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Differential effects of two intraventricularly injected alpha 2 agonists, ST-91 and dexmedetomidine, on electroencephalogram, feeding, and electromyogram.

Central alpha 2 agonists induce feeding in animals, electroencephalographic (EEG) synchronization, and sedation. Recent observations suggest that the investigational compound ST-91 and dexmedetomidine (DMET) may interact with distinct alpha 2 subclasses at spinal sites. We examined these drugs in brain. To accomplish these aims, ST-91, DMET, or methoxamine (METH), an alpha 1 agonist, were administered into the cerebral ventricles of unanesthetized rats prepared with chronic intracerebroventricular (ICVT) cannulae and cortical EEG electrodes. Behavior, EEG, electromyography (EMG), and feeding were assessed. We found that DMET resulted in dose-dependent (1-32 nmol) sedation, EEG synchronization, and a reduced gastrocnemeus EMG, while ST-91 (up to 153 nmol) had no effect. In contrast, ST-91 (1-153 nmol) resulted in a dose-dependent evocation of feeding, while the effects of DMET on feeding, if any, were obscured by the sedation. All effects were antagonized in a dose-dependent fashion by ICVT yohimbine (an alpha 2 antagonist). ICVT atipamezole (an alpha 2 antagonist), but not prazosin (an alpha 1 antagonist), reversed the effects of DMET. With ST-91, both atipamezole and prazosin had modest, but significant, antagonistic effects. ICVT METH had no effect. The differential physiological actions of these two intracerebroventricularly injected drugs, in concert with previous pharmacological studies, suggest two distinct subclasses of yohimbine-sensitive alpha 2 adrenergic receptors in the brain.

Adrenergic alpha-Agonists↗

Effect of intraventricular injection of transmitter substances and temperature on autonomic functions of conscious sheep.

1. Changes in cardiovascular and renal functions following injection of noradrenaline, 5-hydroxytryptamine and carbachol into one lateral cerebral ventricle were investigated in conscious sheep at ambient air temperatures of 0 and 40 degrees C. The dose rates used were known to produce predictable changes in thermoregulation in sheep. 2. The changes in body temperature, respiratory frequency and shivering caused by the intracerebroventricular (I.C.V.) injections of noradrenaline, 5-hydroxytryptamine and carbachol were as reported previously. 3. The cardiovascular and renal responses of the sheep at both high and low ambient temperatures were consistent for each transmitter indicating that these activities had no major dependence on the type of thermoregulatory response. 4. I.C.V. injection of noradrenaline increased heart rate and decreased pulse pressure but caused no change in mean arterial blood pressure (B.P.). Urine flow rate, sodium clearance, potassium clearance and osmolal clearance were decreased whereas solute-free water reabsorption was unaltered. 5. I.C.V. injection of 5-hydroxytryptamine caused no significant alterations in either cardiovascular or renal function. 6. I.C.V. injection of carbachol increased systolic and diastolic B.P., heart rate and haematocrit. Sodium, potassium and osmolal clearances were increased after administration of carbachol. 7. The changes in renal function after noradrenaline and carbachol injection could be explained by the concurrent changes in cardiovascular function.

Animals↗

Widespread gene delivery and structure-specific patterns of expression in the brain after intraventricular injections of neonatal mice with an adeno-associated virus vector.

Developing a system for widespread somatic gene transfer in the central nervous system (CNS) would be beneficial for understanding the global influence of exogenous genes on animal models. We injected an adeno-associated virus serotype 2 (AAV2) vector into the cerebral lateral ventricles at birth and mapped its distribution and transduction pattern from a promoter capable of expression in multiple targets. The injections resulted in structure-specific patterns of expression that were maintained for at least 1 year in most regions, with efficient targeting of some of the major principal neuron layers. The patterns of transduction were explained by circulation of the viral vector in the subarachnoid space via CSF flow, followed by transduction of underlying structures, rather than by progenitor cell infection and subsequent migration. This study demonstrates that gene transfer throughout the CNS can be achieved without germ line transmission and establishes an experimental strategy for introducing genes to somatic cells in a highly predictable manner.

Animals↗

Effects of intraventricular injections of gamma-aminobutyric acid and related substances on feeding behavior in satiated sheep.

Feed intake was measured following injections of gamma-aminobutyric acid (GABA), muscimol (a GABA agonist), and picrotoxin (a GABA antagonist) into the lateral ventricles of satiated sheep. Doses ranging from 0.20 to 3200 nmol of GABA did not affect feeding behavior at 15, 30, 60, and 120 min postinjection. A dose of 160 nmol of muscimol induced a marked increase in feeding, comparable to that provoked by an injection of 78 mumol of pentobarbital. Muscimol-induced feeding was blocked effectively by a preinjection of picrotoxin. These observations implicate that neurons sensitive to gamma-aminobutyric acid may be involved in the control of feeding behavior in ruminants.

Animals↗