Distinctive Neuroanatomic Regions Involved in Cocaine-Induced Behavioral Sensitization in Mice.

The present study aimed to characterize the phenomenon of behavioral sensitization to cocaine and to identify neuroanatomical structures involved in the induction and expression phases of this phenomenon. For this, in experiment 1 (induction phase), mice were treated with saline or cocaine every second day for 15 days (conditioning period), in the open-field or in their home-cages. In experiment 2 (expression phase), the same protocol was followed, except that after the conditioning period the animals were not manipulated for 10 days, and after this interval, animals were challenged with cocaine. Neuroanatomical structures involved in the induction and expression phases were identified by stereological quantification of c-Fos staining in the dorsomedial prefrontal cortex (dmPFC), nucleus accumbens core (NAc core and shell (NAc shell), basolateral amygdala (BLA), and ventral tegmental area (VTA). Neuroanatomical analysis indicated that in the induction phase, cocaine-conditioned animals had higher expression of c-Fos in the dmPFC, NAc core, BLA, and VTA, whereas in the expression phase, almost all areas had higher expression except for the VTA. Therefore, environmental context plays a major role in the induction and expression of behavioral sensitization, although not all structures that compose the mesolimbic system contribute to this phenomenon.

Context-dependent effects of the CB1 receptor antagonist rimonabant on morphine-induced behavioral sensitization in female mice.

Introduction: The endocannabinoid system has been implicated in the neurobiology of opioid use disorder. While the CB1 receptor antagonist rimonabant has been shown to block some of the behavioral effects of opioids, studies suggest that the treatment environment (i.e., receiving treatment in the drug-associated environment, and/or novelty) can influence its effects. In the present study, we investigated the role of the treatment environment in the effects of rimonabant on the expression of morphine-induced behavioral sensitization. Methods: Adult female Swiss mice were submitted to a behavioral sensitization protocol, during which they received morphine (20 mg/kg, i.p.) in the open-field apparatus, and were subsequently treated with vehicle or rimonabant (1 or 10 mg/kg, i.p.) either in the open-field, in the home-cage or in an activity box (novel environment). The expression of conditioned locomotion (increased locomotor activity in the open-field apparatus in the absence of morphine) and of morphine-induced behavioral sensitization (increased locomotor activity in animals sensitized to morphine) was evaluated during asubsequent saline and morphine challenge, respectively. Results: Animals treated with morphine expressed behavioral sensitization, showing a significant increase in locomotor activity over time. Animals sensitized to morphine and treated with vehicle in the home-cage expressed conditioned locomotion, an effect that was blocked by home-cage treatment with rimonabant. During a saline challenge, only animals sensitized to morphine and treated with saline in the home-cage expressed morphine-induced conditioned locomotion. All morphine-treated animals that received saline during the treatment phase (control groups) expressed behavioral sensitization during the morphine challenge. Treatment with rimonabant in the open-field and in the activity box, but not in the home-cage, blocked the expression of morphine-induced behavioral sensitization. Discussion: Our findings suggest that CB1 receptor antagonism can modulate conditioned responses to morphine even when administered in the home-cage. However, exposure to the drug-associated environment or to a novel environment is necessary for the expression of rimonabant's effects on morphine-induced behavioral sensitization during a morphine challenge.

Role of the treatment environment in the effects of aripiprazole on ethanol-induced behavioral sensitization and conditioned place preference in female mice.

BACKGROUND: Evidence suggests that aripiprazole, a partial dopamine D2 and serotonin 5-HT1A receptor agonist and 5-HT2A receptor antagonist, show significant efficacy in reducing alcohol use. We have previously demonstrated that treatment with aripiprazole blocked the reinstatement of cocaine-induced behavioral sensitization in a context-dependent manner, suggesting that the treatment environment may modulate the therapeutic effects of aripiprazole. The present study aimed to evaluate the effects of treatment with aripiprazole on ethanol-induced behavioral sensitization and conditioned place preference in female mice, and the role of the treatment environment in those effects. METHODS: Adult female mice were either sensitized with ethanol injections in the open-field apparatus, or conditioned with ethanol in the conditioned place preference (CPP) apparatus. Animals were then treated with vehicle or 0.1 mg/kg aripiprazole paired to the test environment (open-field or CPP apparatus) or not (home-cage treatments) for 4 alternate days, and the subsequent expression of behavioral sensitization or CPP to ethanol was evaluated during or following an ethanol re-exposure, respectively. RESULTS: Repeated treatment with aripiprazole attenuated the expression of ethanol-induced behavioral sensitization regardless of the treatment environment. Treatment with aripiprazole was only effective at preventing the reinstatement of ethanol-induced CPP when paired with the ethanol-associated environment, but not when administered in the home-cage. CONCLUSIONS: The present findings corroborate previous studies suggesting the effectiveness of aripiprazole for the treatment of alcohol use disorder. Our results also point to an important role of the treatment environment in the therapeutic effects of aripiprazole in rodent models of ethanol abuse.

