S. Robert Snodgrass

Effect ofP-chloroamphetamine and 5,7-dihydroxytryptamine on rotation and dopamine turnover

Injections of p-chloroamphetamine (PCA) or 5,7-dihydroxytryptamine (DHT) (after pretreatment with desmethylimipramine) into the median raphe nucleus (MRN) caused depletions of 5-HT and 5-HIAA in the cortex and striatum, and a decrease of cortical 5-HT uptake without affecting NE uptake. Unilateral injections of these neurotoxins into the MRN caused contralateral rotation, which was blocked by haloperidol. The size of the lesion correlated with the rate of rotation and the decrease in 5-HT turnover in the cortex. We also found a significant correlation between the rate of rotation and the decrease in cortical 5-HT turnover, and the increase in striatal DA turnover. Moreover, there was a significant correlation between the decrease in cortical 5-HT turnover and the increase in striatal DA turnover. It was found that injections of DHT into the SN produced similar behavioral and biochemical changes as did the MRN lesions. In this model, amphetamine and apomorphine produce turning in the same direction, whereas they have opposite effects after lesions of the nigrostriatal pathway where postsynaptic DA supersensitivity occurs. Presynaptic changes appear to determine turning in this model. An inhibitory role of the serotonergic MRN on the dopaminergic nigrostriatal pathway mediated via the substantia nigra (SN) is suggested.

Effects of substantia nigra lesions on forebrain 2-deoxyglucose retention in the rat

A method was developed for the measurement of regional 2-deoxyglucose (2-DG) retention in rat brain by injecting tracer quantities of tritated 2-DG intravenously, dissecting out individual brain regions, making extracts of the tissue, and counting aliquots of the extracts. This technique permits the separation of unreacted 2-DG from 2-deoxyglucose-6-phosphate (2-DGP) by ion exchange chromatography as well as the performance of other biochemical measurements on the extracts. Using this method, the effect of unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra on 2-DG retention and 2-DGP formation by the striatum and the cerebral cortex was investigated. Animals were studied both 3 days and 2--4 weeks after lesioning. The location and efficacy of the lesions were verified histologically, behaviorally (by observing rotational behavior), and biochemically (by assay of striatal dopamine concentration or tyrosine hydroxylase activity). The lesions induced a mean asymmetry of less than 10% in 2-DG retention and in 2-DGP formation in striatum and cerebral cortex. This result was verified by [14C]2-DG autoradiography. Systemic administration of amphetamine (5 mg/kg) or apomorphine HBr (1.5 mg/kg) elicited rotational behavior, but did not induce a marked asymmetry of 2-DG retention in the regions studied. It is concluded that unilateral lesions of the nigrostriatal dopaminergic pathway have, at most, a modest effect on 2-DG retention by forebrain structures. We also conclude that vehicle injections may produce morphological and chemical evidence of brain injury, including small but reproducible changes in deoxyglucose retention.

Studies on GABA and protein synthesis

Abstract The effect of γ-aminobutyric acid (GABA) on protein synthesisin vitro by slices and homogenates of guinea pig brain was studied. GABA was shown to significantly increase the incorporation of l -[1-14C]leucine, alanine, and phenylalanine into protein by slices and homogenates of cortex and forebrain. The stimulatory effect of GABA upon protein synthesis was greater in slices than homogenates, and could not be demonstrated in cerebellar slices or homogenates. GABA stimulation of protein synthesis was demonstrable only when additional non-radioactive amino acids were present in the incubation medium. Tissue which had been exposed to GABA during incubation showed a greater percentage of heavy polysomes, as judge by ultra-violet absorption, than did tissue from control flasks. GABA did not change the incorporation of phenylalanine into polyphenylalanine in response to polyuridylic acid. l -Noradrenaline was shown to stimulate the incorporation of l -[1-14C]leucine into protein, and this increase could be blocked by dichloroisoproterenol.

The pharmacology of amblyopia.

Physiologic and anatomic evidence has suggested an anatomic disconnection between the deprived eye and visual cortical neurons in cats made amblyopic by monocular deprivation. Clinical and visual-evoked response data suggest, however, that inhibition may play a major role in amblyopia. Accordingly, we intravenously administered anti-inhibitory compounds (bicuculline, ammonium ion, naloxone) to amblyopic cats and demonstrated a substantial restoration of binocular input to the visual cortex. Such pharmacologic reversal suggests that amblyopia is not an anatomically fixed lesion.

Comparative pharmacological effects on visual cortical neurons in monocularly deprived cats

Monocularly deprived (MD) cats show a loss of responsiveness to visual stimulation of the deprived eye among visual cortical neurons. Several lines of evidence suggest that this effect involves, at least in part, a suppression of deprived eye input, possibly mediated by GABA inhibition. In order to better understand the nature of this suppression we have evaluated the effectiveness of different types of disinhibitory and excitatory agents to reverse the effects of MD. We investigated bicuculline (a GABA antagonist); picrotoxin (a GABA antagonist with a different mechanism of action from bicuculline); strychnine (a glycine antagonist); ammonium ion (a blocker of membrane chloride channels); physostigmine (a cholinesterase inhibitor); and naloxone (an opiate antagonist and also a GABA antagonist). All drugs were given intravenously. Bicuculline restored binocularity to 50% of the visual cortical neurons tested and naloxone to 36%. With both drugs, receptive fields of the normal eye tended to lose specificity. The emergent deprived eye receptive fields were usually similar to those of the normal eye after drug administration. Ammonium ion produced binocular responses in 27% of neurons tested, but receptive fields were grossly abnormal; moreover, ammonium infusion tended to depress neuronal responsiveness. All other drugs tested failed to restore binocularity. These experiments lend further credence to the hypothesis that GABA inhibition contributes to the cortical effects of MD, since only drugs with GABA antagonistic action were effective in restoring neuronal responsiveness to the deprived eye.

TRANSYNAPTIC REGULATION OF DOPAMINE SYNTHESIS AFTER RAPHE AND STRIATAL LESIONS

Chemical lesions of serotonergic pathways or kainic acid lesions of the striatum induce rotational behavior and changes in the kinetic properties of striatal tyrosine hydroxylase. The behavioral and chemical effects of striatal kainic acid lesions depend upon where the striatal injection is placed.