Search

Repeated exposure to several drugs of abuse has been reported to induce behavioural sensitization. So far no evidence has been provided that such a phenomenon also applies to cannabinoids.In this study we investigated if repeated exposure to Delta(9)-tetrahydrocannabinol (Delta(9)-THC) induces behavioural sensitization. In addition we tested the possibility of cross-sensitization between Delta(9)-THC and morphine.Male Sprague-Dawley rats were administered for 3 days, twice daily, with increasing doses of Delta(9)-tetrahydrocannabinol (2, 4 and 8 mg/kg i.p.) or increasing doses of morphine (10, 20 and 40 mg/kg s.c.) or vehicle. After a washout of 14 days the animals were challenged with Delta(9)-THC (75 and 150 microg/kg i.v.), with a synthetic cannabinoid agonist WIN55212-2 (75 and 150 microg/kg i.v.) or with morphine (0.5 mg/kg i.v.), through a catheter inserted into the left femoral vein 24 h before, and the behaviour recorded.Rats previously administered with Delta(9)-THC showed a greater behavioural activation compared to controls in response to challenge with Delta(9)-THC (150 microg/kg i.v.) and to challenge with morphine (0.5 mg/kg i.v.). Similar to that observed after repeated opiates, this behavioural sensitization was characterized by stereotyped activity. Animals administered with a schedule of morphine that induces behavioural sensitization to morphine also showed a behavioural sensitization to challenge with cannabinoids (Delta(9)-HC and WIN55212-2, 75 and 150 microg/kg i.v.). The effect of the challenge with Delta(9)-THC was prevented by the administration of the CB1 antagonist SR141716A (1 mg/kg i.p.), 40 min beforehand.The results of the present study demonstrate that repeated exposure to Delta(9)-THC induces behavioural sensitization not only to cannabinoids but also to opiates. This cross-sensitization was symmetrical since rats behaviourally sensitized to morphine were also sensitized to cannabinoids. These observations further support the evidence of an interaction between the opioid and the cannabinoid system and might provide a neurobiological basis for a relationship between cannabis use and opiate abuse.

The atypical antidepressant mianserin, administered at doses of 1, 5 and 10 mg/kg SC, dose-dependently increased up to about 6 times extracellular dopamine in the medial prefrontal cortex of the rat, as estimated by vertical concentric microdialysis probes. Mianserin failed to modify extracellular dopamine in the nucleus accumbens. Mianserin also dose-dependently increased extracellular noradrenaline in the prefrontal cortex. Yohimbine, an alpha2 antagonist, increased extracellular dopamine in the prefrontal cortex but the maximal increase was lower than that elicited by mianserin. Yohimbine also increased extracellular noradrenaline in the prefrontal cortex, but to a lesser extent than dopamine. Clonidine, an alpha2 antagonist, decreased extracellular dopamine and noradrenaline in the prefrontal cortex but failed to affect extracellular dopamine in the nucleus accumbens. Ritanserin, a 5HT2 antagonist, at doses of 1.0 mg/kg, failed to increase extracellular dopamine in the prefrontal cortex, but significantly potentiated the increase in extracellular noradrenaline due to yohimbine. Ritanserin failed to potentiate the increase in extracellular noradrenaline elicited by yohimbine in the prefrontal cortex. The results are interpreted to indicate that mianserin increases extracellular DA as a result of the concurrent blockade of alpha2 and 5HT2 receptors. Failure to affect extracellular dopamine in the nucleus accumbens is explained as due to the lack of a significant effect of alpha2 and 5HT2 tone on DA release in the nucleus accumbens as compared to the prefrontal cortex. The results are consistent with the postulated relationship between antidepressant drug action and the ability to increase extracellular dopamine in the prefrontal cortex.