Participation of Dopamine D1 and D2 Receptors in the Rapid-Onset Behavioral Sensitization to Modafinil.

Studies on the abuse potential of modafinil, a psychostimulant-like drug used to treat narcolepsy, are still controversial. While some studies claim no potential for abuse, increasing evidence suggests that modafinil induces abuse-related effects, including rapid-onset behavioral sensitization (i.e., a type of sensitization that develops within hours from the drug priming administration). The rapid-onset sensitization paradigm is a valuable tool to study the neuroplastic changes that occur quickly after drug administration, and shares neuroadaptations with drug abuse in humans. However, the mechanisms involved in the rapid-onset behavioral sensitization induced by modafinil are uncertain. Our aim was to investigate the possible involvement of dopamine D1 and D2 receptors on acute modafinil-induced hyperlocomotion and on the induction and expression of rapid-onset behavioral sensitization induced by modafinil in male Swiss mice. Treatment with the D1 receptor antagonist SCH 23390 or the D2 receptor antagonist sulpiride attenuated the acute modafinil-induced hyperlocomotion in a dose-dependent manner. Pretreatment with either antagonist before the priming injection of modafinil prevented the development of sensitization in response to a modafinil challenge 4 h later. However, only SCH 23390 decreased the expression of modafinil-induced rapid-onset behavioral sensitization. Taken together, the present findings provide evidence of the participation of D1 and D2 receptors on the development of rapid-onset behavioral sensitization to modafinil, and point to a prominent role of D1 receptors on the expression of this phenomenon.

Modafinil Induces Rapid-Onset Behavioral Sensitization and Cross-Sensitization with Cocaine in Mice: Implications for the Addictive Potential of Modafinil.

There is substantial controversy about the addictive potential of modafinil, a wake-promoting drug used to treat narcolepsy, proposed as pharmacotherapy for cocaine abuse, and used indiscriminately by healthy individuals due to its positive effects on arousal and cognition. The rapid-onset type of behavioral sensitization (i.e., a type of sensitization that develops within a few hours from the drug priming administration) has been emerged as a valuable tool to study binge-like patterns of drug abuse and the neuroplastic changes that occur quickly after drug administration that ultimately lead to drug abuse. Our aim was to investigate the possible development of rapid-onset behavioral sensitization to modafinil and bidirectional rapid-onset cross-sensitization with cocaine in male Swiss mice. A priming injection of a high dose of modafinil (64 mg/kg) induced rapid-onset behavioral sensitization to challenge injections of modafinil at the doses of 16, 32, and 64 mg/kg, administered 4 h later. Furthermore, rapid-onset cross-sensitization was developed between modafinil and cocaine (64 mg/kg modafinil and 20 mg/kg cocaine), in a bidirectional way. These results were not due to residual levels of modafinil as the behavioral effects of the priming injection of modafinil were no longer present and modafinil plasma concentration was reduced at 4 h post-administration. Taken together, the present findings provide preclinical evidence that modafinil can be reinforcing per se and can enhance the reinforcing effects of stimulants like cocaine within hours after administration.

Effects of prenatal immune activation on amphetamine-induced addictive behaviors: Contributions from animal models.

BACKGROUND: Prenatal environmental adversities may affect brain development and are associated with increased risk for schizophrenia, an illness with 50% comorbidity with addiction. Maternal immune activation by poly-inosinic-citidilic acid (Poly(I:C)) exposure can promote behavioral alterations consistent with schizophrenia symptoms in rodents. OBJECTIVES: Considering the vulnerability to addiction in patients with schizophrenia, we evaluated the interactions between prenatal Poly(I:C) administration and addiction in two animal models (behavioral sensitization and conditioned place preference - CPP) in mice repeatedly treated with amphetamine (AMP). Additionally, stereotyped behavior and cross-sensitization with cocaine (COC) were also investigated. METHODS: Swiss male mice offspring were submitted to prenatal administration of 5mg/kg Poly(I:C) in the 9(th) day of pregnancy. At the age of 90days, mice were treated with 2.5mg/kg AMP for 9days to evaluate behavioral sensitization or stereotyped behavior. Cross-sensitization with 10mg/kg COC was evaluated 24h after the last treatment day. For AMP-induced CPP evaluation, mice were treated during 8 consecutive days. RESULTS: Prenatal Poly(I:C) administration potentiated both AMP-induced behavioral sensitization and CPP. Furthermore, Poly(I:C) increased cross-sensitization with COC. CONCLUSIONS: Prenatal administration of Poly(I:C) is able to potentiate vulnerability to addiction in two animal models, without however modulating stereotyped behavior.

