Serotonin (5-HT) modulates numerous processes in the central nervous system that are relevant to neuropsychiatric function and dysfunction. It exerts significant effects on anxiety, mood, impulsivity, sleep, ingestive behaviors, reward systems, and psychosis. Serotonergic dysfunction has been implicated in several neuropsychiatric conditions but efforts to more clearly understand the mechanisms of this influence have been hampered by the complexity of this system at the receptor level. There are at least 14 distinct receptors that mediate the effects of 5-HT as well as several enzymes that control its synthesis and metabolism. Pharmacologic agents that target specific receptors have provided clues regarding the function of these receptors in the adult brain. 5-HT is also an important modulator of neural development and several groups have employed a genetic strategy to ablate specific components of the 5-HT system in order to understand the role of different serotonergic in development of brain systems relevant to behavior. Several inactivation mutations of specific 5-HT receptors have been generated producing interesting behavioral phenotypes related to anxiety, depression, drug abuse, psychosis, and cognition. In many cases, knockout mice have been used to confirm what has already been suspected based on pharmacologic studies. In other instances, mutations have demonstrated new functions of serotonergic genes in development and behavior.

Neural mechanisms underlying the regulation of ingestive behavior and energy balance are well conserved among mammals. Many neural pathways, each reflecting the function of many genes, interact to regulate these processes. Systematic genetic perturbations are not feasible in humans—the examination of gene functions relevant to feeding regulation must be performed in other species. Many advances in this field have been made through molecular genetic studies of mice, the most genetically tractable of mammalian species. The relevance of mouse ingestive behavior to the mechanisms underlying the regulation of feeding in humans is discussed. Approaches for evaluating the contribution of genes to the regulation of energy balance and to the actions of anorectic drugs are described in the context of studies focused on a line of mice lacking the serotonin 5-HT2C receptor subtype. These animals display reduced responsiveness to serotonergic anorexic drugs and a late-onset obesity syndrome associated with features reminiscent of common forms of human obesity. Developmental studies of energy balance uncovered a novel age-dependent physiological process that may contribute generally to the predisposition of humans and other mammals to accumulate fat stores during “middle-age.” These findings are presented to illustrate considerations in the use of mouse molecular genetic technologies to investigate genetic influences on ingestive behavior and energy balance.

Antidepressants that primarily target the reuptake of monoamines have been highly successful treatments. However, therapies with these drugs still have several drawbacks, namely severe side effects, delays in the onset of action, and a significant percentage of non-responders. Recently, non-peptidic antagonists of the neurokinin 1 receptor, or substance P antagonists, have emerged as a novel class of drugs with antidepressant efficacy that is comparable to current drugs, but a potentially reduced side effect profile. This review summarizes the pre-clinical evidence derived from pharmacological and transgenic animal studies that suggests an important role for the substance P/neurokinin 1 system in anxiety and depression. Also, potential mechanisms by which substance P antagonists may produce their therapeutic effects are discussed.

Long-term memory is believed to depend on long-lasting changes in the strength of synaptic transmission known as synaptic plasticity. Understanding the molecular mechanisms of long-term synaptic plasticity is one of the principle goals of neuroscience. Among the most powerful tools being brought to bear on this question are genetically modified mice with changes in the expression or biological activity of genes thought to contribute to these processes. This article reviews how strains of mice with alterations in the cyclic adenosine monophosphate/protein kinase A/cyclic adenosine monophosphate-response element-binding protein signaling pathway have advanced our understanding of the biological basis of learning and memory.

An 82-year-old man with treatment-resistant depression and early Alzheimer's disease was started on methylphenidate. Significant obsessive-compulsive behavior ensued but diminished over several weeks when methylphenidate was replaced by fluvoxamine. The patient had no prior psychiatric history, but he had a sister with obsessive-compulsive disorder. It appears that methylphenidate precipitated the patient's pathological behavior.