Dopamine modulation system

The antidepressant effect of thymoleptics manifests after a prolonged latency usually 1-3 weeks pass before subjective or objective improvement becomes noticeable (A). In contrast, somatic effects are immediately evident specifically, the interference with neuronal transmitter/modulator systems (norepinephrine, serotonin, acetylcholine, histamine, dopamine). Reuptake of released serotonin, norepinephrine, or both is impaired (—< elevated concentration in synaptic cleft) and/or receptors are blocked (example in A). These effects are demonstrable in animal studies and are the cause of acute adverse effects. 

PCP binds to a site within the ion channel of the NMDA receptor that blocks the influx of cations, thereby acting as a non-competitive antagonist. PCP produces a syndrome in normal individuals that closely resembles schizophrenia and exacerbates symptoms in patients with chronic schizophrenia. Ketamine is an anesthetic that has approximately a 10- to 15-fold lower affinity for the NMDA receptor, and it produces the characteristic cognitive deficits of schizophrenia. When ketamine is administered to patients with schizophrenia stabilized with antipsychotic medication, it produces delusions, hallucinations, and thought disorder, consistent with the patient s typical pattern of psychotic relapse. Consistent with this model, chronic PCP administration also increases subcortical dopamine release, particularly in the nucleus accumbens, emphasizing the reciprocal modulation of the glutamate and dopamine neuronal systems in schizophrenia. 

Another theory for the action of stimulant diugs in ADHD involves effects on nonstiiatal monoamine systems. Frontal cortical dopamine, norepinephrine, and serotonin are clearly important in cognitive functioning and impulse control. These neurotransmitters directly modulate reward-related behaviors associated with the striatal dopamine system. Moreover, the amygdala may be pharmacologically influenced leading to enhanced... 

Nicotine is an agonist at the nicotinic acetylcholine receptor (nAChR). Activation of this receptor depolarizes target cells (see Ch. 11). nAChRs are composed of five subunits surrounding a central ion-channel pore. Twelve different nicotinic receptor subunits are expressed in the nervous system (a2-oclO and (32—134). Of these, a subset is expressed in the VTA (a3-a7 and P2—134). It is thought that a7 receptors form homomeric receptors a3, a4 and a6 form heteromeric channels with 02 or 04 and a5 and 03 can associate with other a/0 pairs. Studies in knockout mice implicate several subunits in the ability of nicotine to modulate dopamine neurons (a4, a6, a7, 02, 03) but... 

---