Both depression and epilepsy have been linked to the abnormal activity of several neurotransmitters, including serotonin (5-hydroxytryptamine, 5-HT), norepineph-rine (NE), dopamine (DA), y-aminobutyric acid (GABA), and glutamate (Ressler and Nemeroff, 2000; Nemeroff and Owens, 2002; Nestler et al., 2002; Jobe, 2003). Neurotransmitter abnormalities in depression form the theoretical basis for psy-chopharmacologic treatment with monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs); as well as for the use of psychoactive AEDs such as valproic acid (VPA), carbamazepine (CBZ), oxcarbaze-pine (OXC), and lamotrigine (LTG) in the treatment of mood disorders.
Abnormalities in 5-HT and NE networks, in particular, highlight the biological link between the affective disorders and epilepsy. A review by Jobe (2003) offers an extensive overview of several studies that support this association. In addition to being linked to the pathophysiologic mechanisms of depression, decreased 5-HT and NE activity has been demonstrated to facilitate kindling, exacerbate seizure severity, and lower seizure threshold in several animal models of epilepsy (Jobe, 2003).
The genetically epilepsy-prone rat (GEPR), which harbors inborn defects in pre- and postsynaptic transmission of both 5-HT and NE, serves as a valuable animal model to explore the common pathogenic mechanisms in depression and epilepsy. Two strains, GEPR-3 and GEPR-9, are predisposed to sound-induced generalized tonic—clonic seizures, and an accelerated rate of seizure kindling. They have also been found to experience behavioral analogs of depression (Jobe, 2003). Deficiencies in NE in GEPRs result from deficient arborization of neurons arising from the locus coeruleus, with excessive presynaptic suppression of NE release, and lack of compensatory postsynaptic upregulation (Yan et al., 1993 ; Clough et al., 1998; Ryu et al., 1999e. Abnormal serotonergic arborization, a decreased density of postsynaptic 5-HT1A receptors, and excessive feedback inhibition via the 5-HT1b autoreceptor may also contribute to 5-HT abnormalities in the brains of GEPRs (Dailey et al., 1992 ; Statnick et al., 1996a).
Selective destruction of noradrenergic and serotonergic neurons significantly reduced the anticonvulsant effect of vagal nerve stimulation in rats (Browning et al., 1997). Deletion of 5-HT or NE neurons via neurotoxic exposure has also been shown to result in seizure exacerbation in GEPRs (Wang et al., 1994e Statnick et al., 1996b).
Substances that interfere with the synthesis or release of NE or 5-HT have been shown to provoke seizures in GEPRs. These include reserpine and tetraben-azine, which inactivate NE storage vesicles; a-methyl-m-tyrosine, a false NE transmitter; a-methyl-p-tyrosine, a NE synthesis inhibitor; and p-chlorophenylalanine, a 5-HT synthesis inhibitor (Jobe, 2003). 5-HT depleting drugs may also block the anticonvulsant effect of CBZ in GEPRs (Dailey et al., 1997).
Conversely, substances that increase 5-HT and NE transmission may have an anticonvulsant effect in experimental animal models (Jobe, 2003). As reviewed in an article by Kanner highlighting the work of several different groups, certain SSRIs and MAOIs have been shown to be anticonvulsants in GEPRs, and baboons, as well as non-genetically prone cats, rabbits, and rhesus monkeys (Kanner, 2005). The 5-HT precursor, 5-hydroxy-l-tryptophan (5-HTP) in combination with an SSRI or with an MAOI has been shown to have an anticonvulsant effect in GEPRs (Yan et al., 1995 e Jobe, 2003). The AEDs VPA, CBZ, and LTG have also been shown to cause an increase in 5-HT (Yan et al., 1992e Dailey et al., 1997 e Southam et al., 1998).
Areas of the brain involved in common epilepsy syndromes, such as the hippocampus and prefrontal regions, normally contain a high relative density of 5-HT1A receptors (Theodore, 2003). 5-HT1A receptors are expressed pre- and postsynapti-cally. The presynaptic 5-HT1A autoreceptors are located on serotonergic neurons of the raphe nuclei. Activation of presynaptic receptors leads to a reduced firing of 5-HT cell bodies in the raphe nuclei and reduced serotonin release. Postsynaptic 5-HT1A receptors are localized to the axon hillock of pyramidal neurons, GABAergic interneurons, and glia cells in the neocortex and limbic structures. Stimulation of these populations of receptors enhances serotonergic transmission, resulting in a potassium mediated membrane hyperpolarizing response, and tonic inhibition of pyramidal neurons (Savic et al., 2004). Postsynaptic 5-HT1A receptors have been demonstrated to exert their antiepileptic effect by this mechanism in hippocampal-kindled seizures in cats and in intrahippocampal kainic acid induced seizures in rats (Beck and Choi, 1991 e Okuhara and Beck, 1994).
Less experimental data is available on the impact of pharmacological modulation of 5-HT and NE activity in humans (Kanner, 2005). Reserpine, which causes the depletion of monoamines, is associated with an increase in seizure frequency and severity in patients with epilepsy. A reduction in the seizure threshold and a worsened severity of seizures has also been observed in schizophrenic patients using reserpine while undergoing electroshock therapy. In the only double-blind, placebo-controlled study to date, imipramine, a TCA with NE and 5-HT reup-take inhibitory effects, was reported to suppress absence and myoclonic seizures (Fromm ; t al., 1978}. There have been reports of improved seizure frequency in epilepsy from open trials with the use of the TCA doxepin (Ojemann ;t al. ; 1983), and the SSRIs fluoxetine (Favale ;t al., 1995; and citalopram (Hovorka et al.; 2000; Specchio et al., 2004; Albano et al., 2006). To date, no controlled trials studying the effects of SSRI/SNRIs on seizures have been completed.
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