Effects of serotonergic manipulations on the behavioral sensitization and disinhibition associated with repeated amphetamine treatment

This study investigated the effects of repeated amphetamine treatment on locomotor activity and behavioral inhibition in the elevated plus-maze, and the influence of serotonin (5-HT) neurotransmission on these behaviors. Acute administration of amphetamine (1.0 mg/kg subcutaneously [SC]) stimulated locomotor activity, which was attenuated by acute citalopram (5.0 mg/kg SC) pretreatment. Repeated daily treatment with amphetamine (15 days) sensitized the rats to the amphetamine-induced locomotor stimulation. Acute pretreatment with the 5-HT precursor l-5-hydroxytryptophan (5-HTP; 25 mg/kg IP) or chronic treatment with the selective 5-HT reuptake inhibitor citalopram (5.0 mg/kg SC, twice daily), did not alter the expression of amphetamine-induced locomotor sensitization. In the elevated plus-maze, animals subjected to repeated amphetamine treatment expressed behavioral disinhibition after amphetamine exposure (1.0 mg/kg SC; -35 min), which was antagonized both by acute 5-HTP and chronic citalopram treatment. In summary, these findings suggest that behavioral sensitization to amphetamine is associated with amphetamine-induced behavioral disinhibition, and that acute 5-HTP as well as chronic citalopram treatment counteract the expression of amphetamine-induced behavioral disinhibition, but not locomotor sensitization. It appears likely that the antagonistic effects of 5-HTP and citalopram on behavioral disinhibition derive from a drug-induced facilitation of brain 5-HT neurotransmission.     

Behavioral sensitization to nicotine is associated with behavioral disinhibition; counteraction by citalopram

This study investigated the effects of repeated nicotine treatment on locomotor activity and behavioral inhibition, and the influence of citalopram on the behavioral effects obtained. Male rats received daily subcutaneous injections of vehicle + vehicle (veh + veh), citalopram (5.0 mg/kg) + vehicle (cit + veh), vehicle + nicotine (1.0 mg/kg; veh + nic) or citalopram+nicotine (cit + nic). Acutely, nicotine stimulated locomotor activity, and repeated daily nicotine injections sensitized veh+nic rats to the nicotine-induced locomotor stimulation after 5, 10 and 15 treatment days, whereas in cit+nic rats, the enhancement of nicotine-induced locomotion was suppressed. However, when challenged with nicotine after citalopram withdrawal (−36 h), the cit + nic treated animals were also observed to be sensitized. In the elevated plus-maze, repeated nicotine treatment produced behavioral disinhibition, measured as an increase of time spent in and entries made into open arms (%), and chronic citalopram treatment attenuated the expression of behavioral disinhibition. Moreover, the degree of nicotine sensitization correlated to the behavioral disinhibition observed. In summary, these findings suggest that behavioral sensitization to nicotine is associated with behavioral disinhibition and that chronic citalopram treatment counteracts the expression of both phenomena. Since citalopram is a highly selective serotonin reuptake inhibitor, the effects of citalopram may be due to a facilitation of serotonin neurotransmission caused by the chronic citalopram treatment. Received: 2 December 1997/Final version: 16 August 1998     

Testosterone treatment induces behavioral disinhibition in adult male rats

The importance of testosterone for impulsive-like behavior is unclear. Here we studied the effect of testosterone administration during 6 and 14 days (separate experiments) with one, three and five testosterone-filled silastic capsules implanted subcutaneously on shock-induced behavioral inhibition and on flunitrazepam-induced disinhibition in a modified Vogel's drinking conflict model in rats. Alleviation of shock-induced behavioral inhibition has been suggested to reflect impulsive-like behavior and/or anxiolysis. Treatment with the highest testosterone dose used for 6 (Experiment 1) and 14 (Experiment 3) days increased the number of shocks accepted. Testosterone treatment affected serum levels of testosterone and accessory sex organ weights. Flunitrazepam induced behavioral disinhibition in both testosterone-treated (for 14 days) and sham-treated rats. Moreover, testosterone treatment for 14 days resulted in enhanced GABA-induced 36Cl- uptake into synaptoneurosomes as compared to controls. In conclusion, testosterone produces behavioral disinhibition and may enhance brain GABAA receptor function.     

