Optogenetic Activation of a Lateral Hypothalamic-Ventral Tegmental Drive-Reward Pathway.

Electrical stimulation of the lateral hypothalamus can motivate feeding or can serve as a reward in its own right. It remains unclear whether the same or independent but anatomically overlapping circuitries mediate the two effects. Electrical stimulation findings implicate medial forebrain bundle (MFB) fibers of passage in both effects, and optogenetic studies confirm a contribution from fibers originating in the lateral hypothalamic area and projecting to or through the ventral tegmental area. Here we report that optogenetic activation of ventral tegmental fibers from cells of origin in more anterior or posterior portions of the MFB failed to induce either reward or feeding. The feeding and reward induced by optogenetic activation of fibers from the lateral hypothalamic cells of origin were influenced similarly by variations in stimulation pulse width and pulse frequency, consistent with the hypothesis of a common substrate for the two effects. There were, however, several cases where feeding but not self-stimulation or self-stimulation but not feeding were induced, consistent with the hypothesis that distinct but anatomically overlapping systems mediate the two effects. Thus while optogenetic stimulation provides a more selective tool for characterizing the mechanisms of stimulation-induced feeding and reward, it does not yet resolve the question of common or independent substrates.

Endomorphin-1 and -2 immunoreactive cells in the hypothalamus are labeled by fluoro-gold injections to the ventral tegmental area.

Endomorphin-1 and -2 (EM1, EM2) are endogenous opioids with high affinity and selectivity for the mu-opioid receptor. Cells expressing EM-like immunoreactivity (EM-LI) are present in the hypothalamus, and fibers containing EM-LI project to many brain regions, including the ventral tegmental area (VTA). The VTA is one of the most sensitive brain regions for the rewarding and locomotor effects of opioids. It contains mu-opioid receptors, which are thought to mediate gamma-aminobutyric acid-dependent disinhibition of dopamine transmission to the nucleus accumbens. We investigated whether hypothalamic EM-LI cells project to the VTA, where they could play a natural role in this circuitry. The retrograde tracer Fluoro-Gold (FG) was microinjected into the anterior or posterior VTA in rats. Nine days later, colchicine was injected, and 24 hours later, the animals were perfused and processed for fluorescence immunocytochemistry. Numerous FG-labeled cells were detected in the hypothalamus. Both EM1-LI and EM2-LI cells were present in the periventricular nucleus, between the dorsomedial and ventromedial hypothalamus and between the ventromedial and arcuate nuclei. Subpopulations of EM1-LI and EM2-LI cells were labeled by FG. Injections of FG to the anterior and posterior VTA were both effective in producing double-labeled cells, and an anterior-posterior topographical organization between the VTA and hypothalamus was observed. The results support the idea that some endomorphin-containing neurons in the hypothalamus project to the VTA, where they may modulate reward and locomotor circuitry.

Brain and body hyperthermia associated with heroin self-administration in rats.

Intravenous heroin self-administration in trained rats was accompanied by robust brain hyperthermia (+2.0-2.5 degrees C); parallel changes were found in the dorsal and ventral striatum, mediodorsal thalamus, and deep temporal muscle. Temperature began to increase at variable latency after a signal of drug availability, increased reliably (approximately 0.4 degrees C) before the first lever press for heroin, increased further (approximately 1.2 degrees C) after the first heroin injection, and rose more slowly after the second and third injections to stabilize at an elevated plateau (39-40 degrees C) for the remainder of the session. Brain and body temperature declined slowly when drug self-administration was terminated; naloxone precipitated a much more rapid decrease to baseline levels. Changes in temperature were similar across repeated daily sessions, except for the increase associated with the first self-administration of each session, which had progressively shorter latency and greater acceleration. Despite consistent biphasic fluctuations in movement activity associated with heroin self-administrations (gradual increase preceding the lever press, followed by an abrupt hypodynamia after drug infusion), mean brain temperature was very stable at an elevated plateau. Only mean muscle temperature showed evidence of biphasic fluctuations (+/-0.2 degrees C) that were time locked to and correlated with lever pressing and associated movements. Drug- and behavior-related changes in brain temperature thus appear to reflect some form of neuronal activation, and, because temperature is a factor capable of affecting numerous neural functions, it may be an important variable in the control of behavior by drugs of abuse.