Intracranial self-administration (ICSA) and intracranial place conditioning (ICPC)
methodologies have been mainly used to study drug reward mechanisms, but they have
also been applied toward examining brain reward mechanisms. ICSA studies in rodents
have established that the ventral tegmental area (VTA) is a site supporting morphine
and ethanol reinforcement. ICPC studies confirmed that injection of morphine into
the VTA produces conditioned place preference (CPP). Further confirmation that activation
of opioid receptors within the VTA is reinforcing comes from the findings that the
endogenous opioid peptide met-enkephalin injected into the VTA produces CPP, and that
the mu- and delta-opioid agonists, DAMGO and DPDPE, are self-infused into the VTA.
Activation of the VTA dopamine (DA) system may produce reinforcing effects in general
because (a) neurotensin is self-administered into the VTA, and injection of neurotensin
into the VTA produces CPP and enhances DA release in the nucleus accumbens (NAC),
and (b) GABA(A) antagonists are self-administered into the anterior VTA and injections
of GABA(A) antagonists into the anterior VTA enhance DA release in the NAC. The NAC
also appears to have a major role in brain reward mechanisms, whereas most data from
ICSA and ICPC studies do not support an involvement of the caudate-putamen in reinforcement
processes. Rodents will self-infuse a variety of drugs of abuse (e.g. amphetamine,
morphine, phencyclidine and cocaine) into the NAC, and this occurs primarily in the
shell region. ICPC studies also indicate that injection of amphetamine into the shell
portion of the NAC produces CPP. Activation of the DA system within the shell subregion
of the NAC appears to play a key role in brain reward mechanisms. Rats will ICSA the
DA uptake blocker, nomifensine, into the NAC shell; co-infusion with a D2 antagonist
can block this behavior. In addition, rats will self-administer a mixture of a D1
plus a D2 agonist into the shell, but not the core, region of the NAC. The ICSA of
this mixture can be blocked with the co-infusion of either a D1 or a D2 antagonist.
However, the interactions of other transmitter systems within the NAC may also play
key roles because NMDA antagonists and the muscarinic agonist carbachol are self-infused
into the NAC. The medial prefrontal (MPF) cortex supports the ICSA of cocaine and
phencyclidine. The DA system also seems to play a role in this behavior since cocaine
self-infusion into the MPF cortex can be blocked by co-infusing a D2 antagonist, or
with 6-OHDA lesions of the MPF cortex. Limited studies have been conducted on other
CNS regions to elucidate their role in brain and drug reward mechanisms using ICSA
or ICPC procedures. Among these regions, ICPC findings suggest that cocaine and amphetamine
are rewarding in the rostral ventral pallidum (VP); ICSA and ICPC studies indicate
that morphine is rewarding in the dorsal hippocampus, central gray and lateral hypothalamus.
Finally, substance P mediated systems within the caudal VP (nucleus basalis magnocellularis)
and serotonin systems of the dorsal and median raphe nuclei may also be important
anatomical components involved in brain reward mechanisms. Overall, the ICSA and ICPC
studies indicate that there are a number of receptors, neuronal pathways, and discrete
CNS sites involved in brain reward mechanisms.