Chronic desipramine treatment rescues depression-related, social and cognitive deficits in Engrailed-2 knockout mice.

Engrailed-2 (En2) is a homeobox transcription factor that regulates neurodevelopmental processes including neuronal connectivity and elaboration of monoaminergic neurons in the ventral hindbrain. We previously reported abnormalities in brain noradrenergic concentrations in En2 null mutant mice that were accompanied by increased immobility in the forced swim test, relevant to depression. An EN2 genetic polymorphism has been associated with autism spectrum disorders, and mice with a deletion in En2 display social abnormalities and cognitive deficits that may be relevant to multiple neuropsychiatric conditions. This study evaluated the ability of chronic treatment with desipramine (DMI), a selective norepinephrine (NE) reuptake inhibitor and classical antidepressant, to reverse behavioral abnormalities in En2−/− mice. Desipramine treatment significantly reduced immobility in the tail suspension and forced swim tests, restored sociability in the three-chambered social approach task and reversed impairments in contextual fear conditioning in En2−/− mice. Our findings indicate that modulation of brain noradrenergic systems rescues the depression-related phenotype in En2−/− mice and suggest new roles for NE in the pathophysiology of the social and cognitive deficits seen in neuropsychiatric disorders such as autism or schizophrenia.

Evidence for elevated nicotine-induced structural plasticity in nucleus accumbens of adolescent rats.

Male Long-Evans rats were administered nicotine bitartrate or sodium tartrate either during adolescence (p29-43) or adulthood (p80-94). Route of administration was via subcutaneously implanted osmotic pump (initial dose 2.0 mg/kg/day, free base). Five weeks following nicotine administration, brains were processed for Golgi-Cox staining. Medium spiny neurons from nucleus accumbens (NAc) shell were digitally reconstructed for morphometric analysis. Total dendritic length and branch number were greater in medium spiny neurons from animals pretreated with nicotine during adolescence. A branch order analysis indicated that increased branch number was specific to higher order branches. Mean branch lengths did not differ with respect to treatment as a function of branch order. Thus, nicotine-induced increases in total dendritic length were a function of greater numbers of branches, not increased segment length. In contrast, adult nicotine exposure did not significantly alter total dendritic length or branch number of medium spiny neurons. Total dendritic length and branch number of a second morphological type, the large aspiny neuron, did not differ following either adolescent or adult pretreatment. The age-dependent alteration of accumbal structure was associated with qualitatively different behavioral responses to drug challenge. These data provide evidence that drug-induced structural plasticity in nucleus accumbens is considerably more pronounced during adolescence.

Pituitary hormone response to head injury.

Measurements of the serum levels of pituitary hormones were made in six patients with uncomplicated head injury. Samples were obtained at 4-hour intervals for 72 hours to evaluate diurnal rhythms. Three of the six patients revealed elevations of serum growth hormone (GH) and prolactin, but no trends could be established. Likewise, three patients had marked elevations of luteinizing hormone and lesser elevations of follicle-stimulating hormone, but no pattern was discernible. The level of thyroid-stimulating hormone was stable and remained in the normal range throughout. GH was measured after intravenous glucose loading. A paradoxical rise reverted to normal at the late follow-up evaluation. It is suggested that the abnormal levels were related to abnormal hypothalamic function rather than to pituitary damage.

Excretion and tissue distribution of radioactive lysinoalanine, N epsilon-DL-(2-amino-2-carboxyethyl)-U-14C-L-lysine (LAL) in Sprague-Dawley rats.

Rats were fed either a control soybean protein diet or a diet containing 3,000 ppm soybean protein-bound lysinoalanine (LAL) for 4 or 6 weeks, at which time all rats were dosed by stomach tube with 14C-LAL labeled in the lysine moiety. Urinary and fecal excretion and tissue distribution were followed in one experiment at 6, 12, 18, 24, 48 and 72 hours. Excretion in urine, feces and expired air was followed in the other metabolic experiment at 2-hour intervals for 48 hours, and at 24-hour intervals for the next 7 days. Tissue samples were counted and LAL determination was made by amino acid analysis in both experiments. The group of rats fed LAL excreted slightly more LAL than the group fed the control diet. Very little LAL remained in the rat tissues after either experiment, and the largest remaining quantity of radioactivity was found as lysine. Quantitation of 14C-lysine in the original material and in the material from rat organs showed that the rat has some capacity for converting LAL to lysine. Less than 0.5% of the original 14C remained in any organ examined 9 days after dosing in the either control or LAL-fed rats. Autoradiographs of the kidneys 24 hours after dosing showed that the radioactive material had accumulated in the proximal convoluted tubules of the corticomedullary junction.