Co-treatment with low doses of buspirone prevents rewarding effects of methylphenidate and upregulates expression of 5-HT1A receptor mRNA in the nucleus accumbens.

Accumulating studies consistently show that methylphenidate (MPD), the first line drug for treating Attention-Deficit Hyperactivity Disorder (ADHD), is abused by patients to whom the drug is prescribed. Like other psychostimulants, only low doses of MPD improve cognitive performance while higher doses impair it. Preventing the use of high doses of MPD is important for retaining its therapeutic efficacy. Previously, it has been shown that performance in Morris water maze test is improved in rats treated, orally, with MPD in doses of 2.5 mg/kg; but higher doses (5 mg/kg) impair it. The present study is designed to monitor rewarding effects of 2.5 mg/kg MPD in conditioned place preference (CPP) paradigm and its potential inhibition in buspirone co-treated animals. Our results show that rewarding effects of MPD in CPP paradigm are prevented in rats co-treated with buspirone in doses of 0.1 and 0.3 mg/kg. Animals treated with MPD exhibit a downregulation of 5-HT1A receptor mRNA in the nucleus accumbens which is also prevented in rats co-treated with 0.1 and 0.3 mg/kg but not 1.0 and 2.0 mg/kg buspirone. Administration of buspirone in these doses is not rewarding in CPP test and upregulates 5-HT1A receptor mRNA in the nucleus accumbens. The findings suggest that co-use of low doses of buspirone can prevent rewarding effects of MPD to help retain its therapeutic efficacy.

Differential effects of memory enhancing and impairing doses of methylphenidate on serotonin metabolism and 5-HT1A, GABA, glutamate receptor expression in the rat prefrontal cortex.

Methylphenidate (MPD), a psychostimulant, is a prescription medicine for treating attention deficit hyperactivity disorder (ADHD). Previously we have shown that moderate doses of MPD enhanced learning and memory while higher doses impaired it. To understand neurochemical mechanisms and receptors involved in memory enhancing and impairing effects of MPD, the present study concerns the effects of these doses of MPD on serotonin, 5-HT1A, GABA, and NMDA receptor mRNA expression in the prefrontal cortex (PFC). We found that low doses (2.5 mg/kg) of MPD improved performance in the water-maze test but higher doses (5 mg/kg) impaired memory retention. Animals showing improved performance had high 5-HT metabolism in the PFC while these levels were not affected in the group treated with higher MPD doses and exhibiting impaired memory. There was downregulation of 5-HT1A receptors in the PFC of rats treated with higher dose MPD, which didn't occur in low dose of MPD treated animals. Further, a decrease in GABAAreceptor mRNA expression occurred in low doses of MPD treated animals and GluN2A expression was reduced in higher doses of MPD treated animals. The findings suggest that memory enhancing doses of MPD increase 5-HT and reduce GABAA receptor mRNA expression in the PFC to release excitatory glutamate neurons from the inhibitory influence of GABA. Conversely, higher dose of MPD downregulates 5-HT1A receptor mRNA expression to enhance inhibitory GABA influence on glutamate neurons and impair cognitive performance. The findings show an important role of 5-HT1A heteroreceptors in the PFC for improving therapeutic use of MPD and developing novel cognitive enhancers.

Enhancement and impairment of cognitive behaviour in Morris water maze test by methylphenidate to rats.

Methylphenidate (MPD), a psycho-stimulant is a prescription medicine for the treatment of Attention deficit hyperactivity disorder (ADHD). The drug is also being increasingly used by general population for enhancing cognition. Only few preclinical studies have been carried out on the effects of MPD on cognition and these studies show either an enhancement or impairment of memory following the administration of MPD. The present study was designed to evaluate the effects of different doses of methylphenidate on acquisition and retention of memory in Morris water-maze test. Twenty four male Albino Wistar rats (weighing 180-220gm) were randomly assigned to four groups: (1) Control (2) 0.5mg/kg (3) 2.5mg/kg (4) 5 mg/kg methylphenidate. Animals received drug or water orally before training phase. Memory acquisition was monitored 2hrs post drug administration while memory retention was determined next day. It was found that the clinically relevant doses of methylphenidate (0.5mg/kg and 2.5mg/kg) improved memory acquisition and its retention but higher dose (5mg/kg) impaired both. We suggest that MPD-induced increase of catecholamine neurotransmission may have a role in the improvement of water maze performance while agonist activity of the drug for 5HT-1A receptor in the impaired performance at high doses. Food intake and body weight changes were not affected by MPD administration due to short-term administration of the drug. Results may help in improving pharmaco-therapeutic use of MPD for ADHD.