Sex differences and repeated intravenous nicotine: behavioral sensitization and dopamine receptors

The present study examined the sex-dependent expression of behavioral sensitization as well as changes of dopamine (DA) transporters and D1, D2, and D3 receptors following repeated intravenous nicotine administration. Male and female Sprague-Dawley rats were implanted with indwelling jugular catheters, equipped with subcutaneous intravenous injection ports. Rats were habituated to activity chambers for 3 days and were subsequently administered 15-s bolus injections of intravenous nicotine (50 microg/kg/ml) 1/day for 21 days. Animals were placed in activity chambers for 60 min immediately after the 1st and 21st nicotine injection. Observational time sampling was also performed. Brains were subsequently removed and frozen for autoradiographic DA transporter/DA receptor analysis on the afternoon females were in proestrus. With one exception, no robust sex differences were observed for locomotor activity or any rearing measures either during baseline or after initial nicotine injection. Females exhibited markedly more behavioral sensitization of locomotor activity, rearing, duration of rearing, and incidence of observed rearing. There were no sex differences in the number of D1 or D2 receptors. Females exhibited an increased number of DA transporters and decreased D3 receptors in the NAcc, relative to males. Multiple regression analyses suggest that D3 receptors and DA transporters in various striatal and NAcc subregions differentially predicted nicotine-induced behaviors for males and females. Collectively, these findings demonstrate that repeated intravenous nicotine produces sex differences in the expression of behavioral sensitization, and suggest that nicotine-induced changes of DA transporters and D3 receptors are partly responsible for increased behavioral sensitization in female rats.     

Electroencephalographic and behavioral correlates in rats during repeated ethanol withdrawal syndromes

Rats chronically implanted with electrodes in the amygdala, thalamus, hippocampus, and cortex were addicted twice, separated by an interval of 2 weeks, with 18 days of ethanol liquid diet. The diet consumption and the blood ethanol levels (BELs) were carefully controlled twice a day during both addictive phases. After ethanol removal the behavioral and electroencephalographic (EEG) changes were continuously monitored for 24 h. During each withdrawal the behavioral and EEG changes appeared at the same time, the EEG changes being of shorter duration Behavioral and EEG changes (primarily in hippocampus) were more severe and of earlier onset during the second withdrawal. In spite of an ethanol liquid diet intake comparable to that of the first addiction, during the ethanol readdiction the BELs were found to fluctuate. The results support the hypothesis of an ethanol withdrawal potentiation through a mechanism of kindling of different brain areas related to the observed BEL fluctuations.     

Acute ethanol treatment prevents endocannabinoid-mediated long-lasting disinhibition of striatal output

Recent research has suggested that the neuronal circuit adaptations elicited by drugs of abuse share common features with traditional learning models, and that drugs of abuse cause long-term changes in behavior by altering synaptic function and plasticity. Especially, the endocannabinoid (eCB) system appears to be involved in the neuronal circuitry regulating ethanol (EtOH) preference in rodent. The aim of this study was to evaluate if acute EtOH exposure could modulate eCB-mediated plasticity in the dorsolateral striatum. Our data show that EtOH (20–50  mM) prevents eCB-mediated long-lasting disinhibition (DLL) of striatal output induced by a single stimulation train delivered at 5  Hz for 60 s, and reduces long-term depression (LTD) induced by low-frequency stimulation at inhibitory synapses. Acute EtOH-treatment also prevents DLL induced by the L-type calcium channel activator 2,5-dimethyl-4-[2-(phenylmethyl)benzoyl]-1H-pyrrole-3-carboxylic acid methylester (FPL64176; 500  nM), or by the cannabinoid 1 receptor (CB₁R) agonist WIN55,212-2 (300  nM), indicating that EtOH affects eCB-signaling at a stage that is downstream from eCB production and release. Importantly, high-frequency stimulation, or a higher concentration of WIN55,212-2 (1  μM), induces EtOH-insensitive depression of striatal output, suggesting that EtOH affects CB₁R-mediated signaling in a synapse-specific manner. Maintaining the balance between excitation and inhibition is vital for neuronal networks, and EtOH-mediated modulation of eCB-signaling might thus affect the stability and the fine-tuning of neuronal circuits in the striatum. Our data suggest that changes in eCB-signaling could be involved in the physiological response to acute alcohol intoxication.     

