ΔFosB: A Molecular Mechanism of MDMA Dependence

<p>Rationale. 3,4-methylenedioxymethamphetamine (MDMA) is a widely used illicit substance and some users show signs of abuse and dependence. It has been suggested that addiction reflects persistent neuroplasticity and one proposed mechanism has been a change in the expression of the transcription factor, ΔFosB. Objectives. This study determined whether ΔFosB expression in reward-relevant brain areas was altered as a function of MDMA self-administration. Methods. Rats were separated into triads. One rat self-administered MDMA (master rat) and the other 2 rats received either MDMA (yoked MDMA) or saline (yoked saline) infusions contingent on the behaviour of the master rat. Testing continued until a total intake of 350 mg/kg of MDMA was delivered. Two days following the final self-administration session, rats were sacrificed and perfused transcardially. Brains were removed, and ΔFosB immunohistochemistry was conducted. ΔFosB expression in striatum and medial prefrontal cortex was compared across groups. Results. Unfortunately the tissue from many of the yoked MDMA rats was compromised and therefore data from this group were not included in any analyses. MDMA self-administration produced a significantly greater expression of ΔFosB in the ventromedial and ventrolateral portions of the caudate putamen when compared to expression produced following yoked saline exposure. Within the infralimbic cortex, accumbens shell and dorsolateral caudate putamen differences approached significance. A significant correlation between ΔFosB expression in the ventromedial caudate putamen and cumulative active lever presses across the final 5 days of self-administration was also found. Conclusions. These findings provide the first evidence of MDMA-induced expression of ΔFosB. Increased expression of ΔFosB was observed in regions associated with the development and maintenance of drug addiction. These data support the idea that induction of ΔFosB may present a mechanism by which MDMA can induce alterations in genetic transcription, which may underlie the development of MDMA dependence. Future studies should utilise antagonism of ΔFosB via region-selective administration of Δc-jun in order to further elucidate the role of these transcriptional changes in the development and maintenance of self-administration.</p>

ΔFosB: A Molecular Mechanism of MDMA Dependence

<p>Rationale. 3,4-methylenedioxymethamphetamine (MDMA) is a widely used illicit substance and some users show signs of abuse and dependence. It has been suggested that addiction reflects persistent neuroplasticity and one proposed mechanism has been a change in the expression of the transcription factor, ΔFosB. Objectives. This study determined whether ΔFosB expression in reward-relevant brain areas was altered as a function of MDMA self-administration. Methods. Rats were separated into triads. One rat self-administered MDMA (master rat) and the other 2 rats received either MDMA (yoked MDMA) or saline (yoked saline) infusions contingent on the behaviour of the master rat. Testing continued until a total intake of 350 mg/kg of MDMA was delivered. Two days following the final self-administration session, rats were sacrificed and perfused transcardially. Brains were removed, and ΔFosB immunohistochemistry was conducted. ΔFosB expression in striatum and medial prefrontal cortex was compared across groups. Results. Unfortunately the tissue from many of the yoked MDMA rats was compromised and therefore data from this group were not included in any analyses. MDMA self-administration produced a significantly greater expression of ΔFosB in the ventromedial and ventrolateral portions of the caudate putamen when compared to expression produced following yoked saline exposure. Within the infralimbic cortex, accumbens shell and dorsolateral caudate putamen differences approached significance. A significant correlation between ΔFosB expression in the ventromedial caudate putamen and cumulative active lever presses across the final 5 days of self-administration was also found. Conclusions. These findings provide the first evidence of MDMA-induced expression of ΔFosB. Increased expression of ΔFosB was observed in regions associated with the development and maintenance of drug addiction. These data support the idea that induction of ΔFosB may present a mechanism by which MDMA can induce alterations in genetic transcription, which may underlie the development of MDMA dependence. Future studies should utilise antagonism of ΔFosB via region-selective administration of Δc-jun in order to further elucidate the role of these transcriptional changes in the development and maintenance of self-administration.</p>

Treatment with dopamine β-hydroxylase (DBH) inhibitors prevents morphine use and relapse-like behavior in rats

Background Opioid use disorders are serious contributors to the harms associated with the drug use. Unfortunately, therapeutic interventions for opioid addicts after detoxification have been limited and not sufficiently effective. Recently, several studies have led to promising results with disulfiram (DSF), a dopamine β-hydroxylase (DBH) inhibitor, showing that it is a potent agent against not only alcohol but also addiction to various drugs. Materials and methods This study was designed to examine whether DSF and nepicastat (NEP; another DBH inhibitor) modify morphine intake and reinstatement of seeking-behavior using the rat model of intravenous morphine self-administration. Additionally, we intended to estimate the effects of both inhibitors on the locomotor activity as well as on extracellular dopamine and its metabolite levels in the nucleus accumbens using microdialysis in naive rats. Results We demonstrated that both DBH inhibitors reduced responding to morphine self-administration. Moreover, DSF and NEP administered acutely before reinstatement test sessions consistently attenuated the reinforcing effects of morphine and a morphine-associated conditioned cue. The observed effects for lower doses (6.25–25 mg/kg; ip) of both DBH inhibitors seem to be independent of locomotor activity reduction and dopamine level in the nucleus accumbens. Neither DSF nor NEP administered daily during morphine abstinence with extinction training sessions had any effect on active lever-responding and changed the reinstatement induced by morphine priming doses. Reinstatement of drug-seeking behavior induced by a conditioned cue previously associated with morphine delivery was attenuated following repeated administration of DSF or NEP during the abstinence period. Conclusion These results seem to point to the significance of DBH inhibition as a potential pharmacotherapy against morphine use disorders. Graphic abstract

