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Heroin, nicotine, cocaine, and MDMA are abused by billions of people. They are believed to target midbrain dopamine neurons and/or serotonin neurons, but their effects on the dynamic neuronal activity remain unclear in behaving states. By combining cell-type-specific fiber photometry of Ca2+ signals and intravenous drug infusion, here we show that these four drugs of abuse profoundly modulate the activity of mouse midbrain dopamine neurons and serotonin neurons with distinct potency and kinetics. Heroin strongly activates dopamine neurons, and only excites serotonin neurons at higher doses. Nicotine activates dopamine neurons in merely a few seconds, but produces minimal effects on serotonin neurons. Cocaine and MDMA cause long-lasting suppression of both dopamine neurons and serotonin neurons, although MDMA inhibits serotonin neurons more profoundly. Moreover, these inhibitory effects are mediated through the activity of dopamine and serotonin autoreceptors. These results suggest that the activity of dopamine neurons and that of serotonin neurons are more closely associated with the drug's reinforcing property and the drug's euphorigenic property, respectively. This study also shows that our methodology may facilitate further in-vivo interrogation of neural dynamics using animal models of drug addiction.
Given the difficulty in vivo recording in a cell-type-specific manner, we still lack systematic data about how various drugs of abuse directly affect the activity of dopamine neurons and serotonin neurons in freely behaving animals. Although microdialysis studies have detected the release of dopamine and serotonin within minutes during drug administration15,16, this technique does not precisely monitor neuronal activity at sub-second temporal resolution. Fast-scan cyclic voltammetry (FSCV) has been developed to evaluate the sub-second volume transmission of dopamine17,18,19,20. However, FSCV in freely behaving animals faces forbiddingly demanding technical challenges. Similarly, recordings from slice preparations fail to reveal in vivo kinetics of neuronal activity challenged with different doses of drugs of abuse21,22. Again, electrophysiological recordings in vivo are difficult and often lack cell-type specificity and require anesthetic treatment23,24.
Here we studied how acute exposure of cocaine, MDMA, heroin, or nicotine modulates the neuronal activity of VTA dopamine neurons and DRN serotonin neurons by combining fiber photometry with intravenous drug infusion. Fiber photometry, together with the genetically-encoded Ca2+ indicator GCaMP6, has permitted the tracking of the activity dynamics of cell-type-specific neurons with sub-second temporal resolution25,26,27; these ease-of-use techniques are well adapted for freely moving transgenic mice during drug infusion. Our study revealed several interesting features of how four commonly abused drugs dynamically and differentially modulate the activity of dopamine neurons and serotonin neurons in freely behaving states.
This study provides the first demonstration that cocaine causes strong and sustained inhibition of both dopamine neurons and serotonin neurons in behaving state. This result substantiates early observations using single-unit recording in anesthetic animals that psychostimulants decrease the firing rate of dopamine neurons35,38. We further revealed that both dopamine neurons and serotonin neurons undergo the long-lasting inhibition from MDMA exposure, with serotonin neurons exhibiting a much greater extent of inhibition. This is consistent with the concept that cocaine and MDMA enhances extracellular levels of dopamine and serotonin by binding to DAT and SERT, thus blocking their reuptake. MDMA binds more weakly to DAT than to SERT33, which explains a milder effect of MDMA on dopamine neurons. The increased levels of dopamine and serotonin then in turn acts on inhibitory autoreceptors to inhibit dopamine neurons and serotonin neurons through the opening of GIRK-type potassium channels34,55.
By the same letter and with the professed purpose "to avoid any damage to you," defendant instead offered to employ plaintiff as the leading actress in another film tentatively entitled "Big Country, Big Man" (hereinafter, "Big Country"). The compensation offered was identical, as were 31 of [3 Cal. 3d 180] the 34 numbered provisions or articles of the original contract. fn. 1 Unlike "Bloomer Girl," however, which was to have been a musical production, "Big Country" was a dramatic "western type" movie. "Bloomer Girl" was to have been filmed in California; "Big Country" was to be produced in Australia. Also, certain terms in the proffered contract varied from those of the original. fn. 2 Plaintiff was given one week within which to accept; she did not and the offer lapsed. Plaintiff then commenced this action seeking recovery of the agreed guaranteed compensation.
