Esa Meririnne

The Acute Effects of Amphetamine Derivatives on Extracellular Serotonin and Dopamine Levels in Rat Nucleus Accumbens

The acute effects of amphetamine derivatives on extracellular concentration of serotonin (5-HT) and dopamine in the nucleus accumbens were studied with in vivo microdialysis using conscious, freely moving rats. 5-HT, dopamine, and their major metabolites were measured by HPLC with electrochemical detection. Amphetamine (1.0-9.0 mg/kg) elevated dopamine levels considerably, but failed to affect the levels of 5-HT, except at the highest dose administered. 3,4-Methylenedioxyamphetamine (MDA, 1.0-9.0 mg/kg) and 3,4-methylenedioxymethamphetamine (MDMA, 1.0-9.0 mg/kg) elevated both 5-HT and dopamine levels dose dependently. The failure of 2,5-dimethoxy-4-methylamphetamine (DOM, 0.5-1.0 mg/kg) to affect the 5-HT levels suggests that extracellular levels of 5-HT play a minor role in hallucinogenic activity. The strong effects of MDA and MDMA on levels of 5-HT indicate that their actions on serotonergic mechanisms are different from those of the hallucinogens. In addition, methylenedioxyamphetamines may act via dopaminergic mechanisms similar to those of amphetamine.

The effects of diazepam and zolpidem on cocaine- and amphetamine-induced place preference.

Drugs such as benzodiazepines, which enhance the effects of inhibitory neurotransmitter gamma-amino butyric acid (GABA), are known to modulate the mesocorticolimbic dopaminergic system, which is considered to mediate the rewarding effects of psychostimulants. The effects of diazepam, a benzodiazepine that binds unspecifically to omega 1- (omega1-) and omega2-receptors, and zolpidem, a nonbenzodiazepine drug that binds preferentially to omega1-receptors, on cocaine- and amphetamine-induced place preference were evaluated in Wistar rats. In tests using the counterbalanced method, neither diazepam (0.2, 1, and 5 mg/kg) nor zolpidem (2.5, 5, and 10 mg/kg) alone induced place preference or place aversion. Diazepam pretreatment prevented both cocaine- and amphetamine-induced (15 and 9 mg/kg, respectively) place preference; however, at doses that were earlier shown to cause sedation and amnesia, zolpidem failed to prevent either cocaine- or amphetamine-induced place preference. These results suggest that diazepam interferes with the rewarding properties of the psychostimulants, whereas zolpidem is less effective in this respect, possibly due to differential distribution of omega1- and omega2-receptors in the brain.

Oxalic acid stabilizes dopamine, serotonin, and their metabolites in automated liquid chromatography with electrochemical detection

Use of antioxidative agents is required in automated LC assay of microdialysis samples, due to rapid degradation of the monoamine neurotransmitters and their metabolites. Addition of oxalic acid prevented degradation of dopamine, serotonin, 3,4-dihydroxyphenylacetic acid, homovanillic acid and 5-hydroxyindoleacetic acid efficiently: after a 24-h incubation at room temperature the decreases in peak heights were less than 10%. The long-term stability of the analytes, however, was still enhanced when acetic acid and L-cysteine were included in the solution. Using this antioxidative solution, the monoamine neurotransmitters and their metabolites could be determined with an automated LC assay even at room temperature.

Brief Report: Excessive alcohol use negatively affects the course of adolescent depression: one year naturalistic follow-up study

The impact of alcohol use on the course of adolescent depression over one-year was investigated by following 197 consecutive adolescent outpatients with unipolar depression in a naturalistic treatment setting. Their baseline alcohol consumption was categorized in three groups: excessive use (defined as weekly drunkenness), regular use (monthly use, not weekly drunkenness), and no/occasional use (abstinence/less than monthly use). During the monthly BDI follow-up, the excessive users achieved remission less frequently, and after one year, had poorer psychosocial functioning than the no/occasional users. In conclusion, excessive alcohol use negatively affects the course of adolescent depression and psychosocial functioning. Weekly drunkenness seems to be of predictive value and this can be examined with a few simple questions. Means of reducing alcohol consumption among depressed adolescents are worth further investigations.

Rewarding properties of the stereoisomers of 4-methylaminorex: Involvement of the dopamine system

4-Methylaminorex is a potential psychostimulant drug of abuse that exists as four stereoisomers: cis-4R,5S, cis-4S,5R, trans-4S,5S, and trans-4R,5R. The racemic mixture of the cis-isomers has been encountered in illicit samples, but previous animal studies suggest that also the trans-isomers could have similar stimulant-like properties. We tested whether the stereoisomers possess rewarding properties and compared their potency using the conditioned place preference method in rats. Furthermore, the involvement of the brain dopaminergic system in the 4-methylaminorex reward was tested with the dopamine D1- and D2-receptor antagonists SCH 23390 and raclopride administered systemically, or with the neurotoxin 6-hydroxydopamine injected into the nucleus accumbens. All the four isomers induced place preference, with no apparent differences in their potency. SCH 23990 and raclopride attenuated 4-methylaminorex-induced increase in place preference, and 6-hydroxydopamine also tended to be efficacious. These findings indicate that all the four stereoisomers of 4-methylaminorex possess rewarding properties and thus abuse potential; the trans-isomers are at least as potent as the cis-isomers. Furthermore, the brain dopaminergic system appears to be involved in the 4-methylaminorex-reward.

The effects of quinine and 4-aminopyridine on conditioned place preference and changes in motor activity induced by morphine in rats

1. The effects of two unselective potassium (K(+)-) channel blockers, quinine (12.5, 25 and 50 mg/kg) and 4-aminopyridine (1 and 2 mg/kg), on conditioned place preference and biphasic changes in motor activity induced by morphine (10 mg/kg) were tested in Wistar rats. Quinine is known to block voltage-, calcium- and ATP-sensitive K(+)-channels while 4-aminopyridine is known to block voltage-sensitive K(+)-channels. 2. In the counterbalanced method, quinine attenuated morphine-induced place preference, whereas 4-aminopyridine was ineffective. In the motor activity test measured with an Animex-activity meter neither of the K(+)-channel blockers affected morphine-induced hypoactivity, but both K(+)-channel blockers prevented morphine-induced secondary hyperactivity. 3. These results suggest the involvement of quinine-sensitive but not 4-aminopyridine-sensitive K(+)-channels in morphine reward. It is also suggested that the blockade of K(+)-channels sensitive to these blockers is not sufficient to prevent morphine-induced hypoactivity whereas morphine-induced hyperactivity seems to be connected to both quinine- and 4-aminopyridine-sensitive K(+)-channels.