Altered thalamocortical dynamics are the basis for several t

Altered thalamocortical dynamics are the basis for several types of neurological and neuropsychiatric conditions named thalamocortical dysrhythmia syndrome[11,12]. Abnormal activity of relay neurons has been related to an increase of low frequency oscillatory activity due to protracted activation of the low threshold voltage-activated (LVA) T-type calcium currents (CaV3 mediated), and in turn relayed to the cortical mantle resulting in a mistiming between sensory and arousal inputs. In summary, an enhancement of low frequency thalamocortical activity during awake states would underlie aberrant sensory processing [13]. The ventral tegmental area (VTA) is a key neural substrate involved in the modulation of psychostimulant abuse, and its output is essential for the rewarding effects of addictive drugs [14]. The VTA receives cholinergic RAS input from the PPN, which modulates the high frequency states of waking and rapid eye movement (REM) sleep (Fig. 1) [1]. Cholinergic efferents from the PPN to the VTA are part of a loop that includes the medial prefrontal levosimendan (mPFC) [15]. This loop is composed of mPFC glutamatergic efferents to dopaminergic and GABAergic neurons in the VTA and to the nucleus accumbens (NAcc) through a polysynaptic circuit that includes the PPN. In addition, the VTA sends dopaminergic and GABAergic efferents to the NAcc. Activation of the PPN thus increases VTA dopaminergic output, and increases extracellular dopamine (DA) levels in the NAcc and mPFC [16], which suggests that the PPN in part regulates the reward and motivational functions of the VTA [17]. Higher glutamatergic efferent activation from the mPFC would in turn reduce VTA dopaminergic output through its direct activation of local GABAergic interneurons within the VTA. Recent optogenetic experiments confirmed that PPN-VTA pathway stimulation can elicit psychostimulant-like behavior in the absence of any drug administration [18]. Since midbrain dopaminergic neurons originating in the VTA and substantia nigra pars compacta (SNc) have been previously described as the neural substrates underlying individual vulnerability to psychostimulant addiction [19–21], elucidating the functional modulation of the VTA and SNc by the PPN is a key to understanding how drug reinforcing, craving, and psychomotor-stimulant effects are modulated by a wake-promoting nuclei such as the PPN.
Drugs of abuse as modulators of calcium channels in the PPN and its targets Psychostimulants—like thalamic relay neurons, about 40% of PPN cells have T-type calcium channels that mediate low threshold spikes (LTS) [1]. However, the most common calcium channels in the PPN are high threshold voltage-dependent calcium channels. Our group found that every PPN neuron has N- and/or P/Q-type calcium channels [22], which mediate beta/gamma band intrinsic membrane oscillations [23]. PPN calcium channels, in particular the P/Q-type, are modulated by muscarinic M2 receptors, providing a physiologically relevant fine-tuning of beta/gamma band oscillations in this nucleus [23]. P/Q-type (Cav2.1) calcium channels are widely distributed in the CNS [24,25], and play a central role in the physiology of PPN [26–28], as well as its thalamocortical targets [13,29]. High threshold voltage-dependent calcium channels, and P/Q-type channels in particular, have been described in presynaptic terminals mediating synaptic transmission in both glutamatergic pyramidal and inhibitory interneurons [24,25]. Using two-photon imaging, P/Q-type channels have been located in the dendritic compartments of thalamocortical neurons [29]. In PPN neurons, P/Q- and N-type channels have also been associated with distal dendritic compartments [27,28]. These calcium channels are critical to the induction and maintenance of high frequency oscillation states like waking and REM sleep [22,23,27,28]. The study of the effects of psychostimulants on these channels is critical to determining the role of the PPN in psychostimulant abuse.