Drugs of abuse and palatable food share the ability to stimulate dopamine (DA) transmission in the nucleus accumbens shell. However, while the stimulation of shell DA by food undergoes habituation, that by drugs of abuse does not.This study aims to directly compare the changes of extracellular DA, by microdialysis, in shell and core and prefrontal cortex (PFCX) in response to food- and drug-conditioned stimuli (CSs).Rats were trace-conditioned by Fonzies box (FB) or vanilla box (VB; CS), followed by food: Fonzies, intraoral chocolate solution (food-unconditioned stimulus (US)) and morphine (1.0 mg/Kg sc; drug US). Control (unconditioned) rats received standard food instead of Fonzies, tap water instead of chocolate, saline instead of morphine.Food-CSs increased core but not shell DA, while drug-CSs did the opposite. Food and drug-CSs both increased PFCX DA. Exposure to food-CSs potentiated core and PFCX DA response to food while shell responsiveness was dependent upon the relative CS and US nature. If the CS was intrinsic to the food US (CS = FB/US = Fonzies) the response of shell DA to the US was abolished. If the CS was extrinsic to the food US (CS = FB/US = chocolate; CS = VB/US = Fonzies), shell DA increased in response to the US. Exposure to the drug-CS potentiated the DA response to the drug-US in the shell and in the PFCX, but not in the core.Drug-CSs differentially activate DA as compared to food-CSs in shell and core and differentially affect DA response to the US in these areas. These differences might be relevant for the role of DA in the mechanism of drug addiction.

Conditioned stimuli (CSs) by pavlovian association with reinforcing drugs (US) are thought to play an important role in the acquisition, maintenance and relapse of drug dependence. The aim of this study was to investigate by microdialysis the impact of pavlovian drug CSs on behaviour and on basal and drug-stimulated dopamine (DA) in three terminal DA areas: nucleus accumbens shell, core and prefrontal cortex (PFCX). Conditioned rats were trained once a day for 3 days by presentation of Fonzies filled box (FFB, CS) for 10 min followed by administration of morphine (1 mg/kg), nicotine (0.4 mg/kg) or saline, respectively. Pseudo-conditioned rats were presented with the FFB 10 h after drug or saline administration. Rats were implanted with microdialysis probes in the shell, core and PFCX. The effect of stimuli conditioned with morphine and nicotine on DA and on DA response to drugs was studied. Drug CSs elicited incentive reactions and released DA in the shell and PFCX but not in the core. Pre-exposure to morphine CS potentiated DA release to morphine challenge in the shell but not in the core and PFCX. This effect was related to the challenge dose of morphine and was stimulus-specific since a food CS did not potentiate the shell DA response to morphine. Pre-exposure to nicotine CS potentiated DA release in the shell and PFCX. The results show that drug CSs stimulate DA release in the shell and medial PFCX and specifically potentiate the primary stimulant drug effects on DA transmission.

In naive rats, passive administration of drugs of abuse preferentially increases extracellular dopamine (DA) in the nucleus accumbens (NAc) shell as compared to the core. Repeated exposure to the same drugs results in behavioral and biochemical sensitization characterized by stereotyped activity and reduction of the shell/core DA response ratio. The aim of this work is to study the neurochemical and behavioral effects of response-contingent vs response-noncontingent drug administration in rats, who were bilaterally implanted with chronic intracerebral guide cannulae and trained to self-administer cocaine by nose poking in daily 1-h sessions for 3 weeks (5 days/week). Nose poking in the active hole by master rats resulted in intravenous injection of cocaine (0.25 mg/kg) in master rats and in rats yoked to them. Dialysate DA was monitored before, during, and for 30 min after cocaine availability on alternate days by inserting the probe into the NAc shell and core. Stereotyped and non-stereotyped behavior was recorded during the sessions. In master rats, dialysate DA increased preferentially in the NAc shell during cocaine self-administration throughout the 3 weeks of cocaine exposure. In yoked rats, DA increased preferentially in the shell but to a lesser extent than in master rats. With continued exposure to cocaine, the shell/core ratio of DA changes decreased progressively and, on the third week, was reversed so that DA increased more in the core than in the shell. Yoked rats showed a progressive and faster increase in stereotyped behaviors than master rats. Response-noncontingent cocaine administration is particularly prone, compared to response-contingent administration, to induce behavioral and biochemical sensitization.

