Prevention of drug-induced memory impairment by immunopharmacotherapy.

One approach to treating drug abuse uses antidrug antibodies to immunize subjects against the illicit substance rather than administering therapeutics that target the specific CNS site of action. At present, passive vaccination has recognized efficacy in treating certain gross symptoms of drug misuse, namely, motor activation, self-administration, and overdose. However, the potential for antibodies to prevent drug-induced changes involving finer cognitive processes, such as benzodiazepine-associated amnesia, remains unexplored. To address this concept, a flunitrazepam hapten was synthesized and employed in the generation of a panel of high affinity monoclonal antibodies. Anti-flunitrazepam mAb RCA3A3 ( K d,app = 200 nM) was tested in a mouse model of passive immunization and subsequent mole-equivalent challenge with flunitrazepam. Not only was flunitrazepam-induced sedation prevented but immunization also conferred protection to memory consolidation as assessed through contextual and cued fear conditioning paradigms. These results provide evidence that immunopharmacotherapeutic blockade of drug intoxication also preserves complex cognitive function.

Transthyretin protects Alzheimer's mice from the behavioral and biochemical effects of Abeta toxicity.

Cells that have evolved to produce large quantities of secreted proteins to serve the integrated functions of complex multicellular organisms are equipped to compensate for protein misfolding. Hepatocytes and plasma cells have well developed chaperone and proteasome systems to ensure that secreted proteins transit the cell efficiently. The number of neurodegenerative disorders associated with protein misfolding suggests that neurons are particularly sensitive to the pathogenic effects of aggregates of misfolded molecules because those systems are less well developed in this lineage. Aggregates of the amyloidogenic (Abeta(1-42)) peptide play a major role in the pathogenesis of Alzheimer's disease (AD), although the precise mechanism is unclear. In genetic studies examining protein-protein interactions that could constitute native mechanisms of neuroprotection in vivo, overexpression of a WT human transthyretin (TTR) transgene was ameliorative in the APP23 transgenic murine model of human AD. Targeted silencing of the endogenous TTR gene accelerated the development of the neuropathologic phenotype. Intraneuronal TTR was seen in the brains of normal humans and mice and in AD patients and APP23 mice. The APP23 brains showed colocalization of extracellular TTR with Abeta in plaques. Using surface plasmon resonance we obtained in vitro evidence of direct protein-protein interaction between TTR and Abeta aggregates. These findings suggest that TTR is protective because of its capacity to bind toxic or pretoxic Abeta aggregates in both the intracellular and extracellular environment in a chaperone-like manner. The interaction may represent a unique normal host defense mechanism, enhancement of which could be therapeutically useful.

Urocortin 2-deficient mice exhibit gender-specific alterations in circadian hypothalamus-pituitary-adrenal axis and depressive-like behavior.

Gender differences in hypothalamus-pituitary-adrenal (HPA) axis activation and the prevalence of mood disorders are well documented. Urocortin 2, a recently identified member of the corticotropin-releasing factor family, is expressed in discrete neuroendocrine and stress-related nuclei of the rodent CNS. To determine the physiological role of urocortin 2, mice null for urocortin 2 were generated and HPA axis activity, ingestive, and stress-related behaviors and alterations in expression levels of CRF-related ligands and receptors were examined. Here we report that female, but not male, mice lacking urocortin 2 exhibit a significant increase in the basal daily rhythms of ACTH and corticosterone and a significant decrease in fluid intake and depressive-like behavior. The differential phenotype of urocortin 2 deficiency in female and male mice may imply a role for urocortin 2 in these gender differences.

Cortistatin overexpression in transgenic mice produces deficits in synaptic plasticity and learning.

Cortistatin-14 (CST) is a neuropeptide expressed in cortical and hippocampal interneurons that shares 11 of 14 residues with somatostatin. In contrast to somatostatin, infusion of CST decreases locomotor activity and selectively enhances slow wave sleep. Here, we show that transgenic mice that overexpress cortistatin under the control of neuron-specific enolase promoter do not express long-term potentiation in the dentate gyrus. This blockade of dentate LTP correlates with profound impairment of hippocampal-dependent spatial learning. Exogenously applied CST to slices of wild-type mice also blocked induction of LTP in the dentate gyrus. Our findings implicate cortistatin in the modulation of synaptic plasticity and cognitive function. Thus, increases in hippocampal cortistatin expression during aging could have an impact on age-related cognitive deficits.

Mice lacking 5-HT receptors show specific impairments in contextual learning.

Using 5-HT(7) receptor knockout mice it has been shown that the 5-HT(7) receptor is the main mediator of serotonin-induced hypothermia but very little is known about the relevance of 5-HT(7) receptors in behaviour. We here report that lack of 5-HT(7) receptors leads to a specific learning deficit that is not due to general sensory or behavioural deficits. The knockout mice show impaired contextual fear conditioning but no significant deficits in motor and spatial learning or cued and operant conditioning. In addition, we demonstrate that 5-HT(7) receptor knockout mice display decreased long-term synaptic plasticity within the CA1 region of the hippocampus. The results indicate an important role for the 5-HT(7) receptor in contextual hippocampal-dependent learning and suggest a possible neuronal correlate for such a role is present within the CA1 region of the hippocampus.