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Background: The Transient Receptor Potential Melastatin 8 (TRPM8) is a cold/pain-sensitive Ca2+ channel. Testosterone is a high-affinity agonist for TRPM8, and TRPM8 -/- male mice exhibit disrupted sexual behavior: indiscriminate approach, increased mounting, and delayed satiety, possibly due to decreased ventral tegmental area dopamine (DA) neuron activity. DA plays a critical role in motivated behaviors, including behavioral activation, detection of reward-relevant stimuli, and reinforcement learning. Hypothesis: It is hypothesized that TRPM8 KO mice will exhibit disruptions across a range of motivationally-relevant behaviors, including spontaneous locomotor activation, detection of novel stimuli, sucrose preference, and sensitivity to the psychomotor stimulant amphetamine. Methods: Adult mice (Jackson Laboratory) were individually housed and locomotor activity was assessed for 48 hours. To assess detection of novel stimuli, a novel object recognition task was performed. Mice were habituated to two identical objects for two hours. A novel object was introduced and interaction with the novel vs familiar object was recorded. Sucrose (0.1%) preference was assessed using a two-bottle choice procedure. Tests for amphetamine sensitization (1.0 mg/kg i.p.) are in progress. Results: Female mice were more active compared to male mice (F (1,26) = 7.14, p < 0.05). Time course analysis of the nocturnal activity of males revealed a statistically significant decrease (F (1,12) = 23.41, p < 0.001) in activity among TRPM8 -/- compared to wildtype mice. In contrast, the TRPM8 deletion had no effect on the activity of female mice (F (1,12) = 0.32, n.s.). Preliminary analysis of the novel object recognition task revealed a trend towards increased exploration of the novel object and decreased time with the familiar object among male TRPM8 -/- mice compared to wildtype (Cohen’s d > 0.58). Finally, male TRPM8 -/- mice exhibited a robust preference for sucrose compared to wildtype mice. Additional data collection is in progress. Conclusion: TRPM8-/- mice were less active during the active phase of the day/night cycle compared to wildtype mice. However, TRPM8-/- mice exhibited increased interest in a novel object and a robust preference for sucrose, indicating increased sensitivity to motivationally-relevant stimuli. These behavioral data suggest that TRPM8 -/- mice are likely to exhibit decreased basal DA levels in reward-relevant brain areas, but that motivationally relevant stimuli likely elicit robust increases in DA. 

Testosterone exerts high affinity for the Transient Receptor Potential Melastatin 8 (TRPM8) Ca2+ channel. TRPM8 -/- male mice exhibit disrupted sexual behavior (e.g., indiscriminate approach, delayed satiety), possibly due to decreased ventral tegmental area dopamine neuron activity. It is hypothesized that TRPM8 null mutant mice (Jackson Laboratories) will exhibit disruptions across a range of motivationally-relevant behaviors, including spontaneous locomotor activation, detection of novel stimuli, sucrose preference, and sensitivity to the psychomotor stimulant amphetamine. Initial findings indicate that male TRPM8 mutant mice (n=6) exhibit decreased nocturnal locomotor activity (F(1,12)=23.41, p<0.001), increased behavioral anxiety in the light/dark task (t(10)=2.44, p<0.05; d=1.4), and behavioral despair in the forced swim task (t(10)=3.70, p<0.005; d=2.1). In contrast, these mice tended to prefer a low concentration (0.1%) of sucrose compared to wildtype males (n=6; t(10)=1.35, p=0.09; d=0.83). Tests for sensitivity to amphetamine are in progress. These data suggest a pivotal role for TRPM8 in motivated behavior.