Gino Serra

The role of dopamine in the mechanism of action of antidepressant drugs

The present paper reviews evidence on the effect of antidepressant treatments on dopamine transmission. Chronic treatment with antidepressant drugs potentiates the behavioural stimulant responses elicited by the stimulation of dopamine receptors, including reward-related behaviours. Moreover, antidepressants affect dopamine release in several brain areas. The reviewed literature is discussed in terms of the possible mechanisms underlying antidepressant-induced supersensitivity to dopamine-mediated behavioural responses, and of the possible implications for the therapeutic effect of these drugs. It is concluded that the potentiation of dopaminergic neurotransmission induced by chronic antidepressant treatments might contribute to their therapeutic effect.

Anti-inflammatory activity of linalool and linalyl acetate constituents of essential oils

Linalool and linalyl acetate are the principal components of many essential oils known to possess several biological activities, attributable to these monoterpene compounds. In this work, we evaluated individually the anti-inflammatory properties of (-) linalool, that is, the natural occurring enantiomer, and its racemate form, present in various amounts in distilled or extracted essential oils. Because in the linalool-containing essential oils, linalyl acetate, is frequently present, we also examined the anti-inflammatory action of this monoterpene ester. Carrageenin-induced edema in rats was used as a model of inflammation. The experimental data indicate that both the pure enantiomer and its racemate induced, after systemic administration, a reduction of edema. Moreover, the pure enantiomer, at a dose of 25 mg/kg, elicited a delayed and more prolonged effect, while the racemate form induced a significant reduction of the edema only one hour after carrageenin administration. At higher doses, no differences were observed between the (-) enantiomer and the racemate; a further increase in the dose of both forms did not result in an increased effect at any time of observation. The effects of equi-molar doses of linalyl acetate on local edema were less relevant and more delayed than that of the corresponding alcohol. These finding suggest a typical pro-drug behavior of linalyl acetate. The results obtained indicate that linalool and the corresponding acetate play a major role in the anti-inflammatory activity displayed by the essential oils containing them, and provide further evidence suggesting that linalool and linalyl acetate-producing species are potentially anti-inflammatory agents.

Chronic treatment with antidepressants prevents the inhibitory effect of small doses of apomorphine on dopamine synthesis and motor activity

Abstract In control rats small doses of apomorphine (25 to 100 μg/kg) decreased motor activity and reduced DOPAC content in the caudate nucleus. A larger dose (500 μg/kg) increased motor activity and elicited stereotypy. Chronic treatment with imipramine, amitryptiline and mianserine (10, 10 and 2.5 mg/kg twice daily for 10 days respectively) counteracted or reversed the effect of small doses of apomorphine on motor activity, left DOPAC content unchanged and potentiated the central stimulant response to the larger dose of apomorphine. Changes in apomorphine responses were observed after ten but not after two days of imipramine treatment and persisted unaltered up to 4 days after imipramine withdrawal. It is suggested that chronic treatment with antidepressants induces persistent subsensitivity in presynaptic dopamine receptors. The relevance of the findings in the therapeutic effect of these drugs is discussed.

Linalool produces antinociception in two experimental models of pain

Linalool is a monoterpene compound commonly found as a major component of the essential oils of several aromatic plant species, many of which are used in traditional medical systems as analgesic and anti-inflammatory remedies. We previously reported that (-)-linalool, the natural occurring enantiomer, plays a major role in the anti-inflammatory activity displayed by different essential oils, suggesting that linalool-producing species are potentially anti-inflammatory agents. In this study, the antinociceptive activity of (-)-linalool was examined in two different pain models in mice: the acetic acid-induced writhing response, a model of inflammatory pain, and the hot plate test, a model of supraspinal analgesia. Moreover, the effect of (-)-linalool on spontaneous locomotor activity (25, 50, 75 and 100 mg/kg) was evaluated. The results show that this compound induced a significant reduction of the acid-induced writhing at doses ranging from 25 to 75 mg/kg. Such effect was completely reversed both by the opioid receptor antagonist naloxone and by the unselective muscarinic receptor antagonist atropine. In the hot plate test, only the dose of 100 mg/kg of (-)-linalool resulted in a significant effect. (-)-Linalool induced a dose dependent increase of motility effects, thus ruling out the confounding influence of a possible sedative effect. The more pronounced effect of (-)-linalool on the writhing test with respect to the hot plate test is consistent with the observation that (-)-linalool possesses anti-inflammatory activity. Finally, the activation of opioidergic and cholinergic systems appears to play a crucial role in (-)-linalool-induced antinociception.

The oxytocin antagonist d(CH2)5Tyr(Me)-Orn8-vasotocin inhibits male copulatory behaviour in rats

The effect of an intracerebroventricular (i.c.v.) injection of the oxytocin antagonist, d(CH2)5Tyr(Me)-Orn8-vasotocin, on the copulatory behaviour of vigorous male rats in the presence of females in estrus was studied. The peptide (2.5, 25 and 50 ng, 15 min before mating tests) decreased the number of mounts and intromissions, and abolished ejaculation almost completely at all doses tested. The peptide failed to significantly influence motor activity at the doses used. The results support the hypothesis that central oxytocin plays a physiological role in the expression of copulatory behaviour.

