Typical and atypical neuroleptics: differential effects of chronic administration on the activity of A9 and A10 midbrain dopaminergic neurons.

ABSTRACT Extracellular single unit recording techniques were used to study the effects of both acute and repeated oral neuroleptic administration on the in vivo activity of rat A9 and A10 dopaminergic (DA) neurons. All antipsychotic drugs examined acutely (haloperidol, l-sulpiride, chlorpromazine, and clozapine) increased the number of spontaneously firing DA neurons in both A9 and A10 compared to controls. Repeated (21 day) treatment with haloperidol, l-sulpiride, and chlorpromazine (antipsychotic drugs which can cause extrapyramidal side effects) markedly reduced the number of active DA cells below control levels in both regions. The "silent" DA neurons were in an apparent state of tonic depolarization inactivation since they could be induced to discharge by the microiontophoretic application of the inhibitory neurotransmitter gamma-aminobutyric acid, but not the excitatory amino acid glutamate. The depolarization inactivation observed may be specific for antipsychotic drugs since a non-neuroleptic phenothiazine (promethazine), the inactive isomer of sulpiride (d-sulpiride), and a tricyclic antidepressant (desmethylimipramine) neither increased DA activity when given acutely nor induced depolarization inactivation when administered repeatedly. In contrast to the other drugs tested, repeated treatment with clozapine (an effective antipsychotic drug which does not produce extrapyramidal side effects) resulted in the depolarization inactivation of A10 neurons but not A9 cells. These data suggest that neuroleptics which can induce extrapyramidal side effects produce depolarization inactivation of both A9 and A10 neurons whereas antipsychotic drugs which lack this property inactivate only A10 neurons. It is suggested that the time-dependent development of A9 DA neuron inactivation induced by repeated neuroleptic treatment may provide a mechanism for understanding the delayed onset of extrapyramidal side effects often observed with these drugs.

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    ABSTRACT: Midbrain dopamine neurons fire irregularly, with interspersed clusters of high-frequency spikes, commonly called 'bursts'. In this review we examine such heterogeneity in activity, and provide insight into how it can participate in psychiatric conditions such as drug addiction. We first describe several techniques used to evaluate dopamine neuron activity, and comment on the different measures that each provides. We next describe the activity of dopamine neurons in 'basal' conditions. Specifically, we discuss how the use of anesthesia and reduced preparations may alter aspects of dopamine cell activity, and how there is heterogeneity across species and regions. We also describe how dopamine cell firing changes throughout the peri-adolescent period and how dopamine neuron activity differs across the population. In the final section, we discuss how dopamine neuron activity changes in response to life events. First, we focus attention on drugs of abuse. Drugs themselves change firing activity through a variety of mechanisms, with effects on firing while drug is present differing from those seen after drug discontinuation. We then review how stimuli that are rewarding, aversive, or salient can evoke changes in firing rate and discharge pattern of dopamine neurons, and provide behavioral relevance of dopamine signaling. Finally, we discuss how stress can modulate dopamine neuron firing and how this may contribute to the role that stressful experiences play in psychiatric disorders such as addiction and depression.
    Neuroscience 07/2014; DOI:10.1016/j.neuroscience.2014.07.034 · 3.33 Impact Factor
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    ABSTRACT: Direct evidence that dopamine (DA) neurotransmission varies during the 24 h of the day has been lacking. Here, we have characterized the firing activity of DA neurons located in the ventral tegmental area (VTA) using single-unit extracellular recordings in anesthetized rats kept on a standard light-dark cycle. DA neuronal firing activity was measured under basal conditions and in response to intravenous administration of increasing doses of amphetamine (AMPH: 0.5, 1, 2 and 5 mg/kg), apomorphine (APO: 25, 50, 100 and 200 µg/kg) and melatonin (MLT: 0.1, 1 and 10 mg/kg) at different time intervals of the light-dark cycle. DA firing activity peaked between 07:00-11:00 h (3.5 ± 0.3 Hz) and between 19:00-23:00 h (4.1 ± 0.7 Hz), with lowest activity occurring between 11:00-15:00 h (2.4 ± 0.2 Hz) and between 23:00-03:00 h (2.6 ± 0.2 Hz). The highest number of spontaneously active neurons was observed between 03:00-06:00 h (2.5 ± 0.3 neurons/track), whereas the lowest was between 19:00-23:00 h (1.5 ± 0.2 neurons/track). The inhibitory effect of AMPH on DA firing rate was similar in both phases. The inhibitory effect of APO in DA cell firing at a low, D2 autoreceptor selective dose (25 µg/kg) was more potent in the dark phase. Finally, MLT administration (1 mg/kg) produced a moderate inhibition of DA cell firing in both phases. Together, these experiments demonstrate, for the first time, an intradiurnal rhythmic pattern of VTA DA neuronal firing activity and a higher pharmacological response of D2 autoreceptors in the dark phase. Synapse, 2014. © 2014 Wiley Periodicals, Inc.
    Synapse 10/2014; 68(10). DOI:10.1002/syn.21757 · 2.43 Impact Factor

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