Differential behavioral and neuroendocrine effects of repeated nicotine in adolescent and adult rats

Despite the high prevalence of tobacco abuse among adolescents, the neurobiology of nicotine addiction has been studied mainly in adult animals. Repeated administration of this drug to adult rats induces behavioral sensitization. Nicotine activates the HPA axis in adult rats as measured by drug-induced increases in ACTH and corticosterone. Both behavioral sensitization and corticosterone are implicated in drug addiction. We examined the expression of behavioral sensitization induced by nicotine as well as the changes in corticosterone levels after repeated injections of nicotine in adolescent and adult animals. Adolescent and adult rats received subcutaneous (s.c.) injections of saline or 0.4 mg/kg of nicotine once daily for 7 days. Three days after the last injection animals were challenged with saline or nicotine (0.4 mg/kg; s.c.). Nicotine-induced locomotion was recorded in an activity cage. Trunk blood samples were collected in a subset of adolescent and adult rats and plasma corticosterone levels were determined by radioimmunoassay. Adult, but not adolescent, rats expressed behavioral sensitization. Pretreatment with nicotine abolished corticosterone-activating effect of this drug only in adult animals, indicating the development of tolerance at this age. Our results provide evidence that adolescent rats exposed to repeated nicotine display behavioral and neuroendocrine adaptations distinct from that observed in adult animals.     

Simultaneous prenatal ethanol and nicotine exposure affect ethanol consumption,ethanol preference and oxytocin receptor binding in adolescent and adult rats

Ethanol consumption and smoking during pregnancy are common, despite the known adverse effects on the fetus. The teratogenicity of each drug independently is well established; however, the effects of concurrent exposure to ethanol and nicotine in preclinical models remain unclear. This study examined the impact of simultaneous prenatal exposure to both ethanol and nicotine on offspring ethanol preference behaviors and oxytocin system dynamics. Rat dams were given liquid diet (17% ethanol derived calories (EDC)) on gestational day (GD) 5 and 35% EDC from GD 6–20 and concurrently an osmotic minipump delivered nicotine (3–6 mg/kg/day) from GD 4–postpartum day 10. Offspring were tested for ethanol preference during adolescence (postnatal day (PND) 30–43) and again at adulthood (PND 60–73), followed by assays for oxytocin mRNA expression and receptor binding in relevant brain regions. Prenatal exposure decreased ethanol preference in males during adolescence, and decreased consumption and preference in females during adulthood compared to controls. Oxytocin receptor binding in the nucleus accumbens and hippocampus was increased in adult prenatally exposed males only. Prenatal exposure to these drugs sex-specifically decreased ethanol preference behavior in offspring unlike reports for either drug separately. The possible role of oxytocin in reduction of ethanol consumption behavior is highlighted.     

Prolonged effects of chronic ethanol treatment on responses to repeated nicotine administration: interactions with environmental cues

The most common combination of dependence on two drugs occurs with alcohol and nicotine, but little is known of the way in which these drugs interact in the brain. This study investigated the effects in mice of prolonged consumption of alcohol, by liquid diet, on the actions of nicotine on locomotor activity, and the influence of environmental cues on these effects. Administration of nicotine after chronic alcohol intake did not show any significant changes on first administration, but after 28 days of daily nicotine injections, nicotine produced significant locomotor stimulation and increased rearing activity in the mice which had previously received the alcohol diet, compared with the activity of animals that received the control diet. However, significantly increased locomotor activity was also seen, after the repeated nicotine administration, immediately prior to the nicotine injection, only in the mice that had previously consumed alcohol. Examination of the influence of the environment in which the activity was tested demonstrated that the effect on activity prior to injections was seen only if measurement was made in a test environment that was familiar to the animals. The results demonstrate an interaction between chronic alcohol consumption and the effects of environment on the actions of nicotine, that may have relevance to the consumption of these drugs in humans.     

