Environmental novelty modulates the induction and expression of single injection-induced behavioral sensitization to morphine.

Opioid addiction is a growing public health problem, being currently considered an epidemic in the United States. Investigating the behavioral effects of opioids and the factors influencing their development becomes of major importance. In animals, the effects of drugs of abuse can be assessed using the behavioral sensitization model, which shares similar neuronal substrates with drug craving in humans. Importantly, novelty plays a critical role on the development of behavioral sensitization. The aim of the present study was to investigate the influence of a new environment on both the induction and expression phases of morphine (Mor)-induced behavioral sensitization in the two-injection protocol. Mice were initially treated with saline, 15 or 30 mg/kg Mor (induction phase), and subsequently challenged 7 days later with 15 mg/Kg Mor (expression phase). Locomotor frequency was evaluated during behavioral sessions, performed as follow: induction session on a novel environment and expression on a familiar open-filed apparatus; induction session on animals' home-cage (familiar environment) and expression session on an unknown open-filed apparatus; both sessions on novel environments; and both sessions on familiar contexts. Mor-induced behavioral sensitization was only observed when animals were exclusively exposed to novelty during the induction phase, not being observed when both the induction and expression sessions were performed on similar (novel or familiar) environments. Our results suggest that the development of behavioral sensitization to Mor depends on the exposure to novelty during the induction phase and absence of novelty during the expression phase, indicating a complex relationship between novelty and Mor-induced behavioral effects.

The effects of paradoxical sleep deprivation on amphetamine-induced behavioral sensitization in adult and adolescent mice.

Drug-induced behavioral sensitization (BS), paradoxical sleep deprivation (PSD) and adolescence in rodents are associated with changes in the mesolimbic dopaminergic system. We compared the effects of PSD on amphetamine-induced BS in adult and adolescent mice. Adult (90 days old) and adolescent (45 days old) Swiss mice were subjected to PSD for 48h. Immediately after PSD, mice received saline or 2.0mg/kg amphetamine intraperitoneally (i.p.), and their locomotion was quantified in activity chambers. Seven days later, all the animals were challenged with 2.0mg/kg amphetamine i.p., and their locomotion was quantified again. Acute amphetamine enhanced locomotion in both adult and adolescent mice, but BS was observed only in adolescent mice. Immediately after its termination, PSD decreased locomotion of both saline- and amphetamine-treated adolescent mice. Seven days later, previous PSD potentiated both the acute stimulatory effect of amphetamine and its sensitization in adolescent mice. In adult animals, previous PSD revealed BS. Our data suggest that adolescent mice are more vulnerable to both the immediate and long-term effects of PSD on amphetamine-induced locomotion. Because drug-induced BS in rodents shares neuroplastic changes with drug craving in humans, our findings also suggest that both adolescence and PSD could facilitate craving-related mechanisms in amphetamine abuse.

Opposite effects of neonatal hypoxia on acute amphetamine-induced hyperlocomotion in adult and adolescent mice.

We investigated whether the effect of neonatal hypoxia on amphetamine-induced hyperlocomotion can reproduce the ontogenic (age of onset) properties of schizophrenia. Neonatal hypoxia enhanced amphetamine-induced hyperlocomotion in adult mice and decreased it in adolescent mice. These findings provide ontogenic validity for this very simple animal model of schizophrenia.

Effects of group exposure on single injection-induced behavioral sensitization to drugs of abuse in mice.

BACKGROUND: Behavioral sensitization in rodents is hypothesized to reflect neuronal adaptations that are related to drug addiction in humans. We evaluated the effects of group exposure on the acute hyperlocomotion and behavioral sensitization induced by four drugs of abuse in C57BL/6 mice: methylenedioxymethamphetamine (MDMA), d-amphetamine, morphine and ethanol. METHODS: In the priming session, animals received an ip injection of one of the drugs of abuse and were exposed to an open field either individually or in groups of four. Seven days later, we assessed behavioral sensitization in the challenge session. All animals received an ip injection of the same drug and were exposed to the open field in the same social conditions described for the priming session. Locomotion and social interaction were quantified during each session. RESULTS: Acute MDMA, morphine and ethanol, but not d-amphetamine, increased social interaction. However, group exposure only potentiated MDMA-induced hyperlocomotion. After a challenge injection of each drug, there was no sensitization to the facilitating effect of MDMA, morphine or ethanol on social interaction, but locomotion sensitization developed to all drugs of abuse except ethanol. This sensitization was potentiated by group exposure in MDMA-treated animals, attenuated in morphine-treated animals and not modified in d-amphetamine-treated animals. Acute MDMA enhanced body contact and peaceful following, while acute morphine and ethanol increased social sniffing. CONCLUSIONS: These results provide preclinical evidence showing that while different drugs of abuse affect different components of social interaction, the neuronal adaptations related to drug dependence can be critically and specifically influenced by group exposure.

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.

Long-term haloperidol treatment (but not risperidone) enhances addiction-related behaviors in mice: role of dopamine D2 receptors.

The high prevalence of psychostimulant abuse observed in schizophrenic patients may be related to the development of mesolimbic dopaminergic supersensitivity (MDS) or nigrostriatal dopaminergic supersensitivity (NDS) in response to the chronic blockade of dopamine receptors produced by typical neuroleptic treatment. We compared the effects of withdrawal from long-term administration of the typical neuroleptic haloperidol (Hal) and/or the atypical agent risperidone (Ris) on MDS and NDS, behaviorally evaluated by amphetamine-induced locomotor stimulation (AILS) and apomorphine-induced stereotypy (AIS) in mice, respectively. We further evaluated the duration of MDS and investigated the specific role of dopamine D2 receptors in this phenomenon by administering the D2 agonist quinpirole (Quin) to mice withdrawn from long-term treatment with these neuroleptics. Withdrawal (48 hours) from long-term (20 days) Hal (0.5 mg/kg i.p.) (but not 0.5 mg/kg Ris i.p.) treatment potentiated both AILS and AIS. Ris co-administration abolished the potentiation of AILS and AIS observed in Hal-withdrawn mice. Ten days after withdrawal from long-term treatment with Hal (but not with Ris or Ris + Hal), a potentiation in AILS was still observed. Only Hal-withdrawn mice presented an attenuation of locomotor inhibition produced by Quin. Our data suggest that the atypical neuroleptic Ris has a pharmacological property that counteracts the compensatory MDS and NDS developed in response to the chronic blockade of dopamine receptors imposed by Ris itself or by typical neuroleptics such as Hal. They also indicate that MDS may be long lasting and suggest that an upregulation of dopamine D2 receptors in response to long-term treatment with the typical neuroleptic is involved in this phenomenon.