Faculty Bibliography

Previous findings have suggested that brain EPI has a role in behavioral activity based on the finding that inhibition of PNMT reduces motor activity. The present study was undertaken to determine if intraventricular administration of EPI can restore active behavior in PNMT-inhibited mice, and, if so, which adrenergic receptor it activates to produce this effect. Mice previously implanted with intraventricular cannulas were administered either of the two PNMT inhibitors, dichloro-alpha-methylbenzylamine (DCMB), 60 mg/kg ip or LY 134046, 60 mg/kg ip, 30 min before receiving an intraventricular infusion of EPI (31.6 or 100 nmoles/mouse) with or without one of the following adrenoceptor antagonists: terazosin (alpha-1), betaxolol (beta-1) or atipamezole (alpha-2) each at 31.6 nmoles/mouse. Vehicle treated mice were administered either distilled water i.p. or normal saline ivt. Motor activity was measured by videotaping the mice placed individually in a 'moderately' novel clean cage for 90 min after the ivt injection.)EPI at both 31.6 and 100 nmoles produced a significant reversal of the inactivity produced by both of the above PNMT inhibitors. This effect of EPI was attenuated in animals coinjected with terazosin but not with either betaxolol or atipamezole. The latter agent, in fact, enhanced the reversal induced by EPI.)The results support the hypothesis that brain EPI plays a role in the regulation of active motor behavior and does so via activation of central alpha 1-adrenoceptors

The present studies examined the relationship between the blockade of central alpha(1)-adrenoceptors, as measured by ex vivo binding of [3H]prazosin in the cerebral cortex and the inhibition of behavioral activation to a mildly novel environment (cage change). It was found that intraventricular (i.v.t.) terazosin, a saline-soluble alpha(1)-adrenoceptor antagonist, dose dependently inhibited both ex vivo cortical binding and behavioral activation and that there was a highly significant positive correlation between the two with a slope near unity. Prazosin, a nonsaline soluble antagonist which had to be given intraperitoneally (i.p.), was much less potent at blocking both behavioral activity and cortical ex vivo binding, although it blocked ex vivo binding in the lung, indicating that it was effective peripherally but did not readily enter the brain. Despite this, however, the inhibition of cortical binding and behavioral activation that i.p. prazosin did produce were highly correlated with each other and had a slope near unity as with terazosin, whereas the more potent inhibition of lung binding was less well correlated with behavioral inhibition and had a slope significantly less than one. These results confirm our earlier studies, which have shown that alpha(1)-adrenoceptor activity is essential for gross and fine motor behavior in the mouse and that prazosin, which is used extensively in behavioral research, has difficulty entering the mouse brain

Neurotransmission at brain alpha 1B-adrenoceptors has been found to be necessary for motor activity and movement in the mouse, presumably reflecting adrenergic modulation of central dopaminergic activity (Neuropharmacol. 40:254, 2001). The brain region(s) involved in this action however has not yet been fully mapped although a previous study has suggested involvement of the nucleus accumbens (Neurosci. 99:55, 2000). In the present study this was investigated by examining the effect of bilateral microinjection of the nonselective alpha 1-adrenoceptor antagonist, terazosin, on motor activation and movement. Animals (8-10 week old male Swiss Webster mice) were implanted bilaterally with 26 gauge cannula guides in a variety of brain regions and after recovery tested with terazosin (2 nmoles/site) for 10 min in a novel cage. Preliminary results indicate that injection in the nucleus accumbens reduces locomotion and causes episodes of sudden freezing. No reductions in activity have been found from the amygdala, hippocampus, or prefrontal cortex but suggestive effects have been obtained in the ventral tegmental area and locus coeruleus. Studies of thalamic and other medullary regions are currently in progess

Central alpha 1-noradrenergic neurotransmission has been shown to be an important complement of dopaminergic transmission in the control of motor activity but the identity of the responsible alpha 1 receptor subtype has not yet been identified. This was investigated in the present experiment by measuring the effects of intraventricular administration of a series of alpha 1 antagonists varying in affinities for the three known receptor subtypes--1a, 1b and 1d--on active behavior in mice in response to a cage change. It was found that the potency of the drugs to block both gross and small movements correlated highly with published affinities for the cloned 1b receptor but not for those of either the cloned 1a or 1d receptors. It is concluded that central alpha 1B receptors are critically involved in the mediation of the (nor)adrenergic influence on active behavior, a finding which has implications for basic and clinical research in both movement and mood disorders

Central alpha 1-noradrenergic neurotransmission is known to synergize with dopaminergic transmission in the control of movement and active behavior however the responsible alpha 1 receptor subtype has not been identified. We previously reported a high correlation between the affinity of alpha 1 antagonists for the alpha 1B receptor and their ability to block exploration of a novel cage in mice after intraventricular injection (Abstr Soc Neurosci 25:244.5,1999). This study however was problematic in that the vehicle used for the lipophilic antagonists (water/dmso) affected the behavior by itself. We have therefore repeated the experiment using only hydrophilic or near hydrophilic antagonists in a saline vehicle. Mice, previously implanted with intraventricular cannulas, were infused various doses (0.1-300 nmoles) of one of six antagonists: terazosin, benoxathian, 5-methylurapidil, BMY7378, phentolamine and WB4101 in 2 ul saline shortly before being placed in a novel mouse cage in which they were videotaped for 30 min. Activity was measured as total forward movements (gross) and total head movements (small). A significant positive correlation was found between known affinities for the cloned alpha 1b receptor and ID50s for inhibition of both forward (r = 0.93, p < 0.01) and head movements (0.92, p = 0.01). No significant correlations were obtained for the alpha 1A and 1D receptors (0.3-0.4). The present results thus confirm our previous finding that alpha 1B adrenergic receptor actvity is necessary for motor activity and spontaneous movement to environmental stimulation in the mouse