Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
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Neuropsychopharmacology · Oct 2014
Cellular and behavioral outcomes of dorsal striatonigral neuron ablation: new insights into striatal functions.
The striatum is the input structure of the basal ganglia network that contains heterogeneous neuronal populations, including two populations of projecting neurons called the medium spiny neurons (MSNs), and different types of interneurons. We developed a transgenic mouse model enabling inducible ablation of the striatonigral MSNs constituting the direct pathway by expressing the human diphtheria toxin (DT) receptor under the control of the Slc35d3 gene promoter, a gene enriched in striatonigral MSNs. DT injection into the striatum triggered selective elimination of the majority of striatonigral MSNs. ⋯ Mice with DT injection into the dorsal striatum showed altered basal and cocaine-induced locomotion and dramatic reduction of L-DOPA-induced dyskinesia in the parkinsonian condition. In addition, these mice exhibited reduced anxiety, revealing a role of the dorsal striatum in the modulation of behaviors involving an emotional component, behaviors generally associated with limbic structures. Altogether, these results highlight the implication of the direct striatonigral pathway in the regulation of heterogeneous functions from cell survival to regulation of motor and emotion-associated behaviors.
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Neuropsychopharmacology · Sep 2014
Effect of general anesthesia in infancy on long-term recognition memory in humans and rats.
Anesthesia in infancy impairs performance in recognition memory tasks in mammalian animals, but it is unknown if this occurs in humans. Successful recognition can be based on stimulus familiarity or recollection of event details. Several brain structures involved in recollection are affected by anesthesia-induced neurodegeneration in animals. ⋯ Rats that had undergone tissue injury during anesthesia had similar recollection indices as rats that had been anesthetized without tissue injury. These findings suggest that general anesthesia in infancy impairs recollection later in life in humans and rats. In rats, this effect is independent of underlying disease or tissue injury.
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Neuropsychopharmacology · Sep 2014
Neuropharmacological and neurobiological relevance of in vivo ¹H-MRS of GABA and glutamate for preclinical drug discovery in mental disorders.
Proton magnetic resonance spectroscopy ((1)H-magnetic resonance spectroscopy (MRS)) is a translational modality with great appeal for neuroscience since the two major excitatory and inhibitory neurotransmitters, glutamate, and GABA, can be noninvasively quantified in vivo and have served to explore disease state and effects of drug treatment. Yet, if (1)H-MRS shall serve for decision making in preclinical pharmaceutical drug discovery, it has to meet stringent requirements. In particular, (1)H-MRS needs to reliably report neurobiologically relevant but rather small changes in neurometabolite levels upon pharmacological interventions and to faithfully appraise target engagement in the associated molecular pathways at pharmacologically relevant doses. ⋯ Finally, we corroborated the MRS findings with ex vivo biochemical analyses of drug exposure and neurometabolite concentrations. For all five interventions tested, (1)H-MRS provided distinct drug dose-effect relationships in GABA and glutamate over preclinically relevant dose ranges and changes as low as 6% in glutamate and 12% in GABA were reliably detected from 16 mm(3) volumes-of-interest. Taken together, these findings demonstrate the value and limitation of quantitative (1)H-MRS of glutamate and GABA for preclinical pharmaceutical research in mental disorders.
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Neuropsychopharmacology · Sep 2014
Alterations in reward, fear and safety cue discrimination after inactivation of the rat prelimbic and infralimbic cortices.
Accurate discrimination of environmental cues predicting reward, fear, or safety is important for survival. The prelimbic and infralimbic cortices are implicated in regulating reward-seeking and fear behaviors; however, no studies have examined their roles in discriminating among reward, fear, and safety cues. Using a discriminative conditioning task that includes presentations of a reward cue (paired with a reward pellet), fear cue (paired with footshock), and a compound fear+safety cue (no footshock) within the same sessions allowed us to assess the flexibility and precision of fear and reward-seeking behaviors to these cues. ⋯ Inactivating the prelimbic cortex altered discriminative reward seeking as rats with prelimbic inactivation did not increase their reward seeking behavior during the reward cue to the same degree as saline controls. Our results imply dissociable roles of the two cortical regions: the prelimbic cortex in precise discriminative reward seeking and the infralimbic cortex in discriminating between fear and safety cues. These data suggest that alterations in the balance of activity between areas homologous to the prelimbic and infralimbic cortices may be involved in the processes that go awry in anxiety and addiction disorders.
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Neuropsychopharmacology · Aug 2014
Distinct effects of repeated restraint stress on basolateral amygdala neuronal membrane properties in resilient adolescent and adult rats.
Severe and repeated stress has damaging effects on health, including initiation of depression and anxiety. Stress that occurs during development has long-lasting and particularly damaging effects on emotion. The basolateral amygdala (BLA) plays a key role in many affective behaviors, and repeated stress causes different forms of BLA hyperactivity in adolescent and adult rats. ⋯ Furthermore, stress resilience was associated with an opposite pattern of change, with increased slow afterhyperpolarization (AHP) potential, whereas vulnerability was associated with decreased medium AHP. The opposite outcomes in these two populations were further distinguished by differences of anxiety-like behavior in the elevated plus maze that were correlated with BLA neuronal excitability and AHP. These results demonstrate a substrate for BLA hyperactivity after repeated stress, with distinct membrane properties to target, as well as age-dependent factors that contribute to resilience to the effects of stress.