The familiar rule requiring a plaintiff in a tort or contract action to mitigate damages embodies notions of fairness and socially responsible behavior which are fundamental to our jurisprudence. Most broadly stated, it precludes the recovery of damages which, through the exercise of due diligence, could have been avoided. Thus, in essence, it is a rule requiring reasonable conduct in commercial affairs. This general principle governs the obligations of an employee after his employer has wrongfully repudiated or terminated the employment contract. Rather than permitting the employee simply to remain idle during the balance of the contract period, the law requires him to make a reasonable effort to secure other employment. fn. 1 He is not obliged, however, to seek or accept any and all types of work which may be available. Only work which is in the same field and which is of the same quality need be accepted. fn. 2
Over the years the courts have employed various phrases to define the type of employment which the employee, upon his wrongful discharge, is under an obligation to accept. Thus in California alone it has been held that he must accept employment which is "substantially similar" (Lewis v. Protective Security Life Ins. Co. (1962) 208 Cal. App. 2d 582, 584 [25 Cal. Rptr. 213]; de la Falaise v. Gaumont-British Picture Corp. (1940) 39 Cal. App. 2d 461, 469 [103 P.2d 447]); "comparable employment" (Erler v. Five Points Motors, Inc. (1967) 249 Cal. App. 2d 560, 562 [57 Cal. Rptr. 516]; Harris v. Nat. Union etc. Cooks, Stewards (1953) 116 Cal. App. 2d 759, 761 [254 P.2d 673]); employment "in the same general line of the first employment" (Rotter v. Stationers Corp. (1960) 186 Cal. App. 2d 170, 172 [8 Cal. Rptr. 690]); "equivalent to his prior position" (De Angeles v. Roos Bros., Inc. (1966) 244 Cal. App. 2d 434, 443 [52 Cal.Rptr. 783]); "employment in a similar capacity" (Silva v. McCoy (1968) 259 Cal. App. 2d 256, 260 [3 Cal. 3d 186] [66 Cal.Rptr. 364]); employment which is "not ... of a different or inferior kind...." (Gonzales v. Internat. Assn. of Machinists (1963) 213 Cal. App. 2d 817, 822 [29 Cal. Rptr. 190].) fn. 3
FN 4. Although it would appear that plaintiff was not discharged by defendant in the customary sense of the term, as she was not permitted by defendant to enter upon performance of the "Bloomer Girl" contract, nevertheless the motion for summary judgment was submitted for decision upon a stipulation by the parties that "plaintiff Parker was discharged."
In Harris v. Nat. Union etc. Cooks, Stewards, supra, 116 Cal. App. 2d 759, 761, the issues were stated to be, inter alia, whether comparable employment was open to each plaintiff employee, and if so whether each plaintiff made a reasonable effort to secure such employment. It was held that the trial court properly sustained an objection to an offer to prove a custom of accepting a job in a lower rank when work in the higher rank was not available, as "The duty of mitigation of damages ... does not require the plaintiff 'to seek or to accept other employment of a different or inferior kind.'" (P. 764 .)
Rejecting a different or inferior type of employment is not necessary to mitigate damages. Mitigation is required only when the alternative employment is substantially similar to the original offer. In this situation, the Western film was a different and inferior offer because it did not require MacLaine's singing and dancing skills, and it also required onerous travel to Australia. Moreover, she no longer received the rights of approval that she had been granted with the earlier offer. Damages in the full amount of the original contract amount were appropriate.
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BELL BOARDA live sound effects board on which are mounted a number of different types of doorbells / phone bells etc. Usually operated by stage management. The switch or bell push to operate the doorbell (or even the whole bell board) can easily be mounted on the set if the director wants the actors to operate it themselves.
BLACK BOXA kind of flexible small studio theatre where the audience and actors are in the same room, surrounded by black tabs (curtains). Doesn't necessarily describe the audience layout, which can be easily reconfigured.The stage can be defined by a change of flooring (e.g. black dance floor), or a raised platform. If actors leave the stage, they do so through gaps in the curtains. A black box type of venue is easy to set up in non-theatre spaces, and can be found occupying hundreds of spaces around cities such as Edinburgh during their Fringe Festivals. 2b1af7f3a8