Repeated administration of methylphenidate produces reinforcement and downregulates 5-HT-1A receptor expression in the nucleus accumbens.

AIMS: Methylphenidate (MPD) widely prescribed for the treatment of attention deficit hyperactivity disorder (ADHD), is a psychostimulant and can produce addiction in patients treated with it. In view of growing increase in the use of drug by general population as a cognitive enhancer, the present study is designed to investigate reinforcing and cognition enhancing effects of MPD in rats. Associated changes in serotonin-1A receptor expression are investigated as a potential molecular mechanism involved. METHODS: Learning acquisition and memory retention in Morris water-maze test were used to assess cognitive effects of MPD. Reinforcing effects were evaluated in conditioned place-preference (CPP) paradigm. The expression of 5-hydroxytryptamine (5-HT; serotonin)-1A receptor in the nucleus accumbens and prefrontal cortex of repeated MPD treated animals was determined by qRT-PCR. FINDINGS: Lower doses (0.5 and 2.5 mg/kg) of MPD enhanced learning acquisition and memory retention but higher doses (5 mg/kg) impaired these. The drug administered repeatedly at a dose of 2.5 mg/kg was reinforcing in CPP test, but sensitization like effects of this dose were only transient. These animals tested in water-maze test exhibited improved memory retention but no effect occurred on learning acquisition. The expression of 5-HT-1A receptor was markedly attenuated in the nucleus accumbens; attenuation in the prefrontal cortex was not significant. SIGNIFICANCE: The findings suggest that clinically relevant doses of MPD can produce drug addiction, but effects of the drug on memory retention are retained. A downregulation of 5-HT-1A receptor in the nucleus accumbens seems important in the reinforcing effects of MPD.

Neurochemical and behavioral effects of Nigella sativa and Olea europaea oil in rats.

OBJECTIVES: In the last few decades, therapeutic uses of medicinal compounds present in food as a normal constituent has risen substantially, largely because of their fewer side effects and adequate efficacy. This study is designed to investigate a role of brain serotonin (5-HT) and dopamine (DA) in the potential nootropic, anxiolytic, and other beneficial effects of Nigella sativa (NS) and Olea europaea (OE) oil in rat models. METHODS: Animals were treated with NS and OE oil orally at doses of 0.1 ml/kg and 0.25 ml/kg for 5 weeks. Food intake and body weight change, anxiety-like effects in elevated plus maze and activity in a novel and familiar environment were monitored weekly. Effects on learning and memory after 5 weeks treatment were monitored using Morris water maze test. Neurochemical analysis was carried using HPLC-ECD method. RESULTS: NS and OE oil administration enhanced learning and memory in Morris water maze test and the effects were greater in NS than OE oil-treated animals. Low dose of OE oil increased exploration in an open field, higher dose of OE oil and both doses of NS oil produced no consistent effect on open field exploration. Effects of both oils on anxiety-like behavior, food and water intake, and activity in activity box were either not consistent or did not occur. The treatment increased homovanillic acid (HVA). 5-HT levels increased in high dose of NS oil and low dose of OE oil-treated groups. Low dose NS oil decreased 5-HT. DISCUSSION: The present study suggests that active components in NS and OE oil may prove useful in treating impaired cognition. OE oil may produce psychostimulant-like effect. Modulation of DA and serotonin neurotransmission seems important in the pharmacological effect of these oils.