Effects of rimonabant on the development of single dose-induced behavioral sensitization to ethanol, morphine and cocaine in mice.

RATIONALE: The endocannabinoid system has been implicated in the neurobiological mechanism underlying drug addiction, especially the primary rewarding dopamine-dependent processes. Therefore, endocannabinoid receptor antagonists, such as the CB1 cannabinoid antagonist rimonabant, have been proposed as candidates for preventive addiction therapies. OBJECTIVES: Investigate the possible involvement of CB1 receptors in the development of behavioral sensitization to ethanol, morphine and cocaine in mice. METHODS: We compared the effects of different doses of rimonabant (0.3, 1, 3 and 10mg/kg) on spontaneous locomotor activity in the open-field, hyperlocomotion induced by acute administration of ethanol (1.8g/kg), morphine (20mg/kg) or cocaine (10mg/kg) and on subsequent drug-induced locomotor sensitization using a two-injection protocol in mice. We also investigated a possible depressive-like effect of an acute rimonabant challenge at the highest dose and its potential anxiogenic property. RESULTS: At the highest dose, rimonabant abolished ethanol- and cocaine-induced hyperlocomotion and behavioral sensitization without modifying spontaneous and central locomotor activity or inducing depressive-like behavior on the forced swim test in mice. The other doses of rimonabant also selectively blocked acute ethanol-induced central hyperlocomotion. Although rimonabant at 0.3 and 1mg/kg potentiated the central hyperlocomotion induced by acute morphine injection, it was effective in attenuating morphine-induced behavioral sensitization at all doses. CONCLUSIONS: Because the neural basis of behavioral sensitization has been proposed to correspond to some components of addiction, our findings indicate that the endocannabinoid system might be involved in ethanol, cocaine and morphine abuse.

Effects of acute and long-term typical or atypical neuroleptics on morphine-induced behavioural effects in mice.

1. It has been suggested that the high prevalence of drug abuse in schizophrenics is related to chronic treatment with typical neuroleptics and dopaminergic supersensitivity that develops as a consequence. Within this context, atypical neuroleptics do not seem to induce this phenomenon. In the present study, we investigated the effects of acute administration or withdrawal from long-term administration of haloperidol and/or ziprasidone on morphine-induced open-field behaviour in mice. 2. In the first experiment, mice were given a single injection of haloperidol (1 mg/kg, i.p.) or several doses of ziprasidone (2, 4 or 6 mg/kg, i.p.) and motor activity was quantified by the open-field test. The aim of the second experiment was to verify the effects of an acute injection of haloperidol (1 mg/kg) or ziprasidone (6 mg/kg) on 20 mg/kg morphine-induced behaviours in the open-field test. In the third experiment, mice were treated with 1 mg/kg haloperidol and/or 2, 4 or 6 mg/kg ziprasidone for 20 days. Seventy-two hours after the last injection, mice were injected with 20 mg/kg, i.p., morphine and then subjected to the open-field test. Acute haloperidol or ziprasidone decreased spontaneous general activity and abolished morphine-induced locomotor stimulation. 3. Withdrawal from haloperidol or ziprasidone did not modify morphine-elicited behaviours in the open-field test. The results suggest that withdrawal from neuroleptic treatments does not contribute to the acute effect of morphine in schizophrenic patients.

Acute total sleep deprivation potentiates amphetamine-induced locomotor-stimulant effects and behavioral sensitization in mice.

It has been demonstrated that a prolonged period (48 h) of paradoxical sleep deprivation (PSD) potentiates amphetamine (AMP)-induced behavioral sensitization, an animal model of addiction-related neuroadaptations. In the present study, we examined the effects of an acute short-term deprivation of total sleep (TSD) (6h) on AMP-induced behavioral sensitization in mice and compared them to the effects of short-term PSD (6 h). Three-month-old male C57BL/6J mice underwent TSD (experiment 1-gentle handling method) or PSD (experiment 2-multiple platforms method) for 6 h. Immediately after the sleep deprivation period, mice were tested in the open field for 10 min under the effects of saline or 2.0 mg/kg AMP. Seven days later, to assess behavioral sensitization, all of the mice received a challenge injection of 2.0 mg/kg AMP and were tested in the open field for 10 min. Total, peripheral, and central locomotion, and grooming duration were measured. TSD, but not PSD, potentiated the hyperlocomotion induced by an acute injection of AMP and this effect was due to an increased locomotion in the central squares of the apparatus. Similarly, TSD facilitated the development of AMP-induced sensitization, but only in the central locomotion parameter. The data indicate that an acute period of TSD may exacerbate the behavioral effects of AMP in mice. Because sleep architecture is composed of paradoxical and slow wave sleep, and 6-h PSD had no effects on AMP-induced hyperlocomotion or sensitization, our data suggest that the deprivation of slow wave sleep plays a critical role in the mechanisms that underlie the potentiating effects of TSD on both the acute and sensitized addiction-related responses to AMP.

