Increased ethanol consumption despite taste aversion in mice with a human tryptophan hydroxylase 2 loss of function mutation.

Polymorphisms in the gene encoding the brain serotonin synthesis enzyme Tph2 have been identified in mental illnesses, with co-morbidity of substance use disorder. However, little is known about the impact of Tph2 gene variants on addiction. Mice expressing a human Tph2 loss of function variant were used to investigate consequences of aversive conditions on ethanol intake. Mice were familiarized either with ethanol or a solution containing both ethanol and the bittering agent quinine. Effect of familiarization to ethanol or an ethanol-quinine solution was then evaluated using a two-bottles preference test in Tph2-KI and control littermates. Mice from both genotypes displayed similar levels of ethanol consumption and quinine avoidance when habituated to ethanol alone. In contrast, addition of quinine to ethanol during the familiarization period resulted in a reduction of avoidance for the quinine-ethanol solution only in mutant mice. These results indicate that loss of function mutation in Tph2 results in greater motivation for ethanol consumption under aversive conditions and may confer enhanced sensitivity to alcohol use disorder.

Stimulation of 5-HT2C receptors improves cognitive deficits induced by human tryptophan hydroxylase 2 loss of function mutation.

Polymorphisms in the gene encoding the serotonin synthesis enzyme Tph2 have been identified in mental illnesses, including bipolar disorder, major depression, autism, schizophrenia, and ADHD. Deficits in cognitive flexibility and perseverative behaviors are shared common symptoms in these disorders. However, little is known about the impact of Tph2 gene variants on cognition. Mice expressing a human TPH2 variant (Tph2-KI) were used to investigate cognitive consequences of TPH2 loss of function and pharmacological treatments. We applied a recently developed behavioral assay, the automated H-maze, to study cognitive functions in Tph2-KI mice. This assay involves the consecutive discovery of three different rules: a delayed alternation task, a non-alternation task, and a delayed reversal task. Possible contribution of locomotion, reward, and sensory perception were also investigated. The expression of loss-of-function mutant Tph2 in mice was associated with impairments in reversal learning and cognitive flexibility, accompanied by perseverative behaviors similar to those observed in human clinical studies. Pharmacological restoration of 5-HT synthesis with 5-hydroxytryptophan or treatment with the 5-HT(2C) receptor agonist CP809.101 reduced cognitive deficits in Tph2-KI mice and abolished perseveration. In contrast, treatment with the psychostimulant methylphenidate exacerbated cognitive deficits in mutant mice. Results from this study suggest a contribution of TPH2 in the regulation of cognition. Furthermore, identification of a role for a 5-HT(2) receptor agonist as a cognition-enhancing agent in mutant mice suggests a potential avenue to explore for the personalized treatment of cognitive symptoms in humans with reduced 5-HT synthesis and TPH2 polymorphisms.

Contribution of the dorsal subiculum to memory for temporal order and novelty detection using objects, odors, or spatial locations in the rat.

The contribution of the dorsal subiculum (DS) to memory for temporal order and novelty detection was assessed using a spontaneous exploration paradigm with objects (visual/tactile stimuli), odors, or spatial locations (Hunsaker, Fieldsted, Rosenberg, & Kesner, 2008). Rats with selective excitotoxic lesions of the DS were compared to sham-operated rats (SHAM) in the two exploration tests. In temporal order tests, two previously explored stimuli were presented and normal rats typically show a preference for exploring the stimulus that was first explored compared to the other stimulus. In novelty detection tests, a familiar and a new stimulus were presented and normal rats typically have a preference for exploring new stimuli. In temporal order tests, results indicated that Group SHAM explored significantly more the first than the last stimulus they met when the stimuli were odors or objects. In addition, SHAM rats predictably displayed a significant preference for the new stimulus in the novelty detection tests with objects, odors, and spatial locations. Group DS did not differ from controls on the temporal order and the novelty detection tests with objects or odors. However, on the novelty detection test with spatial locations, Group DS differed from Group SHAM. These results suggest that the DS is necessary for the memory of spatial locations but not of objects and odors.