The blockade of D1/D2-like dopamine receptors in the lateral periaqueductal gray region affects morphine self-administration with and without exercise in rats

Introduction: The periaqueductal gray (PAG) region plays an essential role in the modulation of nociception. Also, lateral PAG (lPAG) is involved in reward circuitry by the dopaminergic system in addiction. The present study investigated the blockade of D1/D2-like dopamine receptors in the lateral PAG region affects morphine self-administration with and without exercise. Methods: Rats were divided into six groups. The rats were initially trained to receive small pellets of food by pressing an active lever in the self administration apparatus. Exercise groups were run on a treadmill at 20m/min, 5 days/week, for 4 weeks before the surgery. Then rats were bilaterally implanted with cannulae in lPAG. The SCH23390 and sulpiride were microinjected into the lPAG, 5min before receiving morphine. Afterward, the animals were allowed to self administer morphine in 2h sessions over 11 consecutive days. At last, the numbers of lever pressing, infusion times and withdrawal symptoms were measured. Results: The results showed the number of active lever pressing was significantly increased in the morphine group compared to other groups in self-infusion during 11 days. Exercise significantly reversed the detrimental effects of morphine self-administration after five days. However, the synergistic effect of injected sulpiride into the lPAG region with exercise training was more pronounced on the amelioration of morphine than on the combinatory effect of SCH23390 with exercise. Conclusion: The findings suggested that the D2 dopamine receptor in the lPAG region was involved in the morphine addiction via the dopaminergic system and exercise training in combination with antagonists could reduce the rewarding properties of morphine.

Alternation in dopamine D2-like and metabotropic glutamate type 5 receptor density caused by differing housing conditions during abstinence from cocaine self-administration in rats

Background: Environmental conditions have an important function in substance use disorder, increasing or decreasing the risks of relapse. Several studies strongly support the role of the dopamine D2-like and metabotropic glutamate type 5 receptors in maladaptive neurobiological responses to cocaine reward and relapse. Aims: The present study employed cocaine self-administration with yoked-triad procedure in rats to explore whether drug abstinence in different housing conditions affects the drug-seeking behaviour and the dopamine D2-like and metabotropic glutamate type 5 receptor density and affinity in several regions of the animal brain. Methods: Rats were trained to self-administer cocaine and later they were forced to abstain either in: (a) enriched environment or (b) isolation cage conditions to evaluate the effect of housing conditions on the drug-seeking behaviour and to assess changes concerning receptors in animals brain. Results: Our results show that exposure to enriched environment conditions strongly reduced active lever presses during cue-induced drug-seeking. At the neurochemical level, we demonstrated a significant increase in the dopamine D2-like receptor density in the prefrontal cortex in animals following drug abstinence in isolation cage or enriched environment conditions, and the reduction in their density in the dorsal striatum provoked by isolation cage conditions. The metabotropic glutamate type 5 receptor density decreased only in the prefrontal cortex after isolation cage and enriched environment abstinence. Conclusions: This study shows the different impacts caused by the type of housing conditions during abstinence from cocaine self-administration on drug-seeking behaviour in rats. The observed changes in the dopamine D2-like and metabotropic glutamate type 5 receptor Bmax and/or Kd values were brain-region specific and related to either pharmacological and/or motivational features of cocaine.

Blockade of prelimbic glutamate receptor reduces the reinforcing effect of morphine

The prelimbic cortex (PrL) as a part of the medial prefrontal cortex (mPFC) plays a crucial role in drug addiction. Previous studies have shown that glutamatergic transmission through the NMDA and AMPA receptors plays an important role in morphine rewarding properties. In this study, we evaluated the effect of glutamate receptors blockade within the PrL on morphine self-administration. Male Wistar rats were randomly selected and divided into 7 groups. Trained rats were placed in self-administration apparatus, where they pressed an active lever for receiving morphine (5 mg/mL) in test groups and saline in saline group during 11 consecutive days for 2 h per session. The effects of intra-prelimbic AMPA receptor antagonist (CNQX; 0.5 and 2.5 μg/0.5 μL) and the NMDA antagonist (AP5; 0.1 and 1 μg/0.5 μL) on self-administration were tested. Our results demonstrated that intra-prelimbic injection of different doses of CNQX and AP5, and co-administration of these 2 drugs before self-administration significantly decreased active lever pressing compared with morphine group (p < 0.001). Also, the number of self-infusion significantly decreased in test groups compared with morphine group (p < 0.001). These findings suggest that a reduction in PrL glutamatergic output can modulate morphine reinforcement.