Selective action of an atypical neuroleptic on the mechanisms related to the development of cocaine addiction: a pre-clinical behavioural study.

An increased function in the mesolimbic dopaminergic system has been extensively associated with the rewarding effects of both natural stimuli and drugs of abuse. Thus, dopamine receptor blockers, such as neuroleptic drugs, can be proposed as candidates for potential therapeutic approaches to treat drug dependence. Notwithstanding, this therapeutic potential of neuroleptics critically depends on a selective action on the specific mechanisms related to the development of addiction. We compared the effects of different doses of haloperidol, ziprasidone and aripiprazole (first-, second- and third-generation neuroleptics, respectively) on spontaneous locomotor activity of mice in a novel environment, hyperlocomotion induced by acute cocaine administration and cocaine-induced locomotor sensitization by a two-injection protocol. Whereas high doses of haloperidol abolished the three behavioural paradigms without selectivity, low doses of ziprasidone selectively abolished the development of the behavioural sensitization phenomenon. Finally, low doses of aripiprazole inhibited acute cocaine-induced hyperlocomotion and behavioural sensitization without modifying spontaneous locomotor activity. Thus, aripiprazole at lower doses was the most selective antipsychotic drug concerning the inhibition of the development of behavioural sensitization to cocaine. Because locomotor sensitization in rodents has been proposed to share plastic mechanisms with drug addiction in humans, our data provide relevant suggestions to the clinical practice.

Addictive potential of modafinil and cross-sensitization with cocaine: a pre-clinical study.

Repeated or even a single exposure to drugs of abuse can lead to persistent locomotor sensitization, which is the result of an abundance of neuroplastic changes occurring within the circuitry involved in motivational behavior and is thought to play a key role in certain aspects of drug addiction. There is substantial controversy about the addictive potential of modafinil, a wake-promoting drug used to treat narcolepsy that is increasingly being used as a cognitive enhancer and has been proposed as a pharmacotherapy for cocaine dependence. Male mice were used to investigate the ability of modafinil to induce locomotor sensitization after repeated or single administration in mice. Bidirectional cross-sensitization with cocaine and modafinil-induced conditioned place preference were also evaluated. Both repeated and single exposure to moderate and high doses of modafinil produced a pronounced locomotor sensitization that cross-sensitized in a bidirectional way with cocaine. Remarkably, when cocaine and modafinil were repeatedly administered sequentially, their behavioral sensitization was additive. Supporting these behavioral sensitization data, modafinil produced a pronounced conditioned place preference in the mouse. Taken together, the present findings provide pre-clinical evidence for the addictive potential of modafinil. Our data also strongly suggest that similar neural substrates are involved in the psychomotor/rewarding effects of modafinil and cocaine.

Adolescent mice are more vulnerable than adults to single injection-induced behavioral sensitization to amphetamine.

Drug-induced behavioral sensitization in rodents has enhanced our understanding of why drugs acquire increasing motivational and incentive value. Compared to adults, human adolescents have accelerated dependence courses with shorter times from first exposure to dependence. We compared adolescent and adult mice in their ability to develop behavioral sensitization to amphetamine following a single injection. Adult (90-day-old) and adolescent (45-day-old) male Swiss mice received an acute intraperitoneal injection of saline or amphetamine (1.0, 2.0 or 4.0 mg/kg). Seven days later, half of the mice from the saline group received a second injection of saline. The remaining animals were challenged with 2.0 mg/kg amphetamine. Following all of the injections, mice were placed in activity chambers and locomotion was quantified for 45 min. The magnitude of both the acute and sensitized locomotor stimulatory effect of amphetamine was higher in the adolescent mice. Previous experience with the test environment inhibited the acute amphetamine stimulation in both adolescent and adult mice, but facilitated the detection of elevated spontaneous locomotion in adolescent animals. These results support the notion that the adolescent period is associated with an increased risk for development of drug abuse. Additionally, they indicate a complex interaction between the environmental novelty, adolescence and amphetamine.