Moacyr Luiz Aizenstein

Comparative biochemical and behavioural effects of fencamfamine and dl-amphetamine in rats.

Fencamfamine increased locomotion, rearing and sniffing behaviours at 10 mg/kg intraperitoneal doses in rats. Amphetamine increased rearing, sniffing and locomotion behaviours at respectively higher, same and lesser magnitudes than did fencamfamine at equimolar (5 mg/kg) intraperitoneal doses in rats. Forty-five minutes after fencamfamine (10 mg/kg), the levels of homovanillic acid in the tuberculum olfactorium, nucleus accumbens and striatum, and those of dihydroxyphenylacétic acid in accumbens were increased. Dihydroxyphenylacétic levels in tuberculum olfactorium and striatum were not changed. Forty-five minutes after amphetamine (5 mg/kg) the levels of homovanillic acid in tuberculum olfactorium, accumbens and striatum, and those of dihydroxyphenylacétic in accumbens were not changed; dihydroxyphenilacétic levels in tuberculum olfactorium and striatum were decreased. Fencamfamine-induced behavioural changes can be better correlated with neurochemical changes than those elicited by amphetamine.

Reinforcing properties of fencamfamine: involvement of dopamine and opioid receptors.

Fencamfamine (FCF) is a psychostimulant classified as an indirect dopamine agonist. The conditioning place preference (CPP) paradigm was used to investigate the reinforcing properties of FCF. After initial preferences had been determined, animals were conditioned with FCF (1.75, 3.5, or 7.0 mg/kg; IP). Only at the dose of 3.5 mg/kg FCF produced a significant place preference. Pretreatment with SCH23390 (0.05 mg/kg; SC) or naloxone (1.0 mg/kg; SC) 10 min before FCF (3.5 mg/kg, IP) blocked both FCF-induced hyperactivity and CPP. Pretreatment with metoclopramide (10.0 mg/kg; IP) or pimozide (1.0 mg/kg, IP), respectively, 30 min or 4 h before FCF (3.5 mg/kg; IP), which blocked the FCF-induced locomotor activity, failed to influence place conditioning produced by FCF. In conclusion, the present study suggests that dopamine D1 and opioid receptors are related to FCF reinforcing effect, while dopamine D2 subtype receptor was ineffective in modifying FCF-induced CPP.

Chronic imipramine administration reduces apomorphine inhibitory effects.

Changes in activity of dopaminergic and serotonergic systems were assessed after acute and chronic (14 days) imipramine (10 mg/kg) administration in mice. For this purpose, biochemical and behavioural tests were performed at different intervals of time after withdrawal of treatment. Brain levels of 5-hydroxytryptamine, 5-hydroxyindoleacetic acid, homovanillic acid and 3,4-dihydroxyphenylacetic acid were assayed by a fluorometric method. Locomotion and stationary behaviour were investigated in the open-field test. The results of the experiments suggest that chronic imipramine reduces the inhibitory effects of apomorphine upon the dopaminergic system.

Repeated exposure of adolescent rats to oral methylphenidate does not induce behavioral sensitization or cross-sensitization to nicotine

Several lines of evidence indicate that the use of stimulant drugs, including methylphenidate (MPD), increases tobacco smoking. This has raised concerns that MPD use during adolescence could facilitate nicotine abuse. Preclinical studies have shown that repeated treatment with an addictive drug produces sensitization to that drug and usually cross-sensitization to other drugs. Behavioral sensitization has been implicated in the development of drug addiction. We examined whether repeated oral MPD administration during adolescence could induce behavioral sensitization to MPD and long-lasting cross-sensitization to nicotine. Adolescent male Wistar rats were treated orally with 10 mg/kg MPD or saline (SAL) from postnatal day (PND) 27 to 33. To evaluate behavioral sensitization to MPD in adolescent rats (PND 39), the SAL pretreated group was subdivided into two groups that received intragastric SAL (1.0 mL/kg) or MPD (10 mg/kg); MPD pretreated rats received MPD (10 mg/kg). Cross-sensitization was evaluated on PND 39 or PND 70 (adulthood). To this end, SAL- and MPD-pretreated groups received subcutaneous injections of SAL (1.0 mL/kg) or nicotine (0.4 mg/kg). All groups had 8 animals. Immediately after injections, locomotor activity was determined. The locomotor response to MPD challenge of MPD-pretreated rats was not significantly different from that of the SAL-pretreated group. Moreover, the locomotor response of MPD-pretreated rats to nicotine challenge was not significantly different from that of the SAL-pretreated group. This lack of sensitization and cross-sensitization suggests that MPD treatment during adolescence does not induce short- or long-term neuroadaptation in rats that could increase sensitivity to MPD or nicotine.

Long-term effects of imipramine on striatal dopamine autoreceptor function: Involvement of both noradrenergic and serotonergic systems

1. The effects of apomorphine (APO) administration on DA system activity were assessed by measuring dopamine metabolite levels (HVA) in several circumstances. 2. Pretreatment with IMI reduced the effect of APO on HVA levels. 3. Pretreatments with either IDE or DMI did not reduce the effect of APO on HVA levels. 4. Reductions of either NE and 5-HT levels after DSP4 and pCPA restored the effect of APO after IMI pretreatment.

