Anxiety and panic: from human studies to animal research and back.

The role of learning and conditioning varies across human anxiety disorders, and distinguishing between fear and panic is important to guide investigation in panic disorder. By reminding that some psychological and psychobiological theories view panic attacks as false alarms of unconditioned biological origin, we suggest that employing endophenotypes of biological and evolutionary relevance--such as the respiratory responses to suffocative stimuli--can be fruitful for both human research and animal models of panic, and can help keeping unconditioned components of the clinical picture separate from the conditioned components in the experimental setting. We present a review of a model of panic disorder by which idiosyncratic environmental adverse events can promote unconditioned and unexpected spells of physical alarm. Along the proposed causal pathway the alternative splicing expression of polymorphic genes of the cholinergic system play an important role. The overproduction of the Acetylcholinesterase readthrough splice variant after minor stress can promote passive avoidance and learning through action at the level of the corticolimbic circuitries, as well as heightened sensitivity to suffocative stimuli by action upon the cholinergic components of chemoception. When a component of anticipatory anxiety complicates the clinical picture of recurrent panic attacks, and the HPA becomes activated, the glucocorticoid response element 17 kb upstream of the Acetylcholinesterase gene transcription initiation site may sustain sensitivity to suffocative stimuli for prolonged time. Finally, we review how animal models of human panic based on unconditioned provocation of alarm reactions by the same respiratory panicogens that are employed in man are viable and promising.