Mecamylamine increases nicotine preference and attenuates nicotine discrimination

Eight subjects evaluated various qualities of cigarette smoke after being given a range of doses (0, 2.5, 10 and 20 mg) of the nicotinic receptor blocker mecamylamine. In one test condition, subjects were given either high or low nicotine tobacco smoke to determine the effects of mecamylamine on their subjective responses. In another test condition, subjects were allowed to adjust the nicotine dose level of the smoke to determine the effects of mecamylamine on dose preference. When the subjects evaluated puffs of smoke with high and low nicotine content, mecamylamine caused a dose-related decrease in the self-rated strength and harshness of the high nicotine dose level smoke. In contrast, there was little effect on the low dose smoke. At the highest mecamylamine dose (20 mg) there was no significant difference in the ratings of high and low nicotine cigarettes. Low doses of mecamylamine decreased the reported desire for a cigarette, and also attenuated the reduction in desire for a cigarette caused by smoking. When the subjects were allowed to select their preferred level of nicotine intake using a smoke mixing device, the 10 and 20 mg doses of mecamylamine caused a significant increase in self-administered nicotine dose level. Despite this compensatory increase in nicotine self-administration, the reduction in desire for a cigarette after smoking was still less than after placebo.     

DHEAS repeated treatment improves cognitive and behavioral deficits after mild traumatic brain injury.

Mild traumatic brain injury (mTBI) is characterized by diffused symptoms, which when combined are called "post-concussion syndrome". Dehydroepiandrosterone sulfate (DHEAS) is a neuroactive neurosteroid. Previously, we have reported that closed head mTBI causes long lasting cognitive deficits and depressive-like behavior. In the present study we describe the effects of DHEAS on the behavior of mice that suffered closed head mTBI. Following the induction of mTBI, mice were treated once a week with DHEAS (s.c. 20 mg/kg) and their performance in the passive avoidance test and the forced swimming test (FST) were evaluated 7, 30, 60 and 90 days post-injury. The most important interactions were between injury and injection (passive avoidance; p<0.001 and FST; p=0.001), meaning that DHEAS has beneficial effects only when given to injured animals. Our results demonstrate that the long-term cognitive and behavioral effects induced by mTBI may be improved by a repeated weekly treatment with DHEAS.     

Rimonabant attenuates sensitization, cross-sensitization and cross-reinstatement of place preference induced by nicotine and ethanol

The present study focused on the evaluation of behavioral sensitization, cross-sensitization, and cross-reinstatement processes induced by nicotine and ethanol in rodents. First, we showed that nicotine (0.175 mg/kg, base, intraperitoneally, ip) produced a conditioned place preference in rats. When the nicotine place preference was extinguished, nicotine-experienced animals were challenged with nicotine (0.175 mg/kg, ip) or ethanol (0.5 g/kg, ip), which reinstated a preference for the compartment previously paired with nicotine. In the second series of experiments, we demonstrated that after 9 days of nicotine administration (0.175 mg/kg, subcutaneously, sc) every other day and following its 7-day withdrawal, challenge doses of nicotine (0.175 mg/kg, sc) and ethanol (2 g/kg, ip) induced locomotor sensitization in mice. Finally, when we examined the influence of rimonabant (0.5, 1 and 2 mg/kg, ip), we found that this cannabinoid CB₁ receptor antagonist attenuated reinstatement effect of ethanol priming as well as nicotine sensitization and locomotor cross-sensitization between nicotine and ethanol. Our results indicate that similar endocannabinoid-dependent mechanisms are involved in the locomotor stimulant and reinforcing effects of nicotine and ethanol in rodents, and as such these data may provide further evidence for the use of cannabinoid CB₁ receptor antagonists in treatment of tobacco addiction with or without concomitant ethanol dependence.     

