Ram K. Mishra

Chemical lesion and drug induced supersentivity and subsensitivity of caudate dopamine receptors

In order to elucidate the mechanism of denervation supersensitivity, the effects of 6-hydroxydopamine lesion, placed in the substantia nigra, were examined on rat brain caudate adenylate cyclase and 3H-haloperidol binding to membrane dopamine receptors. In addition, the effects of chronic administration of L-DOPA, bromocriptine and piribedil were also investigated on 3H-haloperidol binding and dopamine, K+ isoproterenol (IPNE) and 2-Cl-adenosine stimulated formation of cyclic AMP in caudate slices. 6-Hydroxydopamine lesions resulted in significantly greater stimulation of adenylate cyclase by dopamine at various concentrations tested. The haloperidol binding sites were increased by 28% on lesioned side caudate without changes in dissociation constants (KD). Three weeks after treatment with L-DOPA, bromocriptine or piribedil, the 3H-haloperidol binding sites were decreased by 40% with no change in KD. The stimulatory effect of dopamine on cyclic AMP formation was also abolished, although there was no change in IPNE, K+, or 2-Cl-adenosine stimulated cyclic AMP formation in caudate slices, suggesting a specific effect of dopamine agonists on dopamine receptors. The results of these studies suggest a close relationship between at least some populations of dopamine receptors and adenylate cyclase in the caudate nucleus.

Effect of L-prolyl-L-leucyl-glycinamide (PLG) on neuroleptic-induced catalepsy and dopamine/neuroleptic receptor bindings

The mechanism of action subserving the potential anti-Parkinsonian properties of L-prolyl-L-leucyl-glycinamide (PLG) was investigated in behavioural and neurochemical models of dopaminergic function in the rat. Acute administration of PLG (20 and 40 mg kg-1 SC) failed to alter appreciably the intensity of the cataleptic response elicited by haloperidol (3 mg kg-1 IP). By contrast, chronic PLG treatment (20, 40 and 80 mg kg-1 SC twice daily for five days) significantly attenuated haloperidol-induced catalepsy. The effect of PLG on in vitro dopamine/neuroleptic receptor binding in rat striatum as differentially labelled by apomorphine and spiroperidol was also examined. PLG selectively enhanced the affinity of the specific binding of agonist [3H] apomorphine to dopamine receptors in the striatum, but had no effect on [3H] spiroperidol binding. The behavioural and biochemical results obtained in the present study raise the possibility that PLG may facilitate nigro-striatal dopaminergic neurotransmission through interacting with a unique PLG receptor functionally coupled to the dopamine receptor-adenylate cyclase complex.

High- and low-affinity states of dopamine D1 receptors in schizophrenia

Using SKF-38393/[3H]SCH-23390 dopamine D1 receptor agonist/antagonist competition binding technique, we showed that schizophrenics distinguished from the neuro-psychiatric and normal controls by exhibiting a significant increase in the density of the low-affinity state, and a concomitant enhancement in the binding affinity of the high-affinity state of D1 dopamine receptors in caudate nucleus. The results suggest that perturbation in dynamic equilibrium of high- and low-affinity states of D1 receptors underlies the pathogenesis of schizophrenia.

Effects of dopaminergic and cholinergic drugs, naloxone and l-prolyl-leucyl-glycinamide on LSD-induced catalepsy

SummaryIn an attempt to elucidate the mechanism of d-lysergic acid diethylamide (LSD) induced catalepsy, the effects of cholinergic and dopaminergic agents, naloxone and l-propyl-leucyl-glycinamide (PLG) were studied in rats. The dose-dependent (50–500 μg kg−1 s.c.) and time-related cataleptic response elecited by LSD was preceded by a phase of hyperexcitability. The non-hallucinogenic analogue, 2-bromo-LSD (BOL), was without effect. Both apomorphine, the dopamine agonist, and l-DOPA antagonized LSD-induced catalepsy whereas the dopamine depleting agent α-methyl-p-tyrosine (α-MPT) slightly prolonged the cataleptic effect. Cholinergic muscarinic receptor stimulation with pilocarpine antagonized LSD-induced catalepsy. The muscarinic antagonists, atropine and scopolamine, intensified the hyperexcitable phase and potentiated the cataleptic effects of LSD. Nicotine slightly potentiated LSD action but mecamylamine antagonized it. While pre-treatment with naloxone, the narcotic antagonist and PLG prolonged the cataleptic response, post-treatment with naloxone effectively attenuated LSD-induced catalepsy. The behavioural data are interpreted to suggest that LSD-induced catalepsy may be mediated through diminished dopaminergic and cholinergic neuronal activity and under enkephalinergic modulation. The neuroanatomical foci and exact mechanism of action remain to be delineated.

Inverse agonist binding of peripheral benzodiazepine receptors in anxiety disorder

Abstract The binding characteristics of the pBR (peripheral benzodiazepine receptor) inverse agonist, [3H]-Ro 5-4864, were examined in patients diagnosed as generalized anxiety disorder. As compared to normal healthy controls, the anxious subjects demonstrated a statistically significant (p < 0.001) increase in the density of pBR in platelets. The enhanced pBR binding correlated significantly with the severity of global anxiety symptom of the Hamilton Anxiety Rating Scale (HAR-S, p < 0.001). The Psychic component, but not the Somatic component, of the HAR-S, correlated significantly (p < 0.001) with the enhanced pBR binding in platelets. The results provide evidence for the hypothesis of dysregulation of peripheral benzodiazepine receptors in generalized anxiety disorder.

3H-Haloperidol binding: some theoretical aspects.

Abstract Evidence is provided to indicate that non-specific binding may in some cases be overlooked due to the non-saturating nature of this type of binding. Some of the theoretical aspects of competition for receptor binding sites are examined.