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Histamine Modulation of Nucleus Accumbens Neurons

Although the mesolimbic dopamine system, acting at the nucleus accumbens (NA), has long been known to play an important role in the rewarding properties of drugs of abuse, 1 there is also evidence that histamine (HA) may be involved in reward and addiction. 2 The tuberomammillary nucleus (TM), the only known HA-containing neuronal group in the central nervous system, 3 projects throughout the mammalian brain including to the NA. 4 Experiments involving lesions in the TM, 5 H 1 antagonists, 6 or self administration of antihistamines 7 have shown the histaminergic system to be involved in the inhibition of reward or reinforcement. Furthermore, HA has been shown to be related to tolerance and physical dependence of morphine. 8 Administration of cocaine increases HA levels and HA metabolic enzyme activity in the NA and striatum and L-histidine inhibits cocaine induced activity. 9 Systemic H 1 antagonists enhance dopamine levels in the NA and striatum. 10 The physiological role of HA in the NA was examined in this experiment using in vivo intracellular and extracellular recording techniques with either TM stimulation or iontophoretic administration of HA. Extracellular recordings indicated that iontophoresis of HA in the NA produced changes in frequency of spontaneously active cells. During low current HA ejection (below 50 nA) firing rate increased from 1.46 ± 0.67 Hz to 4.79 ± 2.98 Hz ( n = 3), whereas at higher ejection currents (above 50 nA) firing rate was reduced to 0.45 ± 0.21 Hz ( n = 2). TM stimulation also resulted in changes in firing rate, with 3 neurons decreasing their firing rate from 3.52 ± 3.57 Hz to 2.26 ± 2.20 Hz and 2 neurons increasing their firing rate from 0.26 ± 0.01 Hz to 3.34 ± 3.22 Hz. NA neurons usually display a bistable membrane potential characterized by a negative resting membrane potential ( down state ) interrupted by plateaus of a more depolarized value ( up state ). In intracellular recordings from eight NA neurons, TM stimulation produced a variety of depolarizing responses. TM train stimulation (5 pulses at 20 Hz) produced either a shift to the up state ( n = 5), small EPSPs during the train ( n = 6), a latent and slow decaying EPSP in response to the first stimulus ( n = 5), or a depolarization during the train ( n = 6). In extracellular recordings of NA cells, most cells (7 out of 9) fired in response to the TM train with the maximum response in the middle of the train and inhibition or a decrease in firing rate after the train.