ExpectancySeeking System

The classical transhypothalamic "reward" system that is facilitated by DA circuits arising from the ventral tegmental area (VTA) has been more accurately conceptualized as the functional network that evokes appetitive/anticipatory eagerness rather than the pleasure of consummatory sensations (Ikemoto and Panksepp, 1999; Robinson and Berridge, 1993; Panksepp, 1981). Overactivity of brain DA has long been implicated in the genesis of schizophrenia, while diminished DA activity is depressogenic. Although there are many neuropeptides that converge on DA neurons, the most impressive, so far, is the tridecapeptide neurotensin, which can both facilitate and inhibit brain DA arousal. Aside from opioids, neurotensin is the only peptide that has so far been found to yield 'reward' effects when placed directly onto VTA cell bodies (Rompre, 1995). The possibility that both neurotensin agonists as well as antagonists might be beneficial in the treatment of schizophrenia continues to be debated (Berod and Rostene, 2002; Kinkead and Nemeroff, 2002). With the recent development of peripherally effective neurotensin agonists (Fredrickson et al., 2003), such issues can be empirically resolved. These agents may effectively ameliorate certain schizophrenic symptoms as well as addictive urges.

Since brain DA activation is a common ingredient in practically all forms of drug addiction (Wise, 2002), investigators will need to worry whether neurotensin agonists may also be addictive. However, considering the anticipated mild effect that neurotensin agonists will probably have on this appetitive system, including complex mixtures of antagonistic and agonistic effects at the terminal fields in the nucleus accumbens and indirect agonistic effects at the DA cell bodies (Legault et al., 2002), neurotensin agonists may help to stabilize psychomotor arousal and sensitization in such a way as to reduce addictive urges at least in the presence of a therapeutic environment (Berod and Rostene, 2002). Also, considering the importance of DA for sustaining psychic "energy," neurotensin receptor stimulants may help counteract mild depressive episodes and low energy without promoting addictive urges.

Another peptide that deserves attention as a putative modulator of the dopamin-ergic SEEKING system is CCK. CCK is colocalized in a population of dopaminergic neurons (Hokfelt et al., 1980), and its release appears to have a bidirectional influence via two distinct receptor subtypes (Wunderlich et al., 2000). Thus, CCK1 antagonists can strongly reduce the locomotor stimulant effects of amphetamine and antagonize the sensitization to amphetamine. In contrast, CCK2 antagonists enhance both acute stimulation of locomotor activity and sensitization to amphetamine. These bidirectional effects, which may be further influenced by experiential environments, suggest complex regulatory mechanisms, some of which are controlled by environmental factors (Ladurelle et al., 1995).

Anxiety and Depression 101

Anxiety and Depression 101

Everything you ever wanted to know about. We have been discussing depression and anxiety and how different information that is out on the market only seems to target one particular cure for these two common conditions that seem to walk hand in hand.

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