Placebo

Psychiatry has proven to be among the least penetrable clinical disciplines for the development of satisfactory in vivo model systems for evaluating novel treatment approaches. However, mood and anxiety disorders remain poorly understood and inadequately treated. With the explosion in the use of genetically modified mice, enormous research efforts have been focused on developing mouse models of psychiatric disorders. The success of this approach is largely contingent on the usefulness of available behavioural models of depression- and anxiety-related behaviours in mice. Here, we assess the current status of research into developing appropriate tests for assessing such behaviours.

The ascent of mouse: advances in modelling human depression and anxiety.

Molecular Imaging with PET

Dopamine receptor pharmacology

Several groups have provided evidence that positron emission tomography (PET) and single-photon emission computed tomography (SPECT) neuroreceptor imaging techniques might be applied to measure acute fluctuations in dopamine (DA) synaptic concentration in the living human brain Competition between DA and radioligands for binding to D2 receptor is the principle underlying this approach This new application of neuroreceptor imaging provides a dynamic measurement of neurotransmission that is likely to be informative to our understanding of neuropsychiatric conditions This article reviews and discusses the body of data supporting the feasibility and potential of this imaging paradigm Endogenous competition studies performed in rodents, nonhuman primates, and humans are first summarized After this overview, the validity of the model underlying the interpretation of these imaging data is critically assessed The current reference model is defined as the occupancy model, since changes in radiotracer binding potential (BP) are assumed to be directly caused by changes in occupancy of D2 receptors by DA Experimental data supporting this model are presented The evidence that manipulation of DA synaptic levels induces change in the BP of several D2 radiotracers (catecholamines and benzamides) is unequivocal The fact that these changes in BP are mediated by changes in DA synaptic concentration is well documented The relationship between the magnitude of BP changes measured with PET or SPECT and the magnitude of changes in DA concentration measured by microdialysis supports the use of these noninvasive techniques to measure changes in neurotransmission On the other hand, several observations remain unexplained First, the amphetamine-induced changes in the BP of D2 receptor antagonists [123I]IBZM and [11C]raclopride last longer than amphetamine-induced changes in DA extracellular concentration Second, nonbenzamide D2 receptor antagonists, such as spiperone and pimozide, are not affected by changes in DA release, or are affected in a direction opposite to that predicted by the occupancy model Similar observations are reported with D1 radiotracers These results suggest that the changes in BP following changes in DA concentration might not be fully accounted by a simple occupancy model Specifically, the data are reviewed supporting that agonist-mediated receptor internalization might play an important role in characterizing receptor-ligand interactions Finally, it is proposed that a better understanding of the mechanism underlying the effects observed with benzamides is essential to develop this imaging technique to other receptor systems

https://journals.sagepub.com/doi/pdf/10.1097/00004647-200003000-00001

Imaging Synaptic Neurotransmission with in Vivo Binding Competition Techniques: A Critical Review

The tail suspension test as a model for assessing antidepressant activity: review of pharmacological and genetic studies in mice.

Recently, selective and systemically active antagonists for the metabotropic glutamate 5 receptor (mGlu(5)) were discovered, and the most potent derivative was found to be MPEP (2-methyl-6-(phenylethynyl)pyridine). Given the high expression of mGlu(5) receptors in limbic forebrain regions, it was decided to evaluate the anxiolytic potential of MPEP. After an acute oral administration, MPEP attenuated the anxiety-dependent variable in a variety of well established anxiety test paradigms. In rats, MPEP (10, 30, and 100 mg/kg) increased punished responses in the Geller-Seifter test, but none of these effects reached statistical significance. MPEP significantly increased the ratio (open/total arm entries; 0.1, 1, and 10 mg/kg), the number of open arm entries (0.1, 1, and 10 mg/kg), as well as time spent on open arm (0.1 and 1 mg/kg) in the elevated plus maze test. Furthermore, MPEP (0.3 and 1 mg/kg) significantly increased the time spent in social contact in the social exploration test. In mice, MPEP attenuated stress-induced hyperthermia (15 and 30 mg/kg) and decreased the number of buried marbles in the marble burying test (7.5 and 30 mg/kg). Finally, MPEP (0.01, 0.1, 1, 10, and 100 mg/kg) was tested on spontaneous locomotor activity in mice, and only a dose of 100 mg/kg significantly reduced vertical activity; no effect was seen on horizontal activity. MPEP (7.5, 15, and 30 mg/kg) was ineffective on d-amphetamine-induced (2.5 mg/kg) locomotor activity in mice and prepulse inhibition in rats (1, 3, or 10 mg/kg). Thus, these findings indicate that MPEP exhibits anxiolytic-like effects and low risks for sedation and psychotomimetic side-effects in rodents.

Anxiolytic-Like Effects of the Prototypical Metabotropic Glutamate Receptor 5 Antagonist 2-Methyl-6-(phenylethynyl)pyridine in Rodents

The selective nicotinic acetylcholine receptor alpha7 agonist JN403 is active in animal models of cognition, sensory gating, epilepsy and pain.

Anticonvulsant properties of CGP 37849 and CGP 39551, two novel phosphono-amino acids which are competitive NMDA receptor antagonists, were examined in rodents. At optimal pretreatment times CGP 37849 suppressed electroshock-induced seizures in mice and rats with ED50s ranging from 8 to 22 mg/kg after oral administration, and 0.4 to 2.4 mg/kg after i. v. and i. p. injection. Relative to CGP 37849, CGP 39551 was more potent after p. o. (ED50 3.7–8.1 mg/kg), and less potent after i.v. or i.p. treatment (ED50 2.7–8.7 mg/kg). Following oral treatment, the duration of action of CGP 37849 was about 8 h, while CGP 39551 still showed good activity after 24 h (ED50 8.7 mg/kg, mouse; 21 mg/kg, rat). Both compounds were anticonvulsant at doses below those at which overt behavioural side effects were apparent. CGP 39551 delayed the development of kindling in rats at doses of 10 mg/kg p. o. and above, and showed weak anticonvulsant activity against pentylenetetrazolevoked seizures. CGP 37849 and CGP 39551 are the first competitive NMDA antagonists to show oral anticonvulsant properties in a therapeutically-useful dose-range, and hence are interesting candidates for novel antiepileptic therapy in man.

Annick Vassout

Papers

The tail suspension test as a model for assessing antidepressant activity: review of pharmacological and genetic studies in mice.

Anxiolytic-Like Effects of the Prototypical Metabotropic Glutamate Receptor 5 Antagonist 2-Methyl-6-(phenylethynyl)pyridine in Rodents

The selective nicotinic acetylcholine receptor alpha7 agonist JN403 is active in animal models of cognition, sensory gating, epilepsy and pain.

The competitive NMDA receptor antagonists CGP 37849 and CGP 39551 are potent, orally-active anticonvulsants in rodents.

The NK1-receptor antagonist NKP608 has an antidepressant-like effect in the chronic mild stress model of depression in rats.