Exploratory behaviour and grooming after repeated restraint and chronic mild stress: effect of desipramine.

In a previous study, we have recently shown that chronic treatment with desipramine either reduced or potentiated the locomotor response to the dopamine D(2)-like receptor agonist quinpirole, a behavioural response mediated by the mesolimbic dopamine system, depending on whether the animals were subjected, respectively, to repeated restraint or to chronic mild stress (different stressors randomly presented). In this study, we examined the interaction between prolonged exposure to either repeated restraint stress or chronic mild stress with the chronic administration of the antidepressant desipramine on two spontaneous behaviours, in which an involvement of the mesolimbic dopamine system has been suggested: novelty-induced exploratory activity and grooming. Exploratory activity in the open field was reduced by chronic mild stress regardless of the drug treatment, while it was not influenced by restraint stress. Desipramine reduced exploratory activity in rats subjected to restraint stress. Restraint stress increased grooming and desipramine reversed this effect, while increasing grooming in the chronic mild stress group. These findings suggest that antidepressants exert their effect by opposing the modifications induced by stress. The available experimental evidence is consistent with the hypothesis that an important role in the observed behavioural changes is played by the mesolimbic dopamine system.

Differential effect of acute and chronic ethanol on dopamine metabolism in frontal cortex, caudate nucleus and substantia nigra

Abstract Acute oral administration of ethanol (3.2g/kg) to normal rats increased DOPAC levels and DOPA formation in the caudate nucleus but had no effect in the substantia nigra and frontal cortex and failed to modify dopamine (DA) levels in any of the above brain areas. Complete tolerance to the stimulant effect on DOPA formation developed after chronic ethanol administration (3.2g daily for 60 days). In chronically treated rats, 24 hrs after ethanol withdrawal, DA levels in the frontal cortex were 60% higher than in controls and were unchanged in the substantia nigra and caudate nucleus as were DOPAC levels in all areas studied. At this time, the administration of ethanol caused a long-lasting depletion of DA and a parallel increase of DOPAC levels in all areas analyzed. The results indicate that acute and chronic ethanol release DA stores but, in the acute condition, DA depletion is prevented by increased synthesis.

Possible role of dopamine D1 receptor in the behavioural supersensitivity to dopamine agonists induced by chronic treatment with antidepressants

The effect of chronic treatment with antidepressants (ADs) on the behavioral responses to LY 171555, a selective D2 receptor agonist, SKF 38393, a selective D1 receptor agonist, and B-HT 920, a selective DA autoreceptor agonist, was studied in rats. In normal rats small, intermediate and high doses of LY 171555 produced hypomotility, hyperactivity and stereotypies, respectively. Chronic but not acute pretreatment with imipramine (IMI) greatly potentiated the motor stimulant effect of LY 171555, but failed to modify its stereotypic and sedative effect. The potentiation of the motor stimulant effect of LY 171555 was observed also after chronic, but not acute, treatment with desmethylimipramine (DMI), mianserin (MIA) or repeated electroconvulsive shock (ECS). Chronic treatment with IMI failed to modify the effect of SKF 38393 (motor stimulation, grooming and penile erection), but reversed the sedative effect of B-HT 920 into a motor stimulant response. The motor stimulant response to LY 171555 in IMI-pretreated animals was suppressed by L-sulpiride, a D2 antagonist, and by a combination of reserpine with alpha-methyltyrosine (alpha-MT), but it was only partially antagonized by high doses of SCH 23390, a selective D1 antagonist. The results indicate that chronic treatment with ADs potentiates the behavioural responses mediated by the stimulation of postsynaptic D2 receptors in the mesolimbic system and suggest that this behavioural supersensitivity is due to enhanced neurotransmission at the D1 receptor level.

Repeated electroconvulsive shock prevents the sedative effect of small doses of apomorphine

Repeated electroconvulsive shock (ECS) (one shock daily for 8 days), but not single ECS, eliminates the sedative response to small doses of apomorphine (25–100 μg/kg) and potentiates the stimulant response to high doses (200 μg/kg) of the drug in rats. This effect is observed 1 and 4 days after the last ECS. However, repeated ECS does not prevent the inhibitory effect of apomorphine on dopamine (DA) synthesis. The results suggest that repeated ECS may lead to the development of subsensitivity in DA receptors that mediate sedation and that these receptors are differentiated from those controlling DA synthesis.

Hyposensitivity of dopamine “Autoreceptors” induced by chronic administration of tricyclic antidepressants*

Summary In saline treated rats small doses of apomorphine (25 to 100 μg/kg) decrease motor activity and reduce DOPAC content in the caudate nucleus. Chronic treatment with imipramine and chlorimipramine (10 mg/kg twice daily for 10 days respectively) counteract or reverse the effect of small doses of apomorphine on motor activity and on DOPAC content. It is suggested that chronic treatment with tricyclic antidepressants induces persistent subsensitivity in presynaptic dopamine receptors.