Behavioral and Neurochemical Effects of Fencamfamine on Rats: A Chronobiologic Approach

Fencamfamine (FCF) is a psychostimulant classified as an indirect dopaminergic agonist. Circadian rhythms of some behavioral and neurochemical parameters were investigated in control rats and in rats which had been treated with a single dose of FCF across the 24-hr span. Rats were entrained to light/dark (LD) 12:12, lights on from 0700 to 1900. In behavioral experiments (performed in March) the rats were injected intraperitoneally with saline or FCF (3.5 mg/kg) at one of six times: 0900, 1300, 1700, 2100, 0100 or 0500. Fifteen minutes after treatment the duration of sniffing, rearing and locomotion was recorded during 120 min. Controls showed circadian rhythms for sniffing and rearing with acrophases at 2255 and 0118, respectively. In animals treated with FCF, only locomotion displayed significant circadian variation with acrophase at 1912. Two-way analysis of variance (ANOVA) showed a statistically significant circadian time-dependent effect of FCF on all behavioral parameters studied; the increase of sniffing, rearing and locomotion induced by FCF was higher in rats treated during the rest phase. In the biochemical studies (performed between March-June), rats were treated (i.p.) with saline or FCF (10 mg/kg) at one of four times: 0900, 1700, 2100 or 0100. The levels of homovanillic acid (HVA) in the striatum and tuberculum olfactorium, 5-hydroxyindolacetic acid (5-HIAA) in the cerebellum and 3-methoxy-4-hydroxypheniglycol (MHPG) in the frontal cortex were determined. Controls showed circadian rhythms for HVA (striatum), MHPG (frontal cortex) and 5-HIAA (cerebellum) with acrophases at 2233, 1955 and 1029, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Striatal dopamine receptor sensitivity after subchronic fencamfamine in the rat

Dopamine (DA) receptor sensitivity was assessed in the rat striatal system following subchronic treatment with fencamfamine or saline for 7 days (10 mg/kg i.p.). Seventy-two hours after the last injection the stereotyped behaviour and general activity induced by apomorphine or saline were evaluated. Apomorphine (2.0 mg/kg s.c.) induced a decrease of the stereotypic response when fencamfamine-pretreated animals were compared to saline-treated ones while apomorphine (0.02 mg/kg s.c.) failed to alter the general activity of animals, treated with fencamfamine or not. In biochemical experiments subchronic fencamfamine did not alter the effects of apomorphine (0.02 mg/kg s.c.) in reducing homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) striatal levels, when compared to saline. In addition we observed a slight but significant reduction in the total dopamine receptor content in the striatum labelled by [3H]spiroperidol. These findings indicate that subchronic fencamfamine treatment leads to a desensitization of postsynaptic DA receptors in rat striatum.

Repeated administration intensifies the reinforcing effect of fencamfamine in rats

1. In the present study, we evaluated the role of repeated administration on conditioning place preference (CPP) induced by fencamfamine (FCF) in male rats. 2. Repeated FCF (3.5 mg/kg) or saline once or daily for ten consecutive days enhanced sniffing duration and decreased locomotion and rearing duration. 3. At the 3.5 mg/kg dose, FCF produced a significant place-preference effect. 4. Repeated exposures to FCF intensified its reinforcing properties. 5. These results suggest that repeated FCF administration sensitizes its rewarding effects, as with other addictive substances.

The effects of chronic treatment with fencamfamine on body weight, food intake and stereotyped behaviour in rats

The effects of chronic treatment with fencamfamine (10.0 mg/kg, i.p.) or saline were studied in rats. Chronic fencamfamine treatment reduced body weight of rats below their normal body weight. Thereafter, weight increased, in parallel to that of control rats. There was an increasing trend in food intake in both groups and a reduction was observed in food intake on the first seven days of fencamfamine-treated rats. Fencamfamine repeated administration enhanced stereotyped sniffing while rearing behaviour gradually declined until 25 days. However, the same treatment did not interfere with the intensity of stereotypy. These findings suggest the need for a re-evaluation of current concept in the tolerance to the effects of fencamfamine and other stimulant drugs.

Reduction of food intake by fencamfamine in rats

Fencamfamine (1.0-10.0 mg/kg, i.p. single dose) reduced the food intake in a dose-effect relationship. The dose needed for the 50% inhibition of food intake (ID50) was 7.3 mg/kg. Fencamfamine-induced anorexia in rats (5.0 and 10.0 mg/kg) was followed by hyperactivity, stereotypy or both. Pretreatment with haloperidol antagonized the anoretic effect induced by fencamfamine. These findings suggest that the activation of central dopaminergic systems involved in feeding regulation may be responsible for the anoretic effect of fencamfamine and that this effect is associated with other central stimulant effects.