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Synaptic and non-synaptic actions of barbiturates on neurons of the cortico-thalamcortical system

University of British Columbia

The cortico-thalamocortical (CTC) system plays an essential role in maintaining consciousness. In this thesis, I examined the interactions of barbiturates with neurons in the CTC system to determine potential mechanisms by which barbiturates generate general anesthetic, anti-epileptic and possible analgesic effects. The thesis addressed four questions: (1) does pentobarbital, at clinically relevant concentrations, modulate intrinsic membrane properties of neurons in the CTC system? (2) how does pentobarbital modulate intrinsic ion channels and synaptic properties in the CTC neurons? (3) how amobaribital and phenobarbital alter neuronal excitation and synaptic transmission? (4) what are the concentration-response relationships for the effects of the barbiturates on neurons of the CTC system? The investigations were carried out on pyramidal neurons in layer IV of neocortex, nucleus reticularis thalami (nRT) and thalamocortical neurons. Differential interference contrast (DIC-IR) videomicroscopy-guided whole-cell patch clamp techniques were used to record from rat brain slice preparation. Outside-out single channel recording techniques were applied to record from acute dissociated thalamic neurons. Pentobarbital, an anesthetic barbiturate, decreased neuronal excitability in thalamocortical neurons by multiple mechanisms: (1) decreased glutamatergic excitatory neurotransmission; (2) potentiated GABAergic inhibitory neurotransmission; (3) increased resting membrane conductance by activating leak and voltage-dependent K⁺ channels; and (4) decreased a hyperpolarization-activated Na⁺/K⁺ inward current (I[sub h]). These actions occurred at different EC₅₀s or IC₅₀s. All these actions contributed to pentobarbital-induced inhibition in vitro and may account for pentobarbital's effects in vivo. Pentobarbital decreased neuronal excitability in neocortical and nRT neurons by mechanisms similar to those in thalamocortical neurons, but with higher EC₅₀s. Hence, the lower EC₅₀ in thalamocortical neurons indicated that these neurons, compared to nRT and neocortical neurons, may be more susceptible to pentobarbital-induced inhibition. This implies that different neurons in the CTC system may have different roles in pentobarbital-induced depression in vivo. Amobarbital is an isomer of pentobarbital with lower potency as an anesthetic and with newly found analgesic properties. Compared with pentobarbital, amobarbital exerted distinct actions on neurons of the CTC system. The most distinguishing actions of amobarbital were that it activated and potentiated GABA[sub A] receptor, increased both the amplitude and duration of inhibitory postsynaptic currents (IPSCs), and did not alter intrinsic ion channels in all the types of neurons that we examined. Therefore, amobarbital may induce anesthesia by selective actions on GABA[sub A] receptors. Amobarbital preferentially suppressed firing in dorsal thalamic neurons which receive nociceptive inputs. This may relate to amobarbital's utility as an analgesic agent. Phenobarbital, which has anti-epileptic properties, selectively inhibited neuronal excitability by inhibiting repetitive neuronal firing and potentiating GABAergic synaptic transmission in neocortical neurons. These findings may provide a possible mechanism for phenobarbital's efficacy in the treatment of generalized tonic-clonic and partial seizures. On the other hand, phenobarbital did not have pronounced effects on thalamocortical neurons, which may account for clinical observations that phenobarbital lacks efficacy or even aggravates absence seizures attributable to CTC mechanism (Mattson, 1995). These investigations showed that synaptic and non-synaptic actions of barbiturates have different but overlapping concentration-dependence. This study is the first investigation to compare three barbiturates in three major types of neurons in the CTC system. The different actions of the barbiturates on neurons in this system may account for their differences in ability to cause CNS depression and to modulate excitability in pathophysiological concentrations.

Thesis/Dissertation

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2009-12-02

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http://hdl.handle.net/2429/16143

Pharmacology and Therapeutics

University of British Columbia

UBCV

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