Actualización en abuso de drogas por vía nasal / Update on drug abuse by nasal route

La vía nasal, ya sea mediante la inhalación o aspiración, se ha convertido en una ruta atractiva para quienes abusan de sustancias, principalmente por la fácil accesibilidad y la rápida absorción sistémica, además de evitar las consecuencias asociadas al uso de drogas intravenosas (enfermedades de transmisión). El objetivo de esta revisión es presentar una actualización de diversas sustancias que son utilizadas por esta vía, enfocándose en aquellas en las que se ha documentado daños en la anatomía nasal.

The nasal route, either by inhalation or aspiration, has become an attractive route for substances abusers, mainly because of its easy accessibility, rapid systemic absorption and also to avoid the consequences associated with intravenous drug use (transmitted diseases). The objective of this review is to present an update of various substances that are used by this route, focusing on those in which damage to the nasal anatomy has been documented.

Chloramphenicol decreases CB1 receptor expression in the nucleus accumbens and prefrontal cortex and prevents amphetamine-induced conditioned place preference in rats.

Drug dependence seems to involve a learning and memory process. Since learning and memory depend on protein synthesis, drug dependence may depend on protein synthesis, too. Drug-induced reward is a crucial effect for the development of drug-dependence. We used chloramphenicol (CAP, a protein synthesis inhibitor), to evaluate its effects on amphetamine (amph)-seeking behavior, on CB1R expression and on protein synthesis in general, in specific areas of the brain. Two groups of Wistar adult male rats were subjected to amph-induced conditioned place preference (CPP). Rats in group 1 received amph and were kept in the chamber for 30min. Once this period elapsed, they received a subcutaneous injection of saline (veh) and were returned to their home-cage. Rats in group 2 were also treated with amph but received CAP (150mg/kgsc) instead of saline. Once CPP was evaluated rats were sacrificed and the prefrontal cortex (PFC), the nucleus accumbens (NAcc) and the hippocampus (Hipp) were isolated and prepared for CB1R Western blot analysis. A vivarium reared group of rats was added as a non-experimentally manipulated control group. Results indicate that group 1 developed CPP while increasing CB1R expression in the NAcc. Group 2 did not develop CPP, had lower CB1R expression in the PFC and lacked the CB1R increase in the NAcc observed in the amph+veh group. These results support the notion that among the underlying mechanisms for amph-seeking reward is an increase in CB1R, further supporting an interaction between dopamine/endocannabinoids in CPP learning.

The antipsychotic aripiprazole selectively prevents the stimulant and rewarding effects of morphine in mice.

Aripiprazole is an antipsychotic that acts as a partial agonist at dopamine D2 receptors, with a favorable pharmacological profile. Due to its unique mechanism of action, this compound has potential application as a substitutive therapy for drug addiction. Considering that distinct neural systems subserve the addictive and analgesic actions of opioids, we tested the hypothesis that aripiprazole selectively inhibit the abuse-related, but not the antinociceptive, effects of morphine. The drugs were tested in male Swiss mice for their effects on locomotion, conditioned place preference (CPP) and nociception. Morphine (20mg/kg) increased motor activity, whereas aripiprazole (0.1, 1 and 10mg/kg) did not induce any change. This antipsychotic, however, prevented morphine-induced locomotion. In the conditioning box, aripiprazole did not induce either reward or aversion. Yet, it prevented both the acquisition and the expression of morphine-induced CPP. Finally, none of the doses of this antipsychotic interfere with morphine (5mg/kg)-induced antinociception in the tail-flick test. In conclusion, aripiprazole inhibited the abuse-related effects of morphine at doses that do not interfere with basal locomotion, reward or aversion. Also, it did not alter morphine-induced antinociceptive effects. This antipsychotic should be further investigated as a possible substitutive strategy for treating certain aspects of opioid addiction.

Lithium increases nerve growth factor levels in the rat hippocampus in an animal model of mania.

Pharmacological studies suggest that neurotrophins may play a role in the effects of lithium and valproate on mood regulation. In this study, we tested the hypotheses that lithium and valproate would reverse and prevent the behavioral and biochemical effects of amphetamine, using a rat model of mania. In the reversal treatment, male Wistar rats were first administered D-amphetamine or saline for 14 days, and then, between days 8-14, rats were treated with lithium, valproate or saline. In the prevention treatment, rats were pretreated with lithium, valproate or saline, and then, between days 8-14, rats were administered D-amphetamine or saline. Locomotor behavior was assessed using the open-field task and hippocampal nerve growth factor levels were determined by enzyme-linked immunosorbent assay. Both lithium and valproate reversed and prevented D-amphetamine-induced hyperactivity. Lithium increased nerve growth factor content in rat hippocampus in both experiments, but this effect was blocked with the co-administration of D-amphetamine. No significant effects on nerve growth factor levels were observed with valproate or D-amphetamine alone. These findings suggest that nerve growth factor may play a role in the neurotrophic effects of lithium but do not support the hypotheses that the nerve growth factor/TrkA pathway is involved in the pathophysiology of bipolar disorder.

