Ghanshyam N. Pandey

Pharmacological effects of methylphenidate on plasma homovanillic acid and growth hormone

The acute pharmacological actions of methylphenidate, a potent psychotogenic stimulant, were studied by measuring plasma homovanillic acid (HVA) and serum growth hormone (GH) as indices of presynaptic and postsynaptic functions, respectively. Twenty psychiatric inpatients participated in a double-blind, placebo-randomized study of methylphenidate infusion. Multiple samples of plasma HVA and GH were measured before and up to 24 hours after both methylphenidate and placebo infusions. There was a robust and significant GH response during the 2-hour postmethylphenidate period when compared to placebo. The peak response was significantly greater in male patients than in female patients. Although there were no changes in plasma HVA during the 2 hours following the infusion, there was a significant decrease in HVA 24 hours after methylphenidate as compared to preinfusion baseline values. Plasma HVA values also tended to be lower 24 hours after methylphenidate when compared to the corresponding postplacebo value. Schizophrenic patients did not differ significantly from nonschizophrenic patients in their physiological or biochemical responses.

Modulation of 5-HT1C receptors and phosphoinositide system by ethanol consumption in rat brain and choroid plexus

The effect of chronic ethanol consumption (60 days) on 5-HT1C receptors as measured by [3H]mesulergine binding in the hippocampus, cortex, and choroid plexus of rats was investigated. The 5-HT1C receptor-mediated phosphoinositide hydrolysis in rat choroid plexus was also investigated. It was observed that chronic ethanol treatment significantly increased the 5-HT-stimulated [3H]inositol 1-phosphate ([3H]IP1) formation, as well as the density (Bmax) of 5-HT1C receptors without causing a significant change in affinity (KD) of [3H]mesulergine binding in rat choroid plexus. It was also observed that chronic ethanol consumption had no significant effect on the Bmax or KD of 5-HT1C receptor binding sites in the hippocampus and cortex brain regions of rats. These results thus suggest that chronic ethanol consumption causes an up-regulation of both 5-HT1C receptors and 5-HT1C receptor-mediated phosphoinositide hydrolysis in rat choroid plexus but has no significant effects on the 5-HT1C receptors in brain. These results also suggest that 5-HT1C receptors and their functional response may be involved in the pathogenesis of alcohol dependence.

Treatment with antidepressants and histamine receptor mediated 3H-cyclic AMP formation in guinea pig cortex

It has been recently reported that most of the antidepressant drugs block histamine H1 and H2 receptors in the brain under in vitro conditions and it has been suggested that this may be related in part to their therapeutic effect. Since the in vitro and in vivo effects of these drugs may differ, we studied the effect of treatment with antidepressant drugs on histamine receptor sensitivity in the guinea pig brain and observed that chronic treatment with tricyclic antidepressants or phenelzine (an MAO inhibitor) causes a reduction in histamine receptor sensitivity. This reduction is probably mediated through two different mechanisms, since only tricyclic antidepressants cause a reduction after acute treatment. Although some of the side effects of antidepressant treatment may be related to the blockade of histamine receptors, these results do not support the assumption that this effect of antidepressant treatment contributes to their clinical effects.

Glutamatergic Neurotransmission Abnormalities and Schizophrenia

Schizophrenia affects approximately 1% of the adult population worldwide and requires lifelong therapy. Hyperfunction of the dopaminergic system has long been hypothesized as the underlying cause of schizophrenia. However, this hypothesis explains mostly the positive symptoms associated with schizophrenia. Several lines of evidence point to the glutamatergic system and suggest that abnormalities in this system may play a crucial role in the pathophysiological features of schizophrenia. Most prominently, N-methyl-d-aspartate receptor hypofunction has been associated with the positive, negative, and cognitive symptoms of schizophrenia. In this chapter, we describe the evidence showing that N-methyl-d-aspartate receptor hypofunction may be crucial in the pathophysiological features of this disorder. Although a plethora of evidence is available from preclinical studies, this chapter is focused mainly on the findings from patients with schizophrenia. In addition to N-methyl-d-aspartate receptors, we also describe the findings of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate/kainate receptors and glutamate transporters in patients with schizophrenia. Overall, these findings suggest that therapeutic agents directed toward glutamatergic systems may be helpful in the treatment of positive and negative symptoms and cognitive deficits associated with schizophrenia.