A large body of evidence indicates an involvement of the mesolimbic dopamine (DA) pathway innervating the ventral striatum in the motivational effects of drug abuse.The goal of the study is to clarify the role of DA D1 and D2 receptors of the rat nucleus accumbens (NAc) shell and core in the motivational effects of morphine as studied by conditioned place preference (CPP).The effect of the intracerebral infusion of DA antagonists specific for DA D1 (SCH 39166) and D2 receptors (L-sulpiride) was studied in a single-trial place conditioning paradigm with fixed assignment of the drug to the unpreferred compartment.Morphine induced significant CPP at all the doses tested (0.5, 1.0, and 2.0 mg/kg, subcutaneously). A dose of 1.0 mg/kg was selected for further studies. Intra-NAc shell infusion of SCH 39166 and L-sulpiride at doses of 25 and 50 ng/1 microl per side impaired the acquisition of CPP by morphine. No effect was observed at 12.5 ng/1 microl per side. Intra-NAc core infusion of SCH 39166 (12.5, 25, and 50 ng/1 microl per side) did not affect the acquisition of morphine-induced CPP, while L-sulpiride (12.5, 25, and 50 ng/1 microl per side) impaired CPP acquisition only at the dose of 50 ng/1 microl per side. No effect on morphine-induced CPP was observed when the DA antagonists were infused into the NAc shell or core 10 min before the test session.These results indicate that DA D1 and D2 receptors in the NAc shell are involved in the acquisition of morphine-induced CPP.

Abstinence from chronic morphine has been shown to reduce extracellular dopamine in the nucleus accumbens as measured by brain microdialysis (Acquas et al. 1991). In the present study, we investigated if similar changes take place in the prefrontal cortex. Withdrawal from a schedule of increasing doses of morphine administered intraperitoneally twice a day for 9 days up to a daily dose of 60 mg/kg resulted in doubling of basal extracellular concentrations of dopamine in the prefrontal cortex and in a mild withdrawal syndrome (ptosis, piloerection, hunched-back posture). Administration of a low dose of naloxone (0.5 mg/kg SC) to rats withdrawn from chronic morphine resulted in a full withdrawal syndrome with wet dog shakes and diarrhoea and an increase of extracellular dopamine that peaked at 40 min and returned to the pre-naloxone values by 80 min. The results show that dopamine neurotransmission in the medial prefrontal cortex responds to opiate withdrawal in a manner opposite to dopamine transmission in the nucleus accumbens and indicate that the dopamine system is affected by abstinence in a topographically specific manner, consistent with a different functional role of mesocortical as compared to mesolimbic dopamine systems.

Fluoxetine and desipramine, two antidepressants that block selectively the serotonin and the noradrenaline carrier, increase extracellular dopamine concentrations in the prefrontal cortex of freely-moving rats. This effect is calcium dependent and is prevented, in the case of fluoxetine but not desipramine, by systemic pretreatment with low doses or by low concentrations in the dialyzing Ringer of the potent 5-HT3 antagonist ICS 205930. Fluoxetine, but not desipramine, increases extracellular serotonin concentrations in the prefrontal cortex. The results indicate that selective serotonin reuptake blockers increase extracellular dopamine in the prefrontal cortex by stimulating local 5-HT3 receptors.

Drugs differing in their primary mechanism of action but having in common the ability to act as antidepressants such as fluoxetine (10 mg/kg SC), clomipramine (10 mg/kg IP), imipramine (10 mg/kg IP), desipramine (10 mg/kg IP) and (+/-) 8-OHDPAT (0.03 mg/kg SC) increase extracellular concentrations of dopamine in the rat prefrontal cortex but not in the medial nucleus accumbens. Buspirone (1 mg/kg SC) increased dopamine both in the prefrontal cortex and in the nucleus accumbens. Extracellular 5HT was increased by fluoxetine, clomipramine and imipramine but not by desipramine while 8-OHDPAT and buspirone decreased it. These results raise the possibility that the property of stimulating dopamine transmission in the prefrontal cortex has a role in the antidepressant properties of these drugs.

In rats unilaterally lesioned with 6-hydroxydopamine, the D-1 agonist SKF 38393 (3 mg/kg SC) induced contralateral turning only after priming with a dopaminergic agonist such as apomorphine. Administration of the N-methyl-d-aspartate receptor antagonist (+) MK 801 (0.1 mg/kg IP) 15 min before apomorphine (0.1 mg/kg SC) prevented the ability of apomorphine to act as a primer while potentiating its acute contralateral turning effects. The inactive isomer (−) MK 801 was without effect. The results indicate that the N-methyl-d-aspartate receptor exerts a permissive role on priming.

The effect of two 5HT3 antagonists, ICS 205-930 and MDL 72222, on drug-induced place aversion was studied in a two-compartment apparatus with a procedure including a pre-test for spontaneous preference. Naloxone (0.8 mg/kg SC), phencyclidine (2.5 mg/kg SC) and picrotoxin (2.0 mg/kg IP) paired with the preferred compartment elicited a significant place aversion. ICS 205-930 and MDL 72222 failed to modify spontaneous place preference when paired with both compartments. ICS 205-930 (30 micrograms/kg SC) paired with the preferred and, in other experiments, with the non-preferred compartment, also failed to modify spontaneous preference. ICS 205-930 (7.5, 15 and 30 micrograms/kg SC), paired with both compartments, dose-dependently reduced the place aversion induced by naloxone (0.8 mg/kg SC), phencyclidine (2.5 mg/kg SC) and picrotoxin (2.0 mg/kg IP). MDL 72222 (30 micrograms/kg SC) paired with both compartments had a similar effect. The result indicate that 5HT, via 5HT3 receptors, plays a role in the aversive properties of drug stimuli.

The influence of the D1 antagonist SCH 23390 on the motivational properties of rewarding (morphine, nicotine and diazepam) and aversive (naloxone, phencyclidine and picrotoxin) drugs was studied in the rat in a two-compartment place-conditioning paradigm, which included a pre-conditioning test for spontaneous place-preference. The specific D1 dopamine-receptor antagonist SCH 23390 (0.05 mg/kg SC), paired with both compartments or, separately, with the preferred or with the non-preferred compartment, failed to affect the spontaneous unconditioned preference of the animal. Pairing of morphine (1.0 mg/kg SC), nicotine (0.6 mg/kg SC) or diazepam (1.0 mg/kg IP) with the less preferred compartment induced significant preference for that compartment. Pairing of SCH 23390 (0.05 mg/kg SC) with both compartments completely blocked the place-preference induced by morphine, nicotine and diazepam. Naloxone (0.8 mg/kg SC), phencyclidine (2.5 mg/kg SC) or picrotoxin (2.0 mg/kg IP) paired with the preferred compartment elicited place-aversion. Pairing of SCH 23390 (0.05 mg/kg SC) with both compartments abolished also the place-aversion induced by naloxone, phencyclidine and picrotoxin. The results indicate that blockade of dopamine transmission blocks the motivational properties of rewarding as well as aversive stimuli. It is suggested that neuroleptics rather than simply blocking the rewarding impact of positive reinforcers (anhedonia, lack of pleasure) exert a more general influence on conditioned behaviour by blocking the affective impact of negative as well as positive reinforcers (apathy, lack of motivation).

The effect of concurrent D-1 receptor stimulation by SKF 38393 on the expression of yawning elicited by D-2 receptor stimulation with LY 171555 was studied in the rat. A low dose of SKF 38393 (2.5 mg/kg SC), while failed to elicit yawning, potentiated the effectiveness of LY 171555 in eliciting yawning at all the doses tested (12.5, 25 and 50 micrograms/kg SC) and this effect was abolished by SCH 23390 (0.012 mg/kg SC). The results indicate that in analogy with typical post-synaptic dopaminergic effects (hypermotility-stereotypy), yawning elicited by a D-2 agonist is facilitated by concurrent stimulation of D-1 receptors and therefore is consistent with previous evidence that yawning in response to a D-2 agonist is not mediated by autoreceptors.