the thalamus and hippocampus from PN18 to PN96, and in the prefrontal and anterior cingulate cortices at PN32. Glutamatergic and GABAergic transmission is therefore chronically altered by this treatment, which has relevance to disease processes that may be involved in schizophrenia.
Keywords: Brain development; GABAA receptor; NMDA receptor; Phencyclidine; Schizophrenia;

Spatio-temporal expression of tryptophan hydroxylase isoforms in murine and human brain: Convergent data from Tph2 knockout mice by Lise Gutknecht; Claudia Kriegebaum; Jonas Waider; Angelika Schmitt; Klaus-Peter Lesch (266-282).
Dysregulation of tryptophan hydroxylase (TPH)-dependent serotonin (5-HT) synthesis, has been implicated in various neuropsychiatric disorders, although the differential expression pattern of the two isoforms is controversial. Here, we report a comprehensive spatio-temporal isoform-specific analysis of TPH1 and TPH2 expression during pre- and postnatal development of mouse brain and in adult human brain. TPH2 expression was consistently detected in the raphe nuclei, as well as in fibers in the deep pineal gland and in small intestine. Although TPH1 expression was found in these peripheral tissues, no significant TPH1 expression was detected in the brain, neither during murine development, nor in mouse and human adult brain. In support of TPH2 specificity in brain 5-HT synthesis, raphe neurons of Tph2 knockout mice were completely devoid of 5-HT, with no compensatory activation of Tph1 expression. In conclusion, our findings indicate that brain 5-HT synthesis across the lifespan is exclusively maintained by TPH2.
Keywords: Tph1; Tph2; Serotonin; Development; Raphe nuclei; Pineal gland;

In light of clinical reports suggesting that early benzodiazepine administration interferes with long-term recovery from traumatic stress, a prospective animal model for PTSD was employed to assess the short- and long-term effects of a brief course of alprazolam following stress exposure. Method: Animals exposed to stress were treated either 1 h or 7 days later with alprazolam or vehicle for 3-days. Outcome measures included behavior in the elevated plus-maze (EPM) and acoustic startle response (ASR) tests 30 days after initial exposure and freezing behavior upon exposure to a trauma-cue on day 31. One group was repeatedly exposed to the triggering trauma shortly before and after treatment and assessed as above. Circulating corticosterone levels were assessed 4 h after initiation of alprazolam and post-treatment. Pre-set cut-off behavioral criteria classified exposed animals according to their EPM and ASR response-patterns into ‘extreme’, ‘minimal,’ or ‘partial’ behavioral response for analysis of prevalence rates. Results: Immediate alprazolam treatment was effective in alleviating anxiety at day 4. No observable anxiolytic effects remained at day 30. Immediate alprazolam also resulted in significantly greater freezing response to trauma-cue exposure and in extreme responses to double-exposure. Corticosterone levels were significantly suppressed by alprazolam during treatment and rebounded after cessation. Conclusion: A brief course of alprazolam in the immediate aftermath of stress-exposure is associated with less favorable responses to additional stress-exposure later on. Alprazolam was associated with a significant attenuation of the HPA-response, suggesting a possible link between initial HPA-axis response disruption and the subsequent unfavorable outcomes.
Keywords: Post-traumatic stress disorder; Animal model; Benzodiazepines; Extreme behavioral response; Minimal behavioral response; Early drug intervention; Secondary prevention; Corticosterone;

Interaction of dopamine D1 with NMDA NR1 receptors in rat prefrontal cortex by Maria Sol Kruse; Joël Prémont; Marie-Odile Krebs; Thérèse M. Jay (296-304).
Despite the tremendous importance of D1 and NMDA receptors to cognition (working memory, executive functions) and synaptic plasticity in the prefrontal cortex (PFC), little is known about the molecular mechanisms underlying D1–NMDA receptors interactions in this brain area. Here, we show that D1 receptors and the NMDA receptor co-localize in single pyramidal neurons and interneurons in adult rat PFC. NR1 and NR2A expression are found in different neuronal types. Conversely, D1 receptors are predominantly localized in pyramidal-like cells and parvalbumin positive cells. NR1 co-immunoprecipitates with D1 receptor in adult medial PFC. In prefrontal primary cultures, NMDA does not affect the D1 receptor dependent-cAMP production. In contrast, activation of D1 receptor potentiates the NMDA mediated increase in cytosolic Ca2+, an effect that was blocked by a PKA inhibitor. We conclude that D1 receptor potentiates the NMDA-Ca2+ signal by a PKA-dependent mechanism.
Keywords: D1R; NR1; Prefrontal cortex; cAMP; Calcium;