A head-attachable device for injecting nanoliter volumes of drug solutions into brain sites of freely moving rats

166

146

The recent findings that ⌬9 tetrahydrocannabinol ( ⌬9 THC), the active agent in marijuana and hashish, (1) is self-administered intravenously, (2) potentiates the rewarding effects of electrical brain stimulation, and (3) can establish conditioned place preferences in laboratory animals, suggest that these drugs activate biologically primitive brain reward mechanisms. Here, we identify two chemical trigger zones for stimulant and rewarding actions of ⌬9 THC. Microinjections of ⌬9 THC into the posterior ventral tegmental area (VTA) or into the shell of the nucleus accumbens (NAS) increased locomotion, and rats learned to lever-press for injections of ⌬9 THC into each of these regions. Substitution of vehicle for drug or treatment with a cannabinoid CB 1 receptor antagonist caused response cessation. Microinjections of ⌬9THC into the posterior VTA and into the posterior shell of NAS established conditioned place preferences. Injections into the core of the NAS, the anterior VTA, or dorsal to the VTA were ineffective. These findings link the sites of rewarding action of ⌬9 THC to brain regions where such drugs as amphetamines, cocaine, heroin, and nicotine are also thought to have their sites of rewarding action.

Section: Methodsmentioning

confidence: 99%

Two Brain Sites for Cannabinoid Reward

Zangen¹,

Solinas²,

Ikemoto³

et al. 2006

166

146

“…Each operant chamber (30 ϫ 22 ϫ 24 cm 3 ) was equipped with a lever (45 mm wide ϫ 2 mm thick; protruding 19 mm from the wall) just below a light assembly (25-mm-diameter disk) and was enclosed in an insulated box equipped with a ventilating fan. Each rat's 31 gauge injection cannula was connected by polyethylene tubing to a micropump (Ikemoto and Sharpe, 2001) hanging a few millimeters above the rat's head. Each pump consisted of a miniature step motor and a small plastic reservoir and was connected to an electrical swivel, which prevented the cable from being tangled and allowed the rats to move freely in the chamber.…”

Section: Methodsmentioning

confidence: 99%

Primary Reinforcing Effects of Nicotine Are Triggered from Multiple Regions Both Inside and Outside the Ventral Tegmental Area

Ikemoto¹,

Qin²,

Z³

2006

144

129

Nicotine is thought to be the key substance responsible for tobacco-smoking habits and appears to trigger reinforcement via the ventral tegmental area (VTA). Recently, multiple anatomical substrates for drug reinforcement have been identified in the vicinity of the ventral midbrain. In addition to the posterior portion of the VTA, the central linear nucleus raphé and the supramammillary nucleus of the posterior hypothalamus mediate drug reinforcement. Using intracranial self-administration procedures, we examined whether these regions mediate the reinforcing effects of nicotine. Rats learned to lever press for self-administration of nicotine into the posterior VTA, central linear nucleus, and supramammillary nucleus, suggesting a reinforcing action of nicotine in these regions. The rats did not self-administer nicotine into surrounding regions including the anterior VTA, substantia nigra, the region just dorsal to the posterior VTA, interpeduncular nucleus, or medial mammillary nucleus. The reinforcing effects of nicotine into the three brain regions were further confirmed by a two-lever discrimination procedure, in which rats learned to selectively respond between active and inactive levers. The reinforcing effects of nicotine administration into the posterior VTA, central linear nucleus, and supramammillary nucleus were blocked by coadministration of the nicotine receptor antagonist mecamylamine. The reinforcing effects of nicotine into the posterior VTA or central linear nucleus were attenuated by coadministration of the D 2 receptor agonist quinpirole. These findings demonstrate that nicotine reinforcement involves multiple regions both inside and outside the VTA.

“…To determine the effectiveness of amphetamine reinforcement in each region, 48 rats with no previous operant training were placed the operant chambers (30 ϫ 22 ϫ 24 cm) equipped with a lever (45 mm wide ϫ 2 mm thick, protruding 20 mm from the wall) below a cue light. Each rat's 31 gauge injection cannula was connected by polyethylene tubing to a micropump (Ikemoto and Sharpe, 2001) hanging a few millimeters above the rat's head. A lever press extinguished the cue light for 5 s and turned on the micropump for 5 s, dispensing a 75 nl infusion; additional lever presses were not rewarded until another 5 s passed, at which time the cue light was reinstated.…”

Section: Methodsmentioning

confidence: 99%

The Functional Divide for Primary Reinforcement of D-Amphetamine Lies between the Medial and Lateral Ventral Striatum: Is the Division of the Accumbens Core, Shell, and Olfactory Tubercle Valid?: Figure 1.

Ikemoto

Qin²,

Z³

2005

112

110

When projection analyses placed the nucleus accumbens and olfactory tubercle in the striatal system, functional links between these sites began to emerge. The accumbens has been implicated in the rewarding effects of psychomotor stimulants, whereas recent work suggests that the medial accumbens shell and medial olfactory tubercle mediate the rewarding effects of cocaine. Interestingly, anatomical evidence suggests that medial portions of the shell and tubercle receive afferents from common zones in a number of regions. Here, we report results suggesting that the current division of the ventral striatum into the accumbens core and shell and the olfactory tubercle does not reflect the functional organization for amphetamine reward. Rats quickly learned to self-administer D-amphetamine into the medial shell or medial tubercle, whereas they failed to learn to do so into the accumbens core, ventral shell, or lateral tubercle. Our results suggest that primary reinforcement of amphetamine is mediated via the medial portion of the ventral striatum. Thus, the medial shell and medial tubercle are more functionally related than the medial and ventral shell or the medial and lateral tubercle. The current core-shelltubercle scheme should be reconsidered in light of recent anatomical data and these functional findings.