Takato Hiranita

Endocannabinoid System Modulates Relapse to Methamphetamine Seeking: Possible Mediation by the Arachidonic Acid Cascade

We clarified the modulating action of the endocannabinoid system, and its possible mediation by the arachidonic acid cascade, on the reinstatement of methamphetamine (METH)-seeking behavior, using the intravenous self-administration paradigm in rats. Following 12 days of self-administration of METH, the replacement of METH with saline resulted in a gradual decrease in lever press responses (extinction). Under extinction conditions, METH-priming or re-exposure to cues previously paired with METH infusion markedly increased the responses (reinstatement of drug-seeking). The cannabinoid CB1 receptor antagonist, SR141716A, blocked this behavior. Although the cannabinoid agonist, Δ8-tetrahydrocannabinol (THC), had no effects by itself, coadministration of the agonist and METH at small doses reinstated the drug-seeking behavior. THC attenuated the effects of the reinstatement-inducing dose of METH, but enhanced the effect of cues. Either given repeatedly during the extinction or singly, 24 h before the first METH-priming or cues challenge, THC suppressed the reinstatement. In another set of experiments, we found that diclofenac, a cyclooxygenase inhibitor, also attenuated the reinstatement induced by exposure to cues or drug-priming. These results suggest that the endocannabinoid system, through possible mediation by the arachidonic acid cascade, serves as a modulator of the reinstating effects of METH-priming and cues. Extending the current view on the treatment of drug dependence, these results indicate that endocannabinoid-activating substances as well as cyclooxygenase inhibitors may be promising as antirelapse agents.

Naltrexone attenuates cue- but not drug-induced methamphetamine seeking: a possible mechanism for the dissociation of primary and secondary reward

The present study was aimed to clarify the role of the opioid system in the reinstatement of methamphetamine (METH)-seeking behavior in METH self-administering rats. Following 12 days of self-administration of METH, the replacement of METH with saline resulted in a gradual decrease in lever press responses (extinction). Under extinction conditions, METH-priming or re-exposure to cues previously paired with METH infusion markedly increased the responses (reinstatement of drug-seeking). Naltrexone administered 30 min before re-exposure to METH-associated cues attenuated reinstatement of drug-seeking behavior. On the other hand, administration of this antagonist had no effect on the reinstatement induced by METH-priming. We discussed these findings in relation with the dissociation of primary and secondary reward, suggesting that an opioid mechanism is responsible for this dissociation. Further, these results indicate the possibility of using naltrexone as an anti-relapse agent.

Miscibility behavior of dipalmitoylphosphatidylcholine with a single-chain partially fluorinated amphiphile in Langmuir monolayers

Surface pressure-area, surface potential-area, and dipole moment-area isotherms were obtained for monolayers made from a partially fluorinated surfactant, (perfluorooctyl)undecyldimorpholinophosphate (F8H11DMP), dipalmitoylphosphatidylcholine (DPPC), and their combinations. Monolayers, spread on a 0.15 M NaCl subphase, were investigated at the air/water interface by the Wilhelmy method, ionizing electrode method, and fluorescence microscopy. Surface potentials were analyzed using the three-layer model proposed by Demchak and Fort. The contribution of the dimorpholinophosphate polar head group of F8H11DMP to the vertical component of the dipole moment was estimated to be 4.99 D. The linear variation of the phase transition pressure as a function of F8H11DMP molar fraction (X(F8H11DMP)) demonstrated that DPPC and F8H11DMP are miscible in the monolayer. This result was confirmed by deviations from the additivity rule observed when plotting the molecular areas and the surface potentials as a function of X(F8H11DMP) over the whole range of surface pressures investigated. Assuming a regular surface mixture, the Joos equation, which was used for the analysis of the collapse pressure of mixed monolayers, allowed calculation of the interaction parameter (xi=-1.3) and the energy of interaction (Delta epsilon =537 Jmol(-1)) between DPPC and F8H11DMP. The miscibility of DPPC and F8H11DMP within the monolayer was also supported by fluorescence microscopy. Examination of the observed flower-like patterns showed that F8H11DMP favors dissolution of the ordered LC phase domains of DPPC, a feature that may be key to the use of phospholipid preparations as lung surfactants.

Nicotine attenuates relapse to methamphetamine-seeking behavior (craving) in rats

Abstract: This study clarifies the modulating action of the nicotinic cholinergic system on reinstatement of methamphetamine (MAP)‐seeking behavior (craving) using an intravenous, self‐administration paradigm in rats. After self‐administration of MAP for 10 days, replacing MAP with saline solution (MAP withdrawal) gradually decreased lever‐pressing responses. On the sixth day of MAP withdrawal, MAP (1.0 mg/kg, i.p.)‐priming injection significantly increased lever‐pressing responses (reinstatement of MAP‐seeking behavior). This MAP‐seeking behavior was attenuated by repeated nicotine administration for 5 days during MAP withdrawal, and this attenuating effect was antagonized by the nicotinic antagonist mecamylamine. These results suggest that the appearance of MAP‐seeking behavior may be due to inactivation of the nicotinic cholinergic neuron. Furthermore, it is suggested that nicotinic activating agents may be useful in preventing relapse to drug abuse.