Effect of chronic nicotine treatment against repeated immobilization stress

Alpha 2 and beta adrenoceptors, and muscarinic cholinoceptors in 2 brain regions (cerebral cortex and hippocampus) were measured in rats which received either tap water or nicotine added to the drinking water (5-8 mg/kg/day) for 4 weeks, and immobilization stress (daily 2 hr) for the last 5 days. The repeated stress induced a reduction in the maximum number of binding sites (Bmax) for (3H)dihydroalprenolol (DHA) in the cerebral cortex of rats with tap water, without affecting (3H)clonidine binding. Nicotine-treatment also caused a decrease in the Bmax of cortical (3H)DHA binding comparable to the case of stress, and increased the (3H)clonidine binding. However, the combination of nicotine- and stress-treatments failed to induce further no changes in the 2 radioligands binding. The binding of (3H)quinuclidinyl benzilate in the cerebral cortex and of the 3 radioligands in the hippocampus was unaltered by nicotine- and/or stress-treatments. These results indicate that long-term administration of nicotine induces down-regulation of cortical beta adrenoceptors and seemingly attenuates the receptor alteration by repeated stress.     

Conditioned stimulus preference after acetaldehyde but not ethanol injections

Acetaldehyde, the first ethanol metabolite, has been suggested to mediate some of the behavioral effects of ethanol and particularly its reinforcing properties, although this later hypothesis remains extremely controversial. While several studies demonstrated the reinforcing effects of brain acetaldehyde, blood acetaldehyde accumulation is believed to be primarily aversive. In the present study, a conditioned reinforcement procedure has been used to investigate the reinforcing and/or aversive effects of intraperitoneal injections of both acetaldehyde and ethanol in Wistar rats. An olfactory stimulus was paired with daily injections of either ethanol (0, 0.25, 0.5, 1 and 2 g/kg) or acetaldehyde (0, 10, 20, 100 and 150 mg/kg). After eight conditioning sessions, all rats were tested for their stimulus preference or aversion. The results show that conditioning with small, 0.25 and 0.5 g/kg, ethanol doses induced neither preference nor aversion for the olfactory cue. In contrast, higher ethanol doses (1.0 and 2.0 g/kg) resulted in significant stimulus aversions. Acetaldehyde conditioning led to a biphasic stimulus preference, with a maximal preference around 20 mg/kg acetaldehyde. No evidence of aversive effects was found with increasing doses of acetaldehyde, even with concentrations close to the lethal limit. The present study clearly shows that systemic acetaldehyde injections induced significant stimulus preferences. This suggests that acetaldehyde may be, at least in part, responsible for the reinforcing effects of alcohol intake.     

Pre- and postsynaptic dopamine mechanisms after repeated nicotine: effects of adrenalectomy

The reinforcing properties of nicotine may be related to its ability to release dopamine in the nucleus accumbens and to increase locomotor activity in experimental animals. Both these effects are sensitized following repeated drug exposure, a phenomenon that may underlie important aspects of addiction. Adrenal steroids may be involved both in positive reinforcement and in sensitization. Adrenalectomy hampers, e.g., the induction of locomotor sensitization to nicotine, and cross-sensitization between stress and psychostimulants may develop. Here, the effect of adrenalectomy on postsynaptic and presynaptic changes of the mesolimbic dopamine system in association with nicotine sensitization was examined. Adrenalectomy or sham-operated rats received daily nicotine (0.4 mg/kg s.c.) or vehicle for 15 days, after which the locomotor responses to nicotine (0.2 mg/kg s.c.) and the dopamine D1/D2 receptor agonist apomorphine (1.0 mg/kg s.c. or 100 microM in the nucleus accumbens by reversed microdialysis) were recorded. In addition, accumbal dopamine output was monitored by in vivo microdialysis after nicotine challenge. Sham/nicotine animals showed a sensitized locomotor response to systemic and local apomorphine compared to all other groups, including the adrenalectomized/nicotine group. Nicotine increased accumbal dopamine output in all animals. In contrast, nicotine induced a pronounced increase in locomotor activity in the sham/nicotine animals compared to the other vehicle group and the adrenalectomized animals. These results indicate that adrenal steroids are involved in the induction of the postsynaptic component of nicotine sensitization, whereas their involvement in tentative presynaptic changes remains unclear.     