Cinnarizine has an atypical antipsychotic profile in animal models of psychosis.

Cinnarizine, a drug known as a calcium channel blocker, is currently used for the treatment of migraine and vertigo. Induction of extrapyramidal signs by cinnarizine has been reported in the elderly, which is related to its moderate antagonistic properties at dopamine D2 receptors, resembling the mechanism of action of most antipsychotic drugs. Despite this effect, cinnarizine has never been tested as a putative antipsychotic drug. Here we evaluate the potential effect of cinnarizine in two pharmacological models of psychosis, namely amphetamine- and MK-801-induced hyperlocomotion, as well as its ability to induce catalepsy. Cinnarizine significantly counteracted MK-801 (0.25 mg/kg) and amphetamine (5mg/kg) locomotor effects at doses as low as 20mg/kg, having no incremental effect at 60 or 180 mg/kg. Regarding side-effects, cinnarizine induced no catalepsy in mice at the effective dose of 20 mg/kg, inducing only mild catalepsy at the doses of 60 and 180 mg/kg. Based on these results and on the antagonist effect of cinnarizine on dopamine D2 receptors, we suggest that it has a potential antipsychotic effect with an atypical profile that should be evaluated clinically.

Effects of fencamfamine on latent inhibition.

The effects of fencamfamine (FCF), an indirect dopamine (DA) agent, were investigated using the latent inhibition (LI) model of schizophrenia. In the LI procedure, rats preexposed (PE) to an unreinforced stimulus show difficulty in subsequent learning of an association in which that stimulus is predictive of an unconditioned stimulus (US). FCF (1.75, 3.5 and 7.0 mg/kg i.p.) yielded an inverse dose-response relationship regarding LI. At 3.5 mg/kg, LI was abolished and no effect was observed at 1.75 and 7.0 mg/kg. The effect of FCF (3.5 mg/kg) on LI was blocked by the antipsychotic risperidone (RIS; 4.0 mg/kg), a D2/5HT2 antagonist. These results confirm the similarity of the behavioral profile of FCF and amphetamine (AMPH). In addition, they provide a further validation of the LI model for psychosis, since RIS was shown to prevent a psychostimulant-induced disruption of LI.

Antipsychotic profile of alstonine: ethnopharmacology of a traditional Nigerian botanical remedy

Although recently developed drugs have brought significant improvement, the treatment of psychotic disorders still presents serious drawbacks. Since inherent complexity and lack of satisfactory understanding of the underlying pathophysiology impose limits for rational drug design, resourceful approaches in the search for antipsychotics are pertinent. This paper reports pharmacological properties of alstonine, a heteroyohimbine type alkaloid, Which exbitited an antipsychotic-like profile, inhibiting amphetamine-induced lethaly, apomorphine-induced steotypy and potentiating barbiturate-induced slleping time. Atypical features of alstonine were the prevention of haloperidol-induced catalepsy and lack of direct interaction with D1, D2 and 5-HT2A receptors, classically linked to antipsychotic mechanism of action.

GABAergic drugs inhibit amphetamine-induced distractibility in the rat.

Drugs facilitating GABAergic neurotransmission have been reported to block some behavioral actions of dopaminergic stimulation but not others. The present experiments were performed with the purpose to extend the range of behaviors in which the interaction between GABA and dopamine have been studied. The ability of the GABAB agonist baclofen and the GABA transaminase inhibitor sodium valproate to block the enhanced distractibility produced by amphetamine was evaluated in a procedure especially designed for analyzing drugs' effects on distractibility. Briefly, rats were trained to traverse a straight runway with a sucrose solution as reinforcement. Once the response had been acquired, an additional runway ending in an empty box was connected. The time spent investigating this additional runway is the measure of distractibility. Male rats treated with amphetamine, 1 mg/kg, displayed an increase of the time spent in the additional runway. Baclofen, 2.5 and 5 mg/kg, and sodium valproate, 100 and 200 mg/kg, had no effect on distraction behavior when administered alone. However, when these drugs were administered together with amphetamine, 1 mg/kg, they completely inhibited the effects of the stimulant on distractibility. These data show that distractibility is similar to discrimination learning with regard to the capacity of GABAergic drugs to block the effects of dopaminergic stimulation. It is different from locomotor activity, however, where GABAergic drugs are ineffective in this respect.

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.