Role of amygdaloid nuclei in the anxiolytic-like effect of nociceptin/orphanin FQ in rats

We investigated the mechanism underlying the anxiolytic actions of the neuropeptide nociceptin/orphanin FQ (N/OFQ) using the elevated plus-maze test and T-maze test. Microinfusions of N/OFQ (10 or 32pmol) into the central amygdala (ACE) increased the time spent in the open arms of the elevated plus-maze (anxiolytic-like effects), whereas microinfusions of N/OFQ (10, 32 or 100 pmol) into the basolateral amygdala (ABL) did not affect the time spent in the open arms. Moreover, microinfusions of N/OFQ (32 pmol) into the ACE impaired escape performance from the open arms of the elevated T-maze (anxiolytic-like effects), but did not change inhibitory avoidance of the open arms. A non-peptidyl N/OFQ receptor (NOP) antagonist, J-113397(1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one) (10 mg/kg, s.c.), blocked the anxiolytic-like effects induced by N/OFQ. These results indicate that the anxiolytic-like effects of N/OFQ might be due to impaired escape performance from the open arms and it implicates the N/OFQ system within the ACE in the mediation of panic action.

Involvement of the GABA/benzodiazepine receptor in the axiolytic-like effect of nociceptin/orphanin FQ

We investigated the mechanism underlying the anxiolytic actions of the neuropeptide nociceptin/orphanin FQ (N/OFQ) with an elevated plus-maze test. In mice, intracerebroventricular (i.c.v.) infusions of N/OFQ (0.1 and 0.32 nmol) led to an increase in time spent in the open arms (anxiolytic-like effects). A non-peptidyl N/OFQ receptor (NOP) antagonist, J-113397(1-{(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl}-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one), (1.0 and 3.2 mg/kg, s.c.) blocked the increase induced by N/OFQ. On the other hand, a benzodiazepine receptor antagonist, flumazenil, (10 mg/kg, i.p.) and a GABAA receptor antagonist, (+)-bicuculline, (5.6 mg/kg, i.p.) also inhibited the increase induced by N/OFQ. In rats, microinfusions of N/OFQ (10 and 32 pmol) into the amygdala led to an increase in time spent in the open arms. However, intracranial infusions of N/OFQ (10-100 pmol) into the dorsal hippocampus did not affect the time spent in the open arms. These findings suggest that the anxiolytic-like effects of N/OFQ may be related to the GABA/benzodiazepine system in the amygdala.

A tryptamine-derived catecholaminergic enhancer, (-)-1-(benzofuran-2-yl)-2-propylaminopentane [(-)-BPAP], attenuates reinstatement of methamphetamine-seeking behavior in rats.

Relapse to drug craving is problematic in treatment for drug abuse. Evidence suggests inactivation of dopaminergic neurotransmission during drug withdrawal. Meanwhile, a tryptamine analogue, (-)-1-(benzofuran-2-yl)-2-propylaminopentane [(-)-BPAP], has been reported to enhance electrical stimulation of monoamine release. This study examined the effect of (-)-BPAP on reinstatement of methamphetamine-seeking behavior in an animal model of relapse to drug abuse. Rats were trained to i.v. self-administer methamphetamine paired with a light and tone (methamphetamine-associated cues) under a fixed-ratio 1 schedule of reinforcement for 10 days. After extinction session under saline infusions without cues, a reinstatement test under saline infusions was begun. Reinstatement induced by methamphetamine-associated cues or methamphetamine-priming injections was attenuated by repeated administration of (-)-BPAP during the extinction phase. Acute administration of (-)-BPAP on test day dose-dependently attenuated both reinstatements. Acute administration of (-)-BPAP neither reinstated methamphetamine-seeking behavior alone nor affected methamphetamine self-administration. Pretreatment with either R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH-23390), a dopamine D(1)-like receptor antagonist, or amisulpride, a dopamine D(2)-like receptor antagonist, did not appreciably affected the acute effect of (-)-BPAP on both reinstatements. Co-pretreatment with the dopamine receptor antagonists failed to alter the effects of (-)-BPAP. Meanwhile, pretreatment with a dopamine D(1)-like receptor agonist, (+/-)-6-chloro-7,8-dihydroxy-l-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF-81297), dose-dependently attenuated reinstatement induced by the cues or methamphetamine-priming injections. In contrast to (-)-BPAP, pretreatment with SCH-23390 reversed the effects of SKF-81297. Our findings suggest activation of dopamine D(1)-like receptors results in attenuation of the reinstatement of methamphetamine-seeking behavior. Additionally, our findings provide evidence to develop (-)-BPAP and dopamine D(1)-like receptor agonists as an anti-relapse medication for methamphetamine abusers.