OCD-like behaviors caused by a neuropotentiating transgene targeted to cortical and limbic D1+neurons

To study the behavioral role of neurons containing the D1 dopamine receptor (D1+), we have used a genetic neurostimulatory approach. We generated tran sgenic mice that express an intracellular form of cholera toxin (CT), a neu ropotentiating enzyme that chronically activates stimulatory G-protein (G(s )) signal transduction and cAMP synthesis, under the control of the D1 prom oter. Because the D1 promoter, like other CNS-expressed promoters, confers transgene expression that is regionally restricted to different D1+ CNS sub sets in different transgenic lines, we observed distinct but related psycho motor disorders in different D1CT-expressing founders. In a D1CT line in wh ich transgene expression was restricted to the following D1+ CNS regions-th e piriform cortex layer II, layers II-III of somatosensory cortical areas, and the intercalated nucleus of the amygdala-D1CT mice showed normal CNS an d D1+ neural architecture but increased cAMP content in whole extracts of t he piriform and somatosensory cortex. These mice also exhibited a constella tion of compulsive behavioral abnormalities that strongly resembled human c ortical-limbic-induced compulsive disorders such as obsessive-compulsive di sorder (OCD). These compulsive behaviors included episodes of perseverance or repetition of any and all normal behaviors, repetitive nonaggressive bit ing of siblings during grooming, and repetitive leaping. These results sugg est that chronic potentiation of cortical and limbic D1+ neurons thought to induce glutamatergic output to the striatum causes behaviors reminiscent o f those in human cortical-limbic-induced compulsive disorders.