Glutamatergic neurons in the medial prefrontal cortex mediate the formation and retrieval of cocaine-associated memories in mice.

In drug addiction, environmental stimuli previously associated with cocaine use readily elicit cocaine-associated memories, which persist long after abstinence and trigger cocaine craving and consumption. Although previous studies suggest that the medial prefrontal cortex (mPFC) is involved in the expression of cocaine-addictive behaviors, it remains unclear whether excitatory and inhibitory neurons in the mPFC are causally related to the formation and retrieval of cocaine-associated memories. To address this issue, we used the designer receptors exclusively activated by designer drugs (DREADD) technology combined with a cocaine-induced conditioned place preference (CPP) paradigm. We suppressed mPFC neuronal activity in a cell-type- and timing-dependent manner. C57BL/6J wild-type mice received bilateral intra-mPFC infusion of an adeno-associated virus (AAV) expressing inhibitory DREADD (hM4Di) under the control of CaMKII promotor to selectively suppress mPFC pyramidal neurons. GAD67-Cre mice received bilateral intra-mPFC infusion of a Cre-dependent AAV expressing hM4Di to specifically silence GABAergic neurons. Chemogenetic suppression of mPFC pyramidal neurons significantly attenuated both the acquisition and expression of cocaine CPP, while suppression of mPFC GABAergic neurons affected neither the acquisition nor expression of cocaine CPP. Moreover, chemogenetic inhibition of mPFC glutamatergic neurons did not affect the acquisition and expression of lithium chloride-induced conditioned place aversion. These results suggest that the activation of glutamatergic, but not GABAergic, neurons in the mPFC mediates both the formation and retrieval of cocaine-associated memories.

Activation of GABAergic Neurons in the Nucleus Accumbens Mediates the Expression of Cocaine-Associated Memory.

Cocaine-associated environmental cues elicit craving and relapse to cocaine use by recalling the rewarding memory of cocaine. However, the neuronal mechanisms underlying the expression of cocaine-associated memory are not fully understood. Here, we investigated the possible contribution of γ-aminobutyrate (GABA)ergic neurons in the nucleus accumbens (NAc), a key brain region associated with the rewarding and reinforcing effects of cocaine, to the expression of cocaine-associated memory using the conditioned place preference (CPP) paradigm combined with designer receptors exclusively activated by designer drugs (DREADD) technology. The inhibitory DREADD hM4Di was selectively expressed in NAc GABAergic neurons of vesicular GABA transporter-Cre (vGAT-Cre) mice by infusing adeno-associated virus (AAV) vectors. Ex vivo electrophysiological recordings revealed that bath application of clozapine-N-oxide (CNO) significantly hyperpolarized membrane potentials and reduced the number of spikes induced by depolarizing current injections in hM4Di-positive NAc neurons. Additionally, systemic CNO injections into cocaine-conditioned mice 30 min before posttest session significantly reduced CPP scores compared to saline-injected mice. These results indicate that chemogenetic inhibition of NAc GABAergic neurons attenuated the expression of cocaine CPP, suggesting that NAc GABAergic neuronal activation is required for the environmental context-induced expression of cocaine-associated memory.

Acute restraint stress augments the rewarding memory of cocaine through activation of α1 adrenoceptors in the medial prefrontal cortex of mice.

Stress augments the rewarding memory of cocaine, which plays a critical role in inducing cocaine craving. However, the neurobiological mechanisms underlying the enhancing effect of stress remain unclear. Here, we show that noradrenaline (NA) transmission in the medial prefrontal cortex (mPFC) mediates stress-induced enhancement of cocaine craving. When mice were exposed to acute restraint stress immediately before the posttest session of the cocaine-induced conditioned place preference (CPP) paradigm, the CPP score was significantly higher than that in non-stressed mice. Because extracellular NA levels have been reported to be increased in the mPFC during stress exposure, we assessed the effects of NA on mPFC layer 5 pyramidal cell activity. Whole-cell recordings revealed that NA application induces depolarization and a concomitant increase in spontaneous excitatory postsynaptic currents (sEPSCs). The NA effects were inhibited by terazosin, but not by yohimbine or timolol, and the sEPSC increase was not observed in the presence of tetrodotoxin, suggesting the involvement of postsynaptic α1, but not α2 or ß, adrenoceptors in the NA effects. Additionally, intra-mPFC injection of terazosin before stress exposure attenuated the stress-induced increase in cocaine CPP. Intra-mPFC injection of phenylephrine, an α1 adrenoceptor agonist, before the posttest session without stress exposure significantly enhanced cocaine CPP. Furthermore, chemogenetic suppression of mPFC pyramidal cells with inhibitory DREADD (designer receptors exclusively activated by designer drugs) also suppressed the stress-induced CPP enhancement. These findings suggest that the stress-induced increase in NA transmission activates mPFC pyramidal cells via α1 adrenoceptor stimulation, leading to enhancement of cocaine craving-related behavior.

[Analyses of cocaine rewarding memories by AAV vector-induced introduction of DREADD system].

The development and persistence of drug addiction are associated with the activation and adaptation of the brain reward circuitry, which consists of dopaminergic projection from the ventral tegmental area to the nucleus accumbens (NAc) and the medial prefrontal cortex (mPFC). In cocaine addiction, cocaine-induced activation and neuroplasticity in the brain reward circuitry may contribute to the acquisition and expression of rewarding memory of cocaine, which is critical for the reinstatement of cocaine seeking. However, it remains unclear which neuronal types causally contribute to the retrieval of cocaine-associated rewarding memory. To address this issue, we used DREADD (Designer Receptors Exclusively Activated by Designer Drugs) technology. To selectively suppress mPFC excitatory neurons, we infused an adeno-associated virus (AAV5 or AAV-DJ) vector expressing hM4Di, an inhibitory DREADD, under the control of CaMKII promotor into the mPFC of wildtype mice. To selectively suppress GABAergic neurons, we infused a Cre-dependent AAV (AAV5 or AAV-DJ) vector expressing hM4Di into the mPFC of GAD67-Cre mice or the NAc of vGAT-Cre mice. We found that, in cocaine conditioned place preference paradigm, the activity of mPFC pyramidal and NAc GABAergic neurons is causally related to the retrieval of cocaine-associated memory. The findings suggest that the mPFC-NAc circuit can be a potential therapeutic target for the drug addiction.

[Professionalization of occupational therapists--based on interviews with the psychiatric nurses and instructors before legislation on occupational therapists was passed].

This article aims to clarify the historical background regarding why psychiatric occupational therapists pointed out the ambiguity of their professional roles in the 1990's after over 25 years of legislation on occupational therapists. Findings regarding their social background and interviews with the nurses and instructors who were engaged in occupational therapy before the legislation are as follows: (1) Actual conditions of the nurses and instructors were not fully reflected in the clauses. This seems to create a separation between old and new people in this field. (2) Although social prejudice against the patients and chronic shortages of manpower existed, the objectives of treating the patients as human beings and collaborating with them (not having them work) were regarded as being important. This seems to have been one of the "guidelines" of Doctor Shuzo Kure in the Meiji Era.