Acute nicotine increases both impulsive choice and behavioural disinhibition in rats

Rationale  

Heavy smokers exhibit greater levels of impulsive choice and behavioural disinhibition than non-smokers. To date, however, the relationship between nicotine use and differing dimensions of impulsivity has not been systematically assessed.     

Effects of 5-HT1A and 5-HT2 receptor agonists on the behavioral and neurochemical consequences of repeated nicotine treatment.

This study investigated the effects of repeated daily (15 days) treatment with nicotine, alone or in combination with the 5-HT1A/7 receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) or the 5-HT2 receptor agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine (DOI) on locomotor sensitization, mesolimbic dopamine neurochemistry and on behavioral inhibition in the rat. Acute nicotine elevated the extracellular dopamine levels in the nucleus accumbens and stimulated locomotor activity, effects that were sensitized after repeated nicotine treatment. Repeated nicotine administration also produced nicotine-induced behavioral disinhibition in the elevated plus-maze. Treatment with DOI counteracted the expression of the nicotine-induced locomotor and neurochemical sensitization, but had no effect on nicotine-induced behavioral disinhibition. Treatment with 8-OH-DPAT decreased the expression of nicotine-induced behavioral disinhibition, but had no effect on locomotor or neurochemical sensitization. Taken together, these findings suggest that the 5-HT1A and the 5-HT2 receptor subtypes are differentially involved in the effects of repeated nicotine on locomotor sensitization, behavioral inhibition and mesolimbic dopamine neurochemistry.     

Behavioral and neurochemical consequences of repeated nicotine treatment in the serotonin-depleted rat

RATIONALE: Repeated exposure to addictive drugs causes neuroadaptive alterations that are proposed to increase the incentive motivation to consume drugs and to decrease the ability to inhibit such inappropriate motivational impulses and responses. Together, these behavioral consequences of drug intake may underlie the compulsive drug-seeking and -taking behaviors observed in drug abuse. OBJECTIVE: Brain serotonin (5-HT) has been implicated in these mechanisms and this study therefore investigated the consequences of brain 5-HT depletion on the behavioral and neurochemical effects induced by repeated daily nicotine treatment (15 days) in male rats. METHODS: The effects of the present pharmacological manipulations were evaluated behaviorally (locomotor activity, the elevated plus-maze) and neurochemically (microdialysis, brain biochemistry). RESULTS: Depletion of brain 5-HT produced behavioral disinhibition in the elevated plus-maze. In 5-HT-depleted animals, nicotine-induced locomotor sensitization was observed on treatment days 5, 10, and 15, but only on day 15 in the sham-operated rats. Postsensitization, the locomotor stimulatory effects of amphetamine and the dopamine receptor agonists SKF 38,393, apomorphine, and quinpirole were decreased in 5-HT-depleted animals, an effect that appeared to be more pronounced in nicotine-treated rats. Repeated nicotine treatment sensitized the nicotine-induced elevation of the extracellular accumbal dopamine levels in sham-operated, but not in 5-HT-depleted rats, and was also associated with decreased D2 autoreceptor function in both nicotine-treated experimental groups. CONCLUSIONS: Depletion of brain 5-HT, which produces behavioral disinhibition, may slightly facilitate the overall expression of locomotor sensitization to nicotine and differentially affect the pre- and postsynaptic neuroadaptive events